Documenti di Didattica
Documenti di Professioni
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in Allergic Disease
Second Edition
Revised and Expanded
edited by
F. Estelle R. Simons
University of Manitoba
Winnipeg, Manitoba, Canada
ISBN: 0-8247-0628-5
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Although 60 years have passed since antihistamines were first developed, new
and exciting observations are still coming forward, new antihistamines are still
being developed, and new uses for existing products are still being established.
Thus, it is timely to produce the second edition of this very successful
volume by F. Estelle R. Simons, M.D. Dr. Simons is widely considered the clini-
cal expert in the use of antihistamines, and she warrants being the creator and
editor of this useful book. This revised edition contains new chapters, new con-
cepts, and information about new products. This book will be exciting reading
for those interested in the study of allergy.
v
Preface
Tennyson
Since the first edition of this successful medical textbook was published in 1996,
high-level interest in histamine as a chemical mediator of inflammation has con-
tinued, and H1-antihistamines such as cetirizine, fexofenadine, and loratadine re-
main the most widely used medications worldwide for allergic disorders, particu-
larly for allergic rhinoconjunctivitis and urticaria.
Several new second-generation, nonsedating H1-antihistamines have been
approved for use during the past few years. These medications include ebastine,
mizolastine, desloratadine, and levocetirizine, soon to be followed by epinastine,
tecastemizole, and others. New topical H1-antihistamine formulations such as
azelastine, levocabastine, ketotifen, emedastine, and olopatadine have also been
introduced for intranasal and ocular use. Two H1-antihistamines, astemizole and
terfenadine, which are no longer approved by regulatory agencies due to their
potential cardiac toxicity, have now almost entirely disappeared from the scene.
Histamine and H1-Antihistamines in Allergic Disease, Second Edition,
Revised and Expanded, reflects these important developments. It provides an up-
to-date, comprehensive analysis of the benefits of this important class of medica-
tions, including their broad antiallergic effects, and it contrasts the excellent
safety profiles of the relatively nonsedating second-generation H1-antihistamines
with those of the sedating first-generation H1-antihistamines.
We sincerely thank the scientists and clinician scientists who have helped
to make this new edition a reality—not only for their contributions to the book,
but also for their sustained contributions to improving the evidence base for H1-
antihistamine use in the treatment of allergic disease.
F. Estelle R. Simons
University of Manitoba
Winnipeg, Manitoba, Canada
vii
Contents
Series Introduction v
Preface vii
Contributors xi
Introduction xiii
ix
x Contents
Index 483
Contributors
Michael S. Blaiss, M.D. University of Tennessee Center for the Health Sci-
ences College of Medicine, Memphis, Tennessee
Michael A. Kaliner, M.D. Institute for Allergy and Asthma, Wheaton and
Chevy Chase, Maryland
xi
xii Contributors
Anne Kobza Black, M.D. Guy’s, King’s & St. Thomas’ School of Medicine,
London, England
Rob Leurs, Ph.D. Leiden/Amsterdam Center for Drug Research, Vrije Uni-
versiteit, Amsterdam, The Netherlands
Eli O. Meltzer, M.D. Allergy and Asthma Medical Group and Research Cen-
ter, University of California, San Diego, San Diego, California
Michael J. Welch, M.D. Allergy and Asthma Medical Group and Research
Center, University of California, San Diego, San Diego, California
Yee Guan Yap, B. Med. Sci., M.B.B.S., M.R.C.P. St. George’s Hospital Med-
ical School, London, England
Introduction
xiii
xiv Introduction
F. Estelle R. Simons
The University of Manitoba
Winnipeg, Manitoba, Canada
1
Histamine in Health and Disease
I. INTRODUCTION
Histamine, by far the most important mediator of acute allergic symptoms, and
the earliest recognized mediator of the immediate hypersensitivity response, was
discovered as a potent vasodilator substance by Dale and Laidlaw in 1910 (1).
In 1953 it was associated with tissue mast cells by Riley and West (2). Human
mast cells contain 2–5 pg histamine per cell. It is unclear if there are differences
in histamine content in different mast cell subsets (Table 1). Rapid advances in
molecular biology have led to the discovery of H 1-, H 2-, and H 3-receptors that
mediate the complex histamine-induced actions. In this chapter we discuss con-
cepts of the synthesis and metabolism, localization, receptors, effects, and the role
of histamine in various syndromes in which basophil and mast cell degranulation
occurs.
II. HISTAMINE
A. Histamine Synthesis and Catabolism
Histamine, 2-(4-imidazolyl)ethylamine or 5β-amino-ethylimidazole, is formed
by decarboxylation of histidine by the pyridoxalphosphate-dependent enzyme 1-
Although the research described in this chapter has been funded wholly or in part by the United
States Environmental Protection Agency through grant number R825814 to James N. Baraniuk, M.D.,
it has not been subjected to the agency’s required peer and policy review and therefore does not
necessarily reflect the views of the Agency and no official endorsement should be inferred.
1
2 Repka-Ramirez and Baraniuk
MCT MCTC
Skin 12 88
Small intestine
mucosa 98 2
submucosa 13 87
Lung bronchi/bronchioles
subepithelium 77 23
alveoli 93 7
dispersed cells 90 10
Figure 1 Histamine synthesis and catabolism. Percentage recovery was calculated fol-
lowing intradermal administration of [14C]histamine in human males. (Reprinted from
Ref. 3.)
4 Repka-Ramirez and Baraniuk
IL, interleukin; MCP, monocyte chemotactive protein; MIP, monocyte inhibitory protein; C, comple-
ment; TGF, transforming growth factor; FcεR1α, high-affinity IgE receptor.
6 Repka-Ramirez and Baraniuk
B. H 2-Receptors
Stimulation of H 2-receptors leads to a slower but more sustained response (3).
Burimamide, the first H 2-receptor ligand, has been used to define the difference
between H 1- and H 2-receptors (22). H 2-receptor stimulation induces a rise in
cyclic adenosine 3′,5′,monophosphate (cAMP) and secondary rise in intracellular
calcium concentrations in the gastric mucosa, vascular smooth muscle, brain,
adipocytes, basophils, neutrophils, and other tissues (23). H 2-receptor stimulation
plays a minor role in vasodilation, but may mediate a substantial portion of the
chronotropic and inotropic cardiac effects of histamine in conditions such as ana-
phylaxis. H 2-receptor stimulation has also been related to tracheobronchial airway
mucus secretion, inhibition of basophil histamine release, stimulation of suppres-
sor T cells, and inhibition of neutrophil chemotaxis and enzyme release (3). The
Histamine in Health and Disease 7
H 2-receptor plays a major role in stomach parietal cell hydrogen ion production
and in esophageal contraction.
Both H 1- and H 2-receptor mRNA have been identified by reverse tran-
scriptase polymerase chain reaction (RT-PCR) in the human nasal mucosa (24).
Even though histamine plays little or no role in the control of vasomotor tone
under normal conditions, a synergy between H 1- and H 2-antagonists has been
demonstrated in the cardiovascular system. The combination significantly blunts
the fall in diastolic blood pressure and pulse pressure associated with infusion
of low-dosage histamine (25). H 2-antagonists alone do not affect results of allergy
skin tests, but concomitant administration with an H 1-antagonist may augment
the inhibitory effect of the H 1-antagonist.
8 Repka-Ramirez and Baraniuk
C. H 3-Receptors
In 1983, Arrang et al. defined a new histamine receptor (H 3) in rat cerebral cortex
(27). The H 3-receptor also belongs to the G-protein-coupled receptor superfamily
(28). The localization and pharmacology of this H 3-receptor are distinct from H 1-
and H 2-receptors. It has a presynaptic localization and is an autoreceptor mediat-
ing inhibition of histamine release and biosynthesis in histaminergic nerve termi-
nals in CNS (29). H 3-receptors have been observed in neurons of the cerebral
cortex, amygdala, hippocampus, striatum, thalamus, and hypothalamus (30),
where they appear to act as ‘‘inhibitory autoreceptors’’ that reduce neural activity
(31). Presynaptic H 3-receptors may participate in the pathophysiology of head-
ache and cardiac ischemia. Post-synaptic H 3-receptors on peripheral neurons of
the gastrointestinal and respiratory tracts may regulate the release of a variety of
neurotransmitters (28). H 3-receptors have been detected in several vascular beds
and may cause vasodilation.
H 3-receptor activity is currently subject to intense investigation in humans.
In 1998, Hey et al. demonstrated that histamine may cause nasal congestion
through activation of inhibitory prejunctional H 3-receptors on sympathetic
nerves, leading to decreased norepinephrine release and subsequent ‘‘default’’
vasodilation with nasal vascular engorgement. They demonstrated that a combi-
nation of H 1- and H 3-receptor antagonists could reduce nasal airflow resistance
and increase nasal cavity airspace volumes (measured by acoustic rhinometry)
in several feline models. They proposed that a dual H 1-/H 3-antagonist could pro-
vide relief for allergic nasal congestion (32).
C. Recruitment Phase
In allergen provocation models, the early allergic response phase is self-limited,
and followed by a relatively symptom-free period. During this ‘‘recruitment
phase’’ the cytokines and chemokines released as part of the early phase stimulate
endothelial cell adhesion marker expression and the diapedesis of the unique set
of inflammatory leukocytes that characterize atopic inflammation. Increased lev-
Histamine in Health and Disease 11
els of IL-4 and expression of vascular cell adhesion molecule 1 (VCAM-1) are
critical for the late-phase response (47). Histamine stimulates endothelial cell
production of IL-6 and IL-8 that increases the adhesion of leukocytes to the endo-
thelium and epithelium (48). Histamine increases IL-8 mRNA expression sixfold
and monocyte chemotactic protein (MCP)-1 mRNA twofold by stimulating tran-
scription of the endothelial cell transcription factor nuclear factor of activated T
cell (NFAT) (49). These effects are potentiated by TNF-α that is also stimulated
during the immediate and late phases. In vitro, both H 1- and H 2-, but not H 3-,
receptors participate in neutrophil adhesion of human umbilical cord endothelial
cells (50). Second messengers appear to include PLC-derived IP3, DAG, calcium
ions, NO, and cGMP. Increases in cAMP may counter this adhesion event. Diesel
exhaust particulates may also potentiate these effects, since they can upregulate
H 1-receptor mRNA and histamine-induced IL-8 and granulocyte macrophage col-
ony-stimulating factor (GM-CSF) production from cultured human nasal epithe-
lial and endothelial cells in vitro (51). The recruited eosinophils, basophils, and
other leukocytes in turn perpetuate the inflammatory process by the liberation of
their own mediators (late-phase response).
Upregulation of leukocyte–endothelial cell interactions is not a universal
consequence of histamine, however. In rat models, only Brown-Norway rats dem-
onstrate upregulation of leukocyte adhesion after histamine exposure (52). It is
curious that Brown-Norway rats are a preferred model for allergen-induced eosin-
ophilia and bronchial hyperresponsiveness. It will be of interest to determine if
mast cells, histamine release, eosinophil–endothelial binding, and tissue eosino-
philia are uniquely linked by a single underlying molecular mechanism that is
present in this, but not other, rat strains.
Antihistamines may exert their anti-inflammatory effects by decreasing his-
tamine-induced adhesion and thereby reducing inflammatory cell influx into the
tissues (53). This, in turn, would mean a reduction in mediator release from these
cells, and so a diminution in symptoms. While an attractive hypothesis, it is still
unclear if these effects are sufficient to alter the long-term outcomes of chronic
allergic diseases. Competition between versus in PLC, nitric oxide synthase
(NOS), and GC activity induced by histamine and β2-adrenergic agonist induced
increases in cAMP may represent one anti-inflammatory action of β2-agonists on
histamine-induced inflammation (50). Intranasal glucocorticoids can also reduce
histamine-related hyperresponsiveness in chronic allergic rhinitis, perhaps by in-
terfering with many of these transcription pathways, normalizing endothelial and
leukocyte adhesion marker expression, and reducing mediator release (54, 55).
D. Late-Phase Response
During the late-phase response, histamine is released without a change in tryp-
tase, suggesting release from basophils rather than a secondary degranulation of
12 Repka-Ramirez and Baraniuk
mast cells (45, 46, 56, 57). Histamine’s effects in the late phase are likely to be
essentially the same as those described above for the early allergic response.
The response of the sinus mucosa to histamine is lower in magnitude than that
of the nose. Sinus challenge with histamine resulted in significant increases in
vascular permeability within the sinus cavity, but no significant change in para-
sympathetic reflex-mediated nasal secretions (69). This indicates the presence of
H 1-receptors on sinus mucosal vessels; however, this mucosa is much thinner than
that covering the inferior or middle turbinates, hence less vascular leak would be
anticipated. The levels of histamine in aspirin-induced, asthma-related polyps
were significantly lower than in nasal polyps related to allergy and infection (70).
This argues against a strong role for mast cells in nasal polyposis unless there
is concomitant atopic disease.
anastomoses combined with closure of venous outlet vessels increases the blood
flow into the sinusoids, causing them to swell. This thickens the mucosa, and
reduces nasal air flow. Sympathomimetic drugs contract both the arteriovenous
anastomoses and sinusoid wall myoepithelial cells to decrease blood flow, reduce
the volume of swollen sinusoids, thin the mucosa, and restore nasal patency.
The components of nasal secretions have three major sources: vascular leak
via the postcapillary venules, glandular exocytosis, and leukocyte infiltration.
Vascular leak accounts for about one-third of nasal secretion protein in healthy
subjects, and is increased in patients with allergic rhinitis and rhinovirus infec-
tions. Glandular exocytosis accounts for about two-thirds of the total protein in
nasal secretions in healthy subjects, with half this amount from seromucous cells
and half from mucous cells. Glandular products are increased in nasal secretions
from patients with allergic rhinitis, rhinovirus infections, cystic fibrosis, and acute
sinusitis. It has been proposed that the relative proportions of seromucous and
mucous cells in glands are modulated in inflammatory states, but as yet there
is little experimental evidence from human diseases. In models of ovalbumin-
immunized mice, IL-4 appears to promote goblet cell hyperplasia and mucus
hypersecretion. IL-13 stimulated goblet cell hyperplasia in an IL-13-overexpres-
sion murine model (73). Leukocyte infiltration from the epithelium into the nasal
lumen is prominent in allergic (eosinophils) and infectious (neutrophils) rhinitis.
The effects of histamine on these processes have been widely studied. His-
tamine induces prominent vascular leakage after nasal provocation. This appears
to be a direct effect on endothelial cells, since histamine H 1-receptors are densely
localized to these cells. Histamine induces itching by activating type C nocicep-
tive nerves. These may generate axon responses with the release of substance P,
calcitonin gene-related peptide, and other neuropeptides (74). Activation of these
trigeminal neurons recruits parasympathetic reflexes that release acetylcholine,
which is responsible for the glandular exocytosis that follows histamine provoca-
tion in vivo (75). In vitro, histamine does not stimulate glandular exocytosis from
nasal explants. In contrast, histamine H 2-receptors may be responsible for exo-
cytosis from bronchial explants in humans and other species. Histamine may
activate epithelial and inflammatory cells based upon in vitro experiments, but
effects on these cells are difficult to appreciate in vivo because of the overwhelm-
ing vascular permeability and nociceptive nerve events.
Based on this framework, the effects of H 1-antihistamines should be clear.
They will reduce vascular leak, itch, and recruitment of parasympathetic glandu-
lar secretion. Antihistamines account for amelioration of 50–60% of the symp-
toms of immediate allergic reactions, explaining their widespread popularity, but
also their inability to block all allergic rhinitis symptoms. These other effects are
mediated by bradykinin, leukotrienes, prostaglandins, neuropeptides, and, in the
chronic situation, cytokines and other mediators. H 1-antagonists and leukotriene
Histamine in Health and Disease 15
Anaphylactoid reactions are clinically similar to anaphylaxis, but they are not
initiated by allergen–IgE interactions. They are generally caused by highly
charged or amphipathic molecules such as intravenous contrast dye and vanco-
mycin (red man syndrome). A wide range of peptides, drugs, complement fac-
tors (e.g., C3a and C5a released by immune complex formation as in serum
sickness), and other IgE-independent mechanisms can trigger histamine, arachi-
donic acid metabolite, or cytokine release (Table 2). The role of histamine and
Histamine in Health and Disease 17
Histamine is the best known chemical mediator that arises from the activation
of mast cells and basophils to elicit the classic triple response of Lewis (88).
Drawing a probe across the skin leads to very transient local endothelial cell
swelling, leading to a sudden decrease in superficial blood flow (‘‘white line’’),
local increased vascular permeability (edema, ‘‘tumor’’), and nociceptive nerve
stimulation resulting in a local axon response with the release of calcitonin gene-
related peptide (CGRP) that causes local erythema (rubor), heat (calor), and cen-
trally mediated pain/itch (‘‘dolor’’) (89). Other vasoactive mediators that may
contribute to vasodilation are PGD 2 , LTC 4 , LTD 4 , PAF, and bradykinin (3). For
decades this model of cutaneous histamine release has shaped therapy for urti-
caria; however, a variety of mechanisms may initiate the histamine release in
physical, solar, cold-induced, and other types of urticaria. The central role of
histamine in urticaria and angioedema is demonstrated clinically by the beneficial
responses that occur when treated exclusively with H 1-antihistamines. Old, sedat-
ing, first-generation H 1-antagonists that have ‘‘nonspecific’’ pharmacological
properties (e.g., cyproheptadine, diphenhydramine, or hydroxyzine) are still
sometimes used in urticaria despite their poor benefit-to-risk ratio. While the
vascular leak (edema) and itch (neurogenically mediated itch ⫹ flare) are medi-
ated primarily by H 1-receptors, other factors also contribute. The histamine re-
lease may be only a marker of mast cell degranulation. Neither old nor new
antihistamines are likely to modify the primary pathogenesis of the urticaria,
although they effectively relieve symptoms and signs (Chap. 8).
Recently, an autoimmune hypothesis of chronic idiopathic urticaria has
emerged. IgG 1 and IgG 3 autoantibodies that bind to the Fcε–RI–α subunit may
fix complement and activate the classic cascade (90). The autoimmune nature is
further suggested by the frequent coexistence of autoantibodies to thyroglobulin
and/or thyroid peroxidase. This hypothesis offers the potential for future innova-
tive therapies for this common clinical disorder, which may frustrate patients and
physicians alike.
Human rhinoviruses account for the majority of common colds, although para-
influenza virus, adenovirus, respiratory syncytial virus, influenza, and other vi-
ruses may also be causative factors. Viral replication may occur in the adenoidal
18 Repka-Ramirez and Baraniuk
tissue and spread anteriorly and posteriorly. Until recently, bradykinin was the
only mediator found to be consistently elevated in nasal secretions in upper respi-
ratory tract infections (91). Vascular leak and symptom severity parallel each
other over the first 3 days of infection, only to subside as glandular secretion
becomes more prominent. Additional mediators such as histamine, interleukins
and prostaglandins, and stimulation of parasympathetic reflexes exacerbate the
vasodilation of nasal blood vessels, plasma transudation, glandular secretion, and
other pathophysiological processes (92). Nociceptive nerve stimulation triggers
sensations of irritation, sore throat, nasal congestion and obstruction, and sneeze and
cough reflexes (93). Computed tomography scans demonstrate the accumulation of
secretions in the maxillary and other paranasal sinuses after 4 days. This may repre-
sent a sterile transudate. It generally resolves completely within 6 weeks.
Rhinovirus infection has been causally linked with changes in lower air-
ways physiology and asthma exacerbations. Rhinoviral colds are associated with
a bronchial mucosal lymphocytic and eosinophilic infiltrate that may be related
to changes in airway responsiveness and asthma exacerbations (94). Trigg et al.
compared bronchial inflammation and the common cold in atopic and nonatopic
subjects. They found that lower airways inflammation was present in allergic and
nonallergic normal subjects with colds, but atopic subjects were less likely to
have positive results of virological tests and more likely to show activated eosino-
philia in the lower airway, even though they had similar symptoms (95). The
increased severity in atopic subjects suggested a potential role for histamine in
this process; however, studies of antihistamines in this setting have produced
mixed results. First-generation antihistamines do appear to decrease rhinorrhea,
but this may be because of their anticholinergic properties (96), which also con-
tribute to their adverse effects.
XV. SUMMARY
ACKNOWLEDGMENTS
This work was supported by U.S. Public Health Service Award AI42403 and
Environmental Protection Agency Award R825814.
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2
Histamine Receptors: Specific
Ligands, Receptor Biochemistry,
and Signal Transduction
I. INTRODUCTION
27
28 Bakker et al.
In this section we will describe the various histaminergic agents that can be used
for the study of the four histamine receptor subtypes. For a detailed description
of the medicinal chemistry of the histamine receptor ligands, the reader is referred
to recent reviews (9–14).
In this section we describe the three histamine-receptor subtypes that were tradi-
tionally characterized by pharmacological techniques, and subsequently, with the
availability of modern molecular biological approaches, have also been identified
by gene cloning. We now have a detailed understanding of the receptor proteins
and their function at the molecular level.
A. The H 1-Receptor
1. Receptor Biochemistry
Using [ 125 I]iodoazidophenpyramine, Ruat et al. irreversibly labeled H 1-receptor
proteins in rat, guinea pig, and mouse brain (50, 51). Following sodium dodecyl
sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the labeled
proteins, two main polypeptides (56 and 41–47 kDa) were found to be specifi-
cally labeled (51). Based on experiments with protease inhibitors, it was sug-
gested that the H 1-receptor is a 56 kDa peptide, whereas the other labeled peptide
was probably a result of protease action (51). Using [ 3 H]azidobenzamide, Yama-
shita et al. recently found receptor peptides of similar size (53–58 kDa) to be
labeled in bovine adrenal medulla membranes (52). Whereas the 56 kDa peptide
was also found in guinea pig lung and ileum, a peptide with a substantially higher
Histamine Receptors 33
molecular weight (68 kDa) was labeled in guinea pig heart tissue (50). Although
at present no pharmacological differences have been observed between the H 1-
receptors from guinea pig heart and brain tissue, these results suggest the occur-
rence of several isoforms for the H 1-receptor. Also, the molecular weight found
for the H 1-receptor after photoaffinity labeling is in sharp contrast with the re-
ported weight (38–40 kDa) of a purified [ 3 H]mepyramine-binding protein from
DDT1-MF2 smooth muscle cells (53, 54). Since several highly potent H 1-receptor
antagonists possess only a moderate affinity for this binding protein, it is not yet
clear whether the binding of [ 3 H]mepyramine to these cells really represents H 1-
receptor binding (53).
Figure 4 Molecular model of histamine docked into the guinea pig histamine H 1-recep-
tor according to information from site-directed mutagenesis studies using AMBER 4.1
molecular dynamics simulations (15). Five of seven helices (II–VI) in the transmembrane
region of the histamine H 1-receptor are shown in yellow (see color plate). In this model,
three residues in the ligand-binding pocket (Asp116 in helix III [71], Lys200 in helix V [74,
75], and Asn207 in helix V [72]) contribute to the binding of histamine via intermolecular
hydrogen bonds.
With the availability of the cloned genes, detailed information on the recep-
tor–ligand interaction can now be obtained. From site-directed mutagenesis stud-
ies of various other aminergic receptors, it is generally accepted that the binding
of biogenic amines mainly occurs within the transmembrane (TM) domains (70).
The H 1-receptor also binds agonists and antagonists within the TM domains. Fig-
ure 4 shows the current concepts regarding the interaction of histamine with the
TM domains 3 and 5. The protonated amine function of histamine interacts with
the aspartate residue in the TM domain TM3 (71, 72), whereas the imidazole ring
makes hydrogen bond contacts with an asparagine and lysine residue in TM5 (73,
74). The asparagine residue appears to be very important for the interaction with
histamine and 2-methylhistamine (73), but seems to be only of minor importance
for 2-(3-bromophenyl) histamine. As was already suggested on the basis of phar-
macochemical studies (33), the aromatic 2-substituent apparently interacts in a
Histamine Receptors 35
specific way with the H 1-receptor (15), and this interaction results in high-affinity
binding to the receptor protein. More detailed studies should identify the amino
acid residues of the H 1-receptor protein involved in the interaction with the aro-
matic ring of the 2-phenylhistamines and/or histaprodifens.
The binding site of the H 1-antagonists was recently investigated in detail
(71, 75). The H 1-agonists, like the antagonists, use the conserved aspartate residue
in TM3 as a counterion for their protonated amine function (71). The combination
of this information and a pharmacophore model derived for a variety of rigid H 1-
antagonists (76) led to the prediction that the binding site of the H 1-antagonists
is located between TMs 3, 4, and 6 (75). Mutagenesis studies revealed trypto-
phane167 (TM4) and phenylalanine433 and phenylalanine435 to be involved in the
binding of the aromatic rings of mepyramine. In addition, using the same model,
an additional recognition site (lysine200 in TM5) was found for the acidic side
chain in the relatively nonsedating H 1-antagonists acrivastine and cetirizine (75).
Since the acid group was previously thought to be responsible only for limiting
brain penetration (and thus sedation), these results illustrate nicely the impact of
molecular biology.
The ultimate example of the power of molecular biology is exhibited in
the generation of histamine H 1-receptor knockout mice by the method of gene
targeting (77, 78). Targeted disruption of the H 1-receptor gene leads to a loss of
both [ 3 H]mepyramine (77, 78) and [ 3 H]doxepin (77) binding in the brain. The
knock-out mice are very useful for clarification of the role of the H 1-receptors
in behavior. The initial studies confirmed results obtained with classic pharmaco-
logical studies: histamine modulates various neurophysiological functions such
as locomotor activity, emotion, memory and learning, nociception, and aggressive
behavior through histamine H 1-receptors (79).
determine whether these oligomers arise from receptor aggregation (82) or repre-
sent true receptor dimers.
2. Molecular Biology
Although the intronless genes encoding the H 1- and H 2-receptors were cloned in
1991 (55, 83), the molecular architecture of the H 3-receptor was unknown until
recently, when Lovenberg et al. showed that, like the H 1- and H 2-receptor, the
H 3-receptor belongs to the large superfamily of GPCRs (93). A potential GPCR-
related expressed sequence tag (EST)-sequence was identified in silico in a search
for orphan GPCRs and used to clone a full-length cDNA from a human thalamus
cDNA library. The cDNA contained an open reading frame (ORF) of 445 amino
acids with all the features of a GPCR for a small biogenic amine (93, 94), which
turned out to be the H 3-receptor. The H 3-receptor protein shows very low homol-
ogy with other GPCRs. Overall homology between the H 3-receptor and the H 1-
and H 2- receptor amounts to only 22% and 20%, respectively. Within the trans-
membrane (TM) domains the homology is somewhat higher (H 1, 27%; H 2 33%),
although still not very high. This remarkable divergence probably explains why
the H 3-receptor gene was not cloned by homology screening with H 1- or H 2-
receptor-specific probes. Using the information on the human H 3-receptor cDNA,
the rat (445 amino acids) and guinea pig (445 amino acids) cDNAs have been
identified recently (95, 96).
For the human, rat, and guinea pig H 3-receptor, various isoforms have been
identified. The various H 3-isoforms are generated as a result of alternative splic-
ing and show differential brain expression (96a–96d) and signaling properties
(96a, 96d), in addition, also non-functional truncated receptors have been identi-
fied (96a–96d).
So far, no data are available on the ligand-binding site or the generation of
knock-out mice; however, in view of the growing interest in the therapeutic po-
tential of H 3-ligands, these studies will certainly be performed in the near future.
ogy within the transmembrane domains of the H 3-receptor. The human H 4-recep-
tor gene exhibits an exon/intron arrangement nearly identical to that of the
H 3-receptor gene (49b). In view of several reports on the existence of multiple
H 3-receptor isoforms (96a–96d), the recent report on H 4-receptor isoforms is per-
haps not surprising (96h).
By means of RT-PCR low expression of the H 4-receptor is reported in a
wide variety of peripheral tissues (8), and expression is predominantly found in
eosinophils (8a, 49a, 49b, 96) and in tissues likely to contain high concentrations
of blood cells, such as bone marrow and lung (49b, 96e, 96f ). In contrast to the
H 3-receptor, expression was not detected in the brain, although in situ hybridiza-
tion analysis showed that mouse H 4-receptor mRNA is selectively expressed in
the hippocampus (96f ). The unique expression profile of the H 4-receptor suggests
it may be a therapeutic target for the regulation of immune function.
Figure 5 Histamine activates various signal transduction pathways via interaction with
the G-protein-coupled histamine receptors (H 1-, H 2-, H 3-, and H 4-). Activated histamine
H 1-receptors will activate the phosphoinositide pathway by activating G-proteins belong-
ing to the G q/11 family of G-proteins, which will result in the activation of PLC and the
subsequent formation of DAG and InsP 3. Histamine H 2-, H 3-, and H 4-receptor activation
will affect the adenylyl cyclase cascade. Adenylyl cyclase is activated upon H 2-receptor
activation to generate cAMP from ATP. Activation of the H 3-receptor will inhibit adenylyl
cyclase and lower cAMP levels.
1. Stimulation of Phospholipase C
Histamine has been shown to induce production of inositol phosphates in several
tissues, including brain, airway smooth muscle, intestinal smooth muscle, vascu-
lar smooth muscle, and heart (2, 102–106). Guinea pig brain regions with the
highest density of H 1-receptors display the largest phosphoinositide response
(107, 108); however, in some tissues (guinea pig ileum and neonatal brain) the
H 1-response to histamine itself appeared to be masked by an H 1-antagonist-insen-
sitive component (109, 110).
In membrane preparations of rat cerebral cortex and 1321N1 astrocytoma
cells, H 1-receptor-stimulated phospholipid hydrolysis was found to be dependent
on the presence of guanine nucleotides (103, 106). Studies in 1321N1 astrocy-
toma cells (106), HeLa cells (111), and CHO cells stably expressing H 1-receptors
(112) showed the inositol phosphate response to be mediated by a pertussis toxin-
insensitive G-protein. Furthermore, histamine increased the incorporation of [α-
40 Bakker et al.
32
P]GTP azidoanilide into G q/11-like proteins in H 1-receptor-expressing Sf9 cells
(113) as well as in membranes prepared from guinea pig heart (114). In addition,
antibodies to the α q subfamily of G-proteins have been shown to inhibit the hista-
mine stimulation of Pl(4,5)P 2 hydrolysis in 1321N1 cells (115), implicating the
involvement of Gα q/11 in the H 1-receptor response.
Activation of PLC will not only generate Ins(1,4,5)P 3 and result in the
release and cellular influx of Ca 2⫹, but will also result in the formation of DAG.
DAG in turn will activate other effectors such as isoforms of PKC and protein
kinase D (PKD). Activated PKC has many cellular functions, including desensiti-
zation of the H 1-receptor by receptor phosphorylation (116, 117) and transcrip-
tional downregulation of histamine H 1-receptor expression (118). More recently,
the histamine H 1-receptor-mediated production of diacylglycerol has been shown
to mediate an influx in [Ca 2⫹ ] i by activating transient receptor potential (TRPC)
channels, homologs of Drosophila TRP proteins (119), which are thought to me-
diate capacitative Ca 2⫹ entry (120). Histamine activated the human TRPC6, a
nonselective cation channel that is activated in a Ca 2⫹-store-depletion-indepen-
dent mechanism by diacylglycerol, independently of protein kinase C in cotrans-
fected Chinese hamster ovary (CHO)-K1 cells (119).
2. Calcium Signaling
One of the physiological consequences of the production of inositol phosphates
is the elevation of intracellular Ca 2⫹. The histamine H 1-receptor has been widely
used to study the mechanism of Ca 2⫹ release from intracellular stores and the
extracellular Ca 2⫹ influx. The histamine-induced Ca 2⫹ response is characterized
by a rapid transient rise of the intracellular Ca 2⫹ concentration, which is followed
by a sustained elevation of the Ca 2⫹ concentration. Experiments in Ca 2⫹-free
medium and with inorganic Ca 2⫹ antagonists suggest that the sustained response
is highly dependent on the influx of extracellular calcium, whereas the transient
increase is caused by the release of Ca 2⫹ from intracellular Ca 2⫹ stores (112, 121–
129). In addition, histamine H 1-receptor stimulation has been shown to result in
a slight increase in the amplitude of the [Ca 2⫹ ] i transient rise due to H 1-receptor-
mediated inhibition of the outward K⫹ current (130).
The Ca 2⫹ signal exhibits a high degree of spatiotemporal complexity in
which intracellular organelles play a key role. Ca 2⫹-signal compartmentalization
after histamine stimulation (131) has been described for various intracellular
compartments, including the cytosol (132–135), the endoplasmic reticulum (136,
137), the mitochondria (133, 138, 139), the Golgi apparatus (140), and the nu-
cleus (141, 142).
Histamine not only results in the rise of intracellular Ca 2⫹ in various com-
partments but also influences Ca 2⫹ oscillations (143, 144). Ins(1,4,5)P 3-receptors
in the ER bind Ins(1,4,5)P 3 and release calcium from the lumen. Repetitive
phosphorylation/dephosphorylation of the Ins(1,4,5)P 3-receptor by calmodulin-
Histamine Receptors 41
(157–161). In cultured bovine aortic cells the actual generation of nitric oxide
could be measured after stimulation with histamine (162). In a variety of airway
and heart preparations, H 1-receptor activation was shown to induce the production
of cGMP, which may be ascribed to generation of nitric oxide (163–168). More
recently, histamine was found to induce the association of heat-shock protein 90
with endothelial nitric oxide synthase (eNOS) and subsequently to activate eNOS
in human umbilical vein endothelial cells (HUVEC) (169). Thus, vascular re-
sponses to histamine may be explained by the generation of nitric oxide, which
appears to be highly dependent on the mobilization of intracellular Ca 2⫹.
6. Stimulation of Phospholipase D
Activation of phospholipase D (PLD) by the H 1-receptor may occur secondarily
to the activation of PLC by the liberation of DAG and subsequent activation of
PKC. PLD mediates the hydrolysis of phosphatidylcholine and other phospholip-
ids, to generate phosphatidic acid. The activation of PLD is believed to serve
diverse functions in signal transduction, membrane vesicle trafficking, and cy-
toskeletal dynamics, and to play an important role in the regulation of cell func-
tion and cell fate (see Ref. 173 for a recent review on PLD).
Agonist-induced PLD activation involves PKC activation and is dependent
on an increase in intracellular Ca 2⫹ (174); however, part of the histamine-stimu-
lated PLD activity may occur in the absence of PKC activation (174, 175). In
Histamine Receptors 43
addition to binding to G q/11 proteins, the H 1-receptor has recently been shown to
mediate PLD activation in 1321N1 human astrocytoma cells via the small G-
protein ARF (176).
8. Coupling to G i/o-Proteins
In contrast to the H 1-receptor-mediated increase in intracellular levels of cAMP,
a phenomenon generally associated with coupling to G-proteins, differentiated
HL-60 cells have been found to express H 1-receptors coupled to both pertussis-
toxin (PTX)-insensitive G-proteins and PTX-sensitive G i-proteins (186, 187).
PTX partially inhibited the stimulatory effect of histamine on [Ca 2⫹ ] i (187), indi-
cating a role for G i/o-proteins in the Ca 2⫹ response. Modulation of a nonselective
cation current through coupling of the H 1-receptor to G i/o-proteins has also been
reported (188).
Figure 6 Constitutive activity of the human histamine H 1-receptor and inverse agonism
of H 1-antagonists. (A) Effect of mepyramine on the basal [ 3 H]inositolphosphate accumu-
lation in COS-7 cells expressing the human histamine H 1-receptor (䊉) and on mock
transfected cells (䊊). The stereoisomers of cetirizine, (R)- (■) and (S)-cetirizine (䊐),
stereospecifically inhibit basal [ 3 H]inositolphosphate accumulation. (B) Correlation graph
of the plC 50 values obtained for the inverse agonists in the [ 3 H]inositolphosphate accumu-
lation assay vs. the pK 1 values obtained by [ 3 H]mepyramine displacement in COS-7 cells
expressing the human histamine H 1-receptor. (Data from Ref. 16.)
Histamine Receptors 45
10. Conclusions
The H 1-receptor is primarily coupled to a PLC-dependent inositol phosphate path-
way via a G q/11-protein. In addition to binding to G q/11, the H 1-receptor can also
couple to G i/o-proteins and has recently been shown to activate phospholipase D
by activation of small G-proteins (176).
4. Conclusions
As previously seen for the H 1-receptor, various intracellular mediators are likely
to be involved in the H 2-receptor-mediated effects. The H 2-receptor is primarily
coupled to the adenylyl-cyclase-dependent production of cAMP. It appears, how-
ever, that in some cell types the breakdown of phosphoinositides, the intracellular
Ca 2⫹ levels, and phospholipase A 2 activity can be regulated by cAMP-indepen-
dent pathways.
Apart from the G-protein-coupled histamine H 1-, H 2-, and H 3-receptors, several
other histamine receptors have been described. Patch-clamp studies on hista-
mine receptors in invertebrate neurons have identified a ligand-gated chloride channel
at a photoreceptor synapse of the housefly (233). Furthermore, similar histamine-
gated chloride channels have been detected in lobster olfactory neurons (234). The
histamine-gated chloride channels in the large monopolar cell, a retinal neuron, have
been utilized to estimate the metabolic cost of neural information (235).
Recently, three histamine-binding proteins have been cloned from the tick
Rhipicephalyus appendiculatus (236). These high-affinity histamine-binding pro-
teins (HBPs) appear to possess two histamine-binding sites, as determined from
the crystal structure of a histamine-bound HBP. They may sequester histamine
at the wound site of the host to outcompete histamine receptors for histamine,
thus overcoming their host’s inflammatory and immune responses (236).
There is as yet no indication of the presence of mammalian counterparts
for these ligand-gated ion channels or histamine-binding proteins. It therefore
remains an intriguing possibility that the family of mammalian histamine recep-
tors consists of ligand-gated ion channels, G-protein-coupled receptors, in addi-
tion to histamine-binding proteins.
VI. SUMMARY
During the past few years, there has been a tremendous increase in our under-
standing of the histamine receptors. Important progress has been made in the
Histamine Receptors 49
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H 2-receptors. Identification of an H 2-receptor-dependent Ca 2⫹ mobilization path-
way in human HL-60 promyelocytic leukemia cells. J Biol Chem 1989; 264:18356–
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203. Gespach C, Saal F, Cost H, Abita JP. Identification and characterization of surface
receptors for histamine in the human promyelocytic leukemia cell line HL-60. Com-
parison with human peripheral neutrophils. Mol Pharmacol 1982; 22:547–553.
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Histamine Receptors 63
Jean Bousquet
Montpellier University, Montpellier, France
I. INTRODUCTION
65
66 Passalacqua et al.
compounds were too weak and too toxic for clinical use, their discovery led to
further research and, in 1942, to the development of phenbenzamine (Antegan),
the first H 1-antagonist used in the treatment of allergic diseases (6). Within a few
years, three other H 1-antihistamines were synthesized: pyrilamine maleate (7),
diphenhydramine (8), and tripelennamine (9), which are still in use today. Despite
their pronounced side effects, these were the first really useful drugs for the symp-
tomatic relief of allergic diseases. During the past 15 years, pharmacological
research has produced several compounds with an improved benefit-to-risk ratio
(therapeutic index) suitable for once-daily dosing: the so-called second-genera-
tion H 1-antihistamines, as opposed to the older first-generation H 1-antihistamines.
This class of drugs has recently been the focus of considerable medical scientific
interest, for two rather different reasons: its multiple antiallergic properties, and
its potential cardiotoxic effects. These topics are the source of much current inter-
est because of the widespread use of H 1-antihistamines in medical practice.
B. Antiallergic Activities
Histamine is not the only mediator released during allergic reactions. The rank
order of relative H 1-antagonism by H 1-antihistamines was studied by Simons et
al. using skin tests with histamine. The order from the most effective to the least
effective was found to be cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60
mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo
(22). Other studies confirmed this ranking (23); however, when these drugs are
compared in placebo-controlled clinical trials in which the outcomes are subjec-
tive relief of ocular, nasal or skin symptoms, it is usually impossible to differenti-
ate their clinical efficacy (24–32). Skin test reactivity does not correlate with
symptoms during nasal challenge (33) or the pollen season (34). This suggests
that the clinical activity of these drugs involves other properties besides H 1-
blocking activity, or alternatively that an incomplete H 1-blockade is sufficient
for clinical efficacy. Moreover, the blockade of the release of histamine by a
synthesis inhibitor was unable to suppress symptoms significantly during nasal
challenge (35).
Thus, it appears that properties in addition to H 1-blockade are desirable for
drugs that relieve the symptoms of the allergic reaction. Over the past 15 years,
it has become clear that most first- and second-generation H 1-antihistamines have
such antiallergic properties (36), although the properties differ depending on the
H 1-antihistamine and the cells and experimental conditions used (37–41). In
vitro, high concentrations of H 1-antihistamines are able to block mediator release
from basophils and human mast cells (42–46) by mechanisms that are not yet
completely understood (47).
These antiallergic effects can also be seen in vivo in skin, nasal, lung, and
ocular challenge studies. Using nasal challenge with allergen, it has been ob-
served that azatadine, loratadine, and terfenadine reduce histamine, PGD2, and
kinin release during challenge (48–51). Cetirizine was found to reduce tryptase
levels in nasal secretions (52). Azelastine (53) and cetirizine (51) decrease release
of leukotrienes. On the other hand, the effects of ketotifen were disappointing
in this particular model since mediator release was not blocked as expected (54).
Ebastine reduced cytokine production (37). Cetirizine, at least in some studies
in the skin, reduced eosinophil chemotaxis after allergen challenge (55–59), but
Structure and Classification 71
had no effect on eosinophils after allergen bronchial (60) or nasal challenge (61).
Moreover, terfenadine, cetirizine, and loratadine decreased the expression of in-
tracellular-adhesion molecule-1 (ICAM-1) on cells from conjunctival or nasal
secretions during allergen challenge (62–66) or natural allergen exposure to pol-
lens (67–72) or mites (73).
The extent of these antiallergic effects is not completely understood, yet
these studies have led to the concept of antiallergic drugs with H 1-blocking prop-
erties (36, 74). It would be premature to attempt to reclassify the H 1-antihista-
mines according to their antiallergic properties because these have not been fully
investigated. Their relative contribution to the overall therapeutic effectiveness
of each H 1-antihistamine is unknown (75).
Due to their variable H 1-blocking activity and antiallergic effects and pos-
sibly due to differences in lipophilicity and tissue deposition, the various H 1-
antihistamines are not equally effective in reducing skin, nose, eye, or lung
symptoms. Moreover, it appears that not all H 1-antihistamines have identical
effects in various patients, since nonresponders to one may respond favorably to
another (76).
(79). These effects have been highlighted recently by the potentially fatal cardio-
toxicity of the H 1-antihistamines astemizole and terfenadine. The cardiac effects
of H 1-antihistamines are reviewed in Chapter 12.
Certain H 1-antihistamines, particularly promethazine, possess α-adrenergic
receptor-blocking properties. Some H 1-antihistamines increase adrenergic effects
by cocaine-like activity, decreasing transmitter reuptake. Other H 1-antihistamines
possess antiserotonin (80) or antidopamine effects (phenothiazines) (81).
Several but not all H 1-antihistamines are analgesic agents or adjuvants.
They include diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyl-
toloxamine, promethazine, methdilazine, and tripelennamine. More than one
mechanism of action exists for them. Considerable evidence suggests that hista-
minergic and serotoninergic central pathways are involved in nociception and
that H 1-antihistamine drugs can modulate these responses. The evidence for a
role for norepinephrine and dopamine and the effects of H 1-antihistamines on
their pathways is less well established (82).
Histamine H 1-receptors are involved in the development of the symptoms
of motion sickness, including emesis. On provocative motion stimulus, a signal
for sensory conflict activates the histaminergic neuron system and the histaminer-
gic descending impulse then stimulates H 1-receptors in the emetic center of the
brainstem. The histaminergic input to the emetic center via H 1-receptors is inde-
pendent of dopamine D2-receptors in the chemoreceptor trigger zone and seroto-
nin 5HT3-receptors in the visceral afferents that are also involved in the emetic
reflex. H 1-antihistamines block emetic H 1-receptors to prevent motion sickness.
Acetylcholine muscarinic receptors are involved in the generation of signals for
sensory conflict. Anticholinergic drugs prevent motion sickness by modifying
the neural store to facilitate habituation to provocative motion stimuli (83–85).
barrier (87). This latter concept involves a number of different factors: lipophilic-
ity (88, 89), ionization, binding to serum proteins, and presence of active transpor-
tation. Second-generation relatively nonsedative H 1-antihistamines do not cross
this barrier to the same extent as their predecessors. Moreover, there is a highly
significant correlation between the sedation caused by H 1-antihistamines and the
level of their binding to brain receptors (90). Nonsedative H 1-antihistamines may
have a reduced affinity for CNS histamine receptors (91, 92).
The second-generation H 1-antihistamines are mostly devoid of CNS side
effects (93). A battery of cognitive and psychomotor tests has been used to assess
both objective and subjective sedative effects of these medications. They include
tests of psychomotor performance, sensorimotor coordination, speed, information
processing, sensory skills, as well as physiological measures and subjective rating
scales. At therapeutic doses, most of the new compounds are relatively free from
sedative effects (for review see 94–99), and, unlike the first-generation H 1-
antihistamines (100), do not exacerbate the CNS effects of alcohol and vice versa
(101–103).
Elderly patients present a greater risk for CNS side effects and first-genera-
tion H 1-antihistamines should no longer be used in this population (104)
(Chap. 15).
ion channels. On the other hand, cetirizine (149) and fexofenadine (150, 151)
are eliminated mostly unchanged. Mizolastine is extensively metabolized. In
doses up to 40 mg (four times the therapeutic dose) there is no evidence of an
effect on ventricular repolarization in healthy volunteers (153).
F. Gastrointestinal Disturbances
Gastrointestinal disturbances including nausea, vomiting, diarrhea, loss of appe-
tite, and epigastric distress are produced by some members of the ethylenedi-
amine class.
G. Tumor Promotion
The potential tumor-promoting effects of some H 1-antihistamines were reported
in a single study in mice injected in the intraperitoneal space with melanoma or
fibrosarcoma cells (154), but these results have not been confirmed. Moreover,
results obtained in rodents are not directly applicable to humans because of the
experimental conditions and the different cellular metabolic systems involved (155,
156). During 60 years of use there has been no clinical evidence of tumor-promoting
effects of the commercially available H 1-antihistamines (157). Therefore, this
should not be considered to be a possible side effect of H 1-antihistamines.
A. Group I: Ethylenediamines
These include pyrilamine, antazoline, methapyrilene (158), and tripelennamine.
These drugs have relatively weak CNS effects but gastrointestinal side effects
are common. Methapyrilene was found to possess carcinogenic properties (159)
and is no longer available for use.
E. Group V: Piperazines
These include cyclizine (170, 177), buclizine, chlorcyclizine, hydroxyzine (178,
179), and meclizine, and induce mild to moderate sedation and anticholinergic
side effects in most users. Cyclizine, buclizine, and meclizine are used for treating
motion sickness or vertigo. Hydroxyzine is used as an H 1-antagonist (180, 181)
as well as a sedative, tranquilizer, and antiemetic.
V. SECOND-GENERATION H 1-ANTIHISTAMINES
A. General Properties
Ideally, second-generation H 1-antihistamines should incorporate the properties
discussed below.
1. Pharmacological Properties
Agents should provide potent and noncompetitive H 1-receptor blockade as well
as antiallergic activities.
2. Side Effects
Formulations should cause no or little sedation, have no anticholinergic effect,
and cause neither weight gain nor cardiac side effects.
3. Pharmacokinetics
The ideal agent should have a rapid onset of action and food should not interfere
with its absorption. It should have a long duration of action (24 h) after once-
daily administration. It should not cause development of tachyphylaxis (192, 193)
and should not interact with cytochrome P-450. All the newer H 1-antihistamines
(except cetirizine and fexofenadine) undergo hepatic metabolism via the cyto-
chrome P-450 system and most are transformed into active metabolites. Cyto-
chrome P-450 (CYP3A) is involved in the metabolism of many chemically di-
verse drugs administered to humans (194, 195). Moreover, its localization in high
concentrations both in the small intestinal epithelium and liver makes it a major
contributor to presystemic first-pass elimination following oral drug administra-
tion. Drug interactions involving enzyme inhibition or induction are common
following the coadministration of two or more CYP3A substrates (196).
4. Clinical Activities
The new H 1-antihistamines are highly selective for H 1-receptors and therefore
they are effective in reducing itching, sneezing, and watery rhinorrhea in allergic
rhinitis (for review on clinical efficacy, see Refs. 197–202), but they are less
Structure and Classification 77
B. Specific Properties
Second-generation H 1-antihistamines have similar efficacy, but differ in their
clinical pharmacology and safety profiles. Additional H 1-antihistamines in vari-
ous stages of development at this time include desloratadine, emedastine, epinas-
tine, levocetirizine, and tecastemizole (208).
1. Acrivastine
Acrivastine is a side-chain-reduced relative of the first-generation antihistamine
triprolidine. It is a very short-acting histamine H 1-receptor antagonist with a rapid
onset of action. Randomized controlled trials have shown acrivastine (usually 8
mg three times daily) to be an effective antihistamine in the treatment of chronic
urticaria (209) and allergic rhinitis (210). Acrivastine was found to cause less
drowsiness than clemastine (211), but it does seem to have some sedative effects
(212) and CNS interactions with alcohol have been observed (213). Because of
its rapid onset of action, acrivastine is useful for ‘‘on demand’’ therapy in patients
with intermittent symptoms (214).
2. Astemizole
Astemizole [1-(4-fluorophenylmethyl)-N-1(2-(4-methoxyphenyl)ethyl)-4-
piperidinyl-1H-benzamidazole-2-amine] is a long-acting, highly selective H 1-
antagonist with no CNS or anticholinergic effects (20, 215, 216). Due to its
78 Passalacqua et al.
potential cardiac toxicity, it has been withdrawn from the market in most coun-
tries.
3. Cetirizine
Cetirizine, [2-[(4-chlorophenyl)phenylmethyl-1-piperazinyl)ethoxy] acetic acid
dihydrochloride, a piperazine derivative and carboxylated metabolite of hy-
droxyzine, is a specific and long-acting histamine H 1-receptor antagonist. The H 1-
blocking activity of cetirizine is extremely potent (22). It also inhibits eosinophil
chemotaxis during the allergic response in the skin (217–219) but not in the nose.
Cetirizine is not extensively metabolized in the liver and no cardiac side effects
have been reported. Randomized controlled trials indicate that cetirizine 10 mg
daily is an effective treatment for seasonal and perennial allergic rhinitis (220–
230) and for allergic conjunctivitis (231, 232). It also has a role in the treatment
of certain forms of physical urticaria, atopic dermatitis, and reactions to mosquito
bites (233). It is associated with a significantly lower incidence of sedation than
hydroxyzine; however, when sedation was subjectively assessed, cetirizine ap-
peared to be more sedating than placebo or other second-generation H 1-antihista-
mine such as loratadine in some, but not all, double-blind studies (234). In con-
trast, when assessed objectively in pharmacodynamic comparisons, cetirizine
rarely had more CNS effects than placebo or other second-generation histamine
H 1-antagonists (197, 235).
4. Ebastine
Ebastine, 4-diphenylmethoxy-1-[3-(4-ter-butylbenzoyl)-propyl piperidine, a pi-
peridine derivative, and its active metabolite carebastine are selective H 1-receptor
antagonists (236) devoid of any other noticeable receptor binding. Ebastine has
less affinity for central than for peripheral H 1-receptors. Randomized controlled
trial have shown that, administered at a dosage of 10 mg daily, ebastine was
effective in the treatment of seasonal (237–239) and perennial allergic rhinitis
(240, 241). However, a dosage of 20 mg daily was found to be more effective
and a dual dosage has been suggested; 10 mg for seasonal (242) and 20 mg for
perennial rhinitis (241, 243). Administered at a dosage of 10 or 20 mg daily,
ebastine was not found to induce sedation (244). No interactions with alcohol
(245) have been reported. Ebastine appears to be free from cardiovascular side
effects at dosages of 10 mg or 20 mg daily (246).
5. Fexofenadine
Fexofenadine is the pharmacologically active metabolite of terfenadine (247). It
is a potent H 1-antihistamine in skin test models (198, 248, 249). Its pharmacoki-
netics have been studied in adults and children (250) and support once-daily
Structure and Classification 79
6. Levocabastine
Levocabastine (3S-(1(cis)-3α, 4β))-1[-[4-cyano-4(4-fluorophenyl)cyclohexyl]-
3-methyl-4-phenyl-4-piperidine carboxylic acid monochloride] is a cyclohexyl-
piperidine derivative shown to possess long-lasting H 1-antagonism and anti-
allergic properties (255). It has only been developed for nasal mucosal and
conjunctival administration due to its sedative effects. In controlled trials, levoca-
bastine was effective and well tolerated in the treatment of allergic rhinitis and
allergic conjunctivitis. Randomized controlled trials have demonstrated that levo-
cabastine is superior to placebo and at least as effective as sodium cromoglycate
in alleviating symptoms of seasonal allergic rhinitis (256–261) and conjunctivitis
(262–268); however, it is less effective than topical corticosteroids in relieving
rhinorrhea and nasal congestion. The incidence of adverse effects associated with
topical levocabastine therapy is low and similar to that observed with placebo
or sodium cromoglycate (269). No sedation was observed after use of eye drops
(270).
7. Loratadine
Loratadine (ethyl-4 (8-chloro-5,6-dihydro-11H-benzo (5-6)-cyclo-hepta (1,2-b)
pyridine 11-ylidene)-1 piperidine carboxylate) has high selectivity for peripheral
histamine H 1-receptors (271). It is rapidly metabolized into an active metabolite,
descarboethoxyloratadine. Although it is metabolized by the cytochrome
CYP3A4 system in the liver, an alternative pathway CYP2D6 is available and
no accumulation has been reported. Randomized controlled trials have shown
that loratadine (10 mg daily) is a well-tolerated and effective H 1-antagonist in
seasonal and perennial allergic rhinitis and chronic urticaria (24–28, 34, 272–
277). No sedative effect of loratadine is observed at recommended dosages (92,
188, 278, 279). No cardiac side effects have been observed.
8. Mizolastine
Mizolastine, an H 1-antihistamine (153, 280) without anticholinergic effects (281,
282), has antiallergic and anti-inflammatory effects in animals (283–285) and
healthy volunteers. Randomized controlled trials have shown that mizolastine is
effective in the treatment of seasonal and perennial allergic rhinitis (200, 286–
289). Mizolastine 10 mg daily is generally well tolerated, with the most common
80 Passalacqua et al.
adverse events, including sedation, being similar to those reported after placebo.
The incidence of prolonged QTc interval was similar in mizolastine- and placebo-
treated subjects (153, 290), although mizolastine is contraindicated in those with
cardiac disease or hepatic impairment or in those receiving erythromycin, ketoco-
nazole, or class I or III antiarrhythmic agents.
9. Terfenadine
Terfenadine (alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-
piperidinebutanol) is a selective histamine H 1-receptor antagonist devoid of CNS
and anticholinergic activity (291). Due to its potential cardiac toxicity, terfena-
dine has been withdrawn from use in most countries (292).
B. Ketotifen
Ketotifen [(4-/1-methyl-4-piperidylidene/-4H-benzo[4,5]cyclohepta[1,2-b] thio-
phen-10(9H)-1-one hydrogen fumarate)] is an H 1-antagonist with antiallergic
properties. After 6–12 weeks of administration, ketotifen significantly reduces
respiratory symptoms and the need for concomitant antiasthmatic drugs in pa-
tients with mild to moderate bronchial asthma; however, improvement in lung
Structure and Classification 81
C. Oxatomide
Oxatomide, ((diphenylmethyl-4-piperazinyl-1)-3 propyl)-1,3 H benzimidazo-
lone-2, is an orally active H 1-histamine receptor antagonist that also inhibits me-
diator release (312). It is mostly used in the treatment of chronic urticaria. Some
patients responding to oxatomide were said to have been unresponsive to previ-
ously administered antihistamines. Sedation is a common side effect, as is weight
gain (313).
With cloning of the gene encoding the histamine H 1-receptor (314–316), a new
area of histamine research has become reality. It seems feasible to study the target
of the therapeutically important H 1-antihistamines. Expression of the genes in
mammalian cells allows detailed investigations of the various signal transduction
routes of the histamine H 1-receptor (317). Moreover, using molecular biological
techniques, it is now possible to investigate ligand–receptor interaction at the
molecular level (318, 319). It is expected that these new developments will pro-
vide fundamental information about ligand interaction with the H 1-receptor (320).
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98 Passalacqua et al.
I. INTRODUCTION
101
102 Assanasen and Naclerio
helper cells (Th: CD4⫹) and, in turn, B cells. Interleukins (IL), especially IL-4
and IL-13 from Th2 lymphocytes, favor IgE synthesis by B cells. Allergen-spe-
cific IgE binds to high-affinity receptors on mast cells and basophils and to low-
affinity receptors on other cells, including monocytes, eosinophils, and platelets
(2–5).
The early-phase response (EPR) begins when subsequent exposure to an
allergen leads to cross-linking of adjacent IgE molecules, and mast cells degranu-
late, releasing multiple inflammatory mediators such as histamine, leukotriene
C4 (LTC4 ), and prostaglandin D2 (PGD2 ) (6). In allergic rhinitis, the mediators
stimulate the nasal end organs (nerves, glands, and blood vessels) to produce
itching, sneezing, rhinorrhea, and congestion. These symptoms usually resolve
spontaneously, but may return 3–10 h after allergen challenge.
Spontaneous recurrence of symptoms occurs in approximately 50% of per-
sons with seasonal allergic rhinitis (7). The dominant symptom in this late-phase
response (LPR) is nasal congestion. On histological examination, the LPR is
Antiallergic Anti-Inflammatory Effects 103
A. General Considerations
Several methods for the provocation and measurement of the nasal response have
been used in recent years. Each technique or model has its own advantages and
disadvantages. For experimental research, quantitative measurements with high
reproducibility are essential (25). The interpretation of the results demands basic
knowledge of the techniques employed, as well as of the study design. All provo-
cation studies require careful selection of participants, including an assessment
of the disease state by using subjective and objective parameters. The participants
should be free of other underlying diseases and should not be taking any medica-
tions that may confound the interpretation of results. We prefer to challenge pa-
tients with seasonal allergic rhinitis out of season, because pollen exposure can
prime their mucosa and affect the laboratory responses in vivo during the season
and for weeks afterward. They should be studied during the asymptomatic stage
several weeks after termination of the pollen season, and at least 2 weeks should
pass between challenges, to avoid the priming effect.
Nasal challenges with histamine or methacholine have been used to assess
the nonspecific hyperreactivity of the nasal mucosa after allergen challenge. Both
histamine and methacholine induce a dose-dependent increase in secretion
weights on the challenged (ipsilateral) side, whereas only histamine induces a
contralateral reflex rhinorrhea (26). The use of a control group is essential for
assessment of the ‘‘placebo effect’’ or other potential confounding environmental
factors (27).
B. Allergen
Precise quantification of the amount of allergen to be used for challenge is essen-
tial. The purity and stability of the allergen must be known. Allergens are usually
given as aqueous solutions, powder, or pollen grains mixed with lactose in cap-
sules. We prefer to use standardized and lyophilized extracts. Aqueous extracts
106 Assanasen and Naclerio
must be stored appropriately as their potency may decrease rapidly. Optimal aller-
gen concentrations, which vary for seasonal and perennial allergens, should be
selected. In general, the amount of administered allergen that causes asymptom-
atic individuals to respond is far greater than that required during several days
of natural pollen exposure, mostly because of the priming effect that occurs dur-
ing natural exposure.
C. Delivery System
Delivery systems for liquid extracts commonly include nebulizers, atomizers,
metered-dose inhalers, direct instillation, and placement of extract-soaked paper
discs in the nose. The choice of a delivery system depends on the question being
addressed by the experiment. It must be reproducible, and its effect on the param-
eters being measured must be known. The diluent used for the allergen extract
and preservatives such as glycerol, benzalkonium chloride, or phenol may induce
nonspecific nasal reactions. The diluent is often administered before the allergen
exposure so that its effect can be studied. In addition, with all delivery systems,
an attempt should be made to minimize the exposure of the lower airways to
allergen, because allergen deposited in the lower airway can cause bronchocon-
striction.
2. Outcomes Evaluated
Nasal Airway Resistance. Nasal congestion is one of the cardinal symp-
toms of allergic inflammation and the major symptom of the LPR following aller-
gen challenge.
Rhinomanometry measures nasal airway resistance (NAR) by quantita-
tively measuring nasal airflow and pressure. Active anterior rhinomanometry is
used most frequently as it is well tolerated by patients. Posterior rhinomanometry
is preferable because it does not distort the nasal valve, but only about 85%
of volunteers can successfully perform this maneuver (28). The physiological
fluctuation in nasal resistance, termed the nasal cycle, may interfere with nasal
Antiallergic Anti-Inflammatory Effects 107
monitoring in the nasal provocation test (29). A large number of subjects and/
or a large change in resistance are needed to overcome the variations in this
measurement.
Inspiratory Nasal Peak Flow. This is the simplest technique for detecting
changes in nasal patency for repeated measurements before and after nasal chal-
lenge. It can also be performed at home for monitoring nasal congestion as a
response to treatment. Peak flow measurements are less reproducible than rhino-
manometry measurements (30).
Nasal Volume. The geometric cross-sectional area and nasal volume can
be measured using acoustic rhinometry. This rapidly performed test, which does
not assess flow, complements NAR measurement and provides information about
the site of obstruction. It is also affected by nasal cycle.
Measurement of Mucosal Swelling. Rhinostereometry is an optical
method that exclusively measures changes in nasal swelling using stereotactic
measurement of one defined point through an eyepiece of a microscope to evalu-
ate changes in mucosal edema. Although it is highly accurate, correlation with
the subjective symptom of nasal obstruction is poor (31).
Nasal Secretions. Several methods have been used for collecting and
quantifying nasal secretions: suction, blowing, dripping, washing, lavage, and
absorption. Blown secretions can be quantified by weighing of paper tissues. The
amount of nasal secretions can also be obtained by the placement of discs or
other substances on the nasal mucosa to determine the weight of secretions gener-
ated during a fixed period of time. Nasal lavage samples epithelial lining fluid
(ELF) from a large mucosal area, whereas discs sample a localized area. The
volume of ELF in the lavage fluid can be estimated by using urea as a marker
(32). Nasal secretions can be processed for assessment of both their cellular and
their biochemical contents.
Biological Markers. Biological markers can be measured in collected se-
cretions to monitor changes in the underlying pathophysiology. These markers
include inflammatory mediators, cytokines, plasma proteins and glandular secre-
tory products. It is important to know the stability of each marker after recovery,
the sensitivity and specificity of each assay, and the potential cellular sources
of the markers when interpreting the results. The changes in markers reflect
their levels on the mucosal surface, but may not reflect levels in the underlying
tissue.
Cells. Cells can be obtained from the nasal cavity using various tech-
niques. The epithelial layer can be scraped or brushed for evaluation of specific
areas of the nasal cavity. Obtaining blown secretions is simple and painless; how-
ever, the specimen only reflects secretions and usually yields few cells. Nasal
108 Assanasen and Naclerio
lavage samples secretions from the entire nasal cavity. It provides a technique
for simultaneous measurement of cells and biological markers. Nasal biopsy sam-
ples provide information about structural elements and cellular contents of the
epithelial layer and the deeper submucosa. A wide range of histochemical or
immunohistochemical techniques can be employed for light microscopy to pro-
vide a more detailed evaluation of the cellular content. As an alternative, samples
may be processed specifically for either transmission or scanning electron micros-
copy.
A. Acrivastine
Acrivastine, which is related to triprolidine, is a short-acting H 1-antagonist with
a rapid onset of action. Lau and colleagues studied the effect of acrivastine on
histamine release from rat peritoneal mast cells and found it to be ineffective in
inhibiting anti-IgE- or calcium ionophore A 23187-induced histamine release at
concentrations from 10⫺9 M to 10⫺4 M (33). Acrivastine was, however, demon-
strated to inhibit PAF-induced airway hyperreactivity in guinea pigs (34). The
mechanism responsible for this finding is unclear, but is not related to H 1-antago-
nism. Antiallergic activities of acrivastine have not been studied in humans.
B. Astemizole
Astemizole, a benzimidazole–aminopiperidine compound, is a long-acting,
highly selective H 1-antagonist with no central nervous system (CNS) or anticho-
linergic effects. Because of its rare but potentially serious cardiac side effects,
it has been removed from the market. It significantly decreased IL-1 levels in
nasal lavage fluid and also decreased IL-8 and LTB4 levels (35, 36).
C. Azatadine
Azatadine, a tricyclic antihistamine of the piperidine class, is an effective H 1-
receptor antagonist for relieving the histamine-mediated symptoms of seasonal
allergic rhinitis (37). In vitro experimentation with azatadine base showed that
it inhibited histamine and LTC4 release from human lung mast cells by 45 and
Antiallergic Anti-Inflammatory Effects 109
D. Azelastine
Azelastine, a phthalazinone compound, can be administered orally or as an intra-
nasal spray. In addition to histamine H 1-receptor blockade, it has inhibitory ef-
fects on cells and chemical mediators of the inflammatory response in vitro (40–
45). For example, it inhibits histamine release from human basophils (41) and
from animal (43, 44) and human lung mast cells (45) in vitro. Anti-inflammatory
effects of azelastine have also been shown in vivo. Shin and colleagues performed
a double-blind, placebo-controlled, crossover study comparing the effect of treat-
ment with oral azelastine or placebo on the EPR to nasal challenge with allergen
in 13 asymptomatic allergic subjects (46). Pretreatment with a single oral 2 mg
dose of azelastine resulted in a dramatic reduction in the number of sneezes as
well as in the levels of TAME-esterase activity, LTC4 , and kinins without a sig-
nificant reduction of histamine and PGD2 compared to placebo. These results
suggest that azelastine blocked the effects of histamine on nerves and blood ves-
sels.
An interesting finding in this study was the inhibition of leukotriene pro-
duction by azelastine. This finding probably reflects the fact that the concentra-
tion of azelastine in vivo was sufficient to inhibit only LTC4 , but not histamine
release, because in vitro studies showed that azelastine inhibited LTC4 release at
a dose lower than that required to inhibit histamine release (39, 47). Alternatively,
since mast cell activation was not inhibited, eosinophils, macrophages, and endo-
thelial cells may have contributed to the production of LTC4. Another possible
explanation is that azelastine may have some 5-lipoxygenase inhibitory activity
that leads to a preferential reduction of leukotriene generation in nasal mast cells
(48, 49). Because histamine itself does not affect LTC4 production (50), this is
not an H 1-receptor blockade effect. These results emphasize the importance of
correlating in vivo and in vitro results, and the greater complexity of in vivo
systems.
IL-4 from CD4⫹ lymphocytes and CD23 antigen from B lymphocytes are
important triggering mechanisms in cells producing IgE antibodies (51, 52). Ito
110 Assanasen and Naclerio
and colleagues studied the effect of azelastine on IL-4 and soluble CD23
(s-CD23), the soluble component of membrane-type CD-23, in subjects with al-
lergic rhinitis. They performed a randomized, placebo-controlled, parallel trial
in allergic subjects who were treated with either azelastine (orally 2 mg daily)
or placebo for 4 weeks during the allergy season (53). Compared to placebo,
azelastine significantly decreased symptoms and the levels of IL-4 and s-CD23
from baseline.
Ciprandi and colleagues studied the effect of azelastine nasal spray on the
EPR and LPR to nasal challenge with allergen in 20 subjects with pollen allergy
in a randomized, double-blind, placebo-controlled, parallel study (54). Azelastine
significantly decreased the total symptom score, as well as eosinophil and neutro-
phil infiltration and ICAM-1 expression during both EPR and LPR (Table 1).
Furthermore, ECP levels in nasal lavage fluid decreased significantly during the
LPR. The antiallergic effect of intranasal azelastine was more prominent and
effective when treatment was used continuously, rather than as needed (55). Us-
ing a conjunctival provocation model, Ciprandi and colleagues also demonstrated
the antiallergic activity of azelastine eye drops on the EPR and LPR to conjuncti-
val challenge with allergen (56). In contrast, Pelucchi and colleagues failed to
show an inhibitory effect of intranasal azelastine on the number of eosinophils
recovered in nasal lavage in allergic subjects during the pollen season (57).
A possible explanation for its antiallergic effect in the LPR is that azelastine
may downregulate ICAM-1 expression by acting on epithelial cells directly, or
by acting on mast cells or other cells that are able to release factors that upregulate
ICAM-1 expression (58).
Jacobi and colleagues studied the effect of a 1-week pretreatment with in-
tranasal azelastine or systemic cetirizine on allergen-induced release of mast cell
mediators from the human nasal mucosa (59). They performed a randomized,
double-blind, placebo-controlled, three-way crossover study on 11 allergic sub-
jects and 5 nonallergic subjects. Each subject was treated with azelastine nasal
spray, 0.14 mg per nostril twice daily, cetirizine 10 mg once daily, or placebo
for 1 week. There were significant increases in the number of sneezes and the
levels of histamine and tryptase in lavage fluid after allergen challenge. Both
azelastine and cetirizine significantly reduced allergen-induced sneezing and the
associated increases in histamine and tryptase levels (Fig. 2). Reduced levels of
mast cell mediators in nasal lavage fluid may result from a reduced release of
mediators from mast cells and/or a reduced transfer of released mediators from
the nasal mucosa to lavage fluid. The fact that antihistamines reduce histamine-
induced plasma exudation and secretion from nasal glands supports the latter
concept (26). The discrepancies between this study and that of Shin and col-
leagues may be related to the differences in study population and methods (e.g.,
allergen concentrations, or route of administration).
Table 1 Results of Parameters Measured During Early- and Late-Phase Response After Nasal Challenge with Allergen
Early-phase response Late-phase response
Twenty asymptomatic subjects with allergic rhinitis were studied in a randomized, double-blind, placebo-controlled, parallel trial. Numbers represent the
median values (range) after allergen challenge. T0, allergen challenge performed at baseline; T7, allergen challenge, which was done 1 week after T0,
performed 30 min after subjects received either azelastine (0.137 mg intranasally) or placebo; ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil
cationic protein; NS, not significant.
Source: Ref. 54.
111
112 Assanasen and Naclerio
Figure 2 Effect of 1 week pretreatment with intranasal azelastine, oral cetirizine, and
placebo on the early allergic response. Eleven asymptomatic subjects with allergic rhinitis
were treated with azelastine nasal spray (0.14 mg per nostril twice daily), cetirizine tablets
(10 mg daily), or placebo 1 week prior to allergen challenge in a randomized, double-
blind, placebo-controlled, three-way crossover trial. The challenge protocol is shown on
the abscissa. The nasal challenge was begun with 0.9% NaCl solution as a control chal-
lenge, followed by three incremental dosages of allergen. The median values of number
of sneezes and the levels of histamine and tryptase in nasal lavage fluid are shown. Pre-
treatment with azelastine or cetirizine significantly inhibited the allergen-induced sneezes
and the increase in the levels of tryptase and histamine compared with placebo. SQU,
standardized quality units. (From Ref. 59.)
Antiallergic Anti-Inflammatory Effects 113
E. Cetirizine
Cetirizine, a piperazine derivative and the carboxylated metabolite of hydroxy-
zine, is a specific H 1-receptor antagonist. To evaluate the effects of cetirizine
on mediator release during the early allergic response, Naclerio and colleagues
performed a double-blind, placebo-controlled, crossover study in 10 asymptom-
atic patients with seasonal allergic rhinitis, comparing pretreatment with cetiri-
zine 20 mg daily for three doses, or placebo, on the response to nasal challenge
with allergen (60). After pretreatment with placebo, the volunteers sneezed in
response to antigen stimulation, and there was a dose-dependent increase in the
levels of histamine, TAME-esterase activity, albumin, LTC4 , and PGD2 in the
recovered nasal lavage fluid. After cetirizine pretreatment, there was a significant
reduction in the number of sneezes, TAME-esterase activity, LTC4 , and albumin,
whereas the histamine and PGD2 levels were not reduced. These findings support
the notion that cetirizine competes with histamine for H 1-receptors on nerves
(reduced sneezing) and blood vessels (decreased vascular permeability). The inhi-
bition of leukotriene production by cetirizine could be explained in the same way
as discussed above for azelastine.
In another study, the effect of cetirizine on histamine-induced changes in
lavage protein concentration was studied in 10 healthy volunteers in a random-
ized, double-blind, placebo-controlled manner (61). The increase in lavage total
protein and albumin concentration after histamine challenge was almost com-
pletely abolished by cetirizine compared to placebo. This finding supports the
concept that the increase in albumin after allergen challenge is mediated by hista-
mine acting through H 1-receptors on blood vessels, resulting in plasma leakage,
which is inhibited by cetirizine.
The effect of cetirizine on accumulation of inflammatory cells has also
been studied in the skin and upper airways. Double-blind, placebo-controlled,
crossover studies evaluating its effect on the cutaneous allergic response have
shown that it reduces eosinophilic infiltration at the site of allergen challenge in
a skin chamber challenge model (62), and also in a similar study in which it
decreased eosinophil infiltration by approximately 80% in ragweed-sensitive sub-
jects (63). Furthermore, cetirizine has been shown to inhibit cellular recruitment,
particularly eosinophils, into bronchial washings from asthmatic subjects with an
early and late response (64). Klementsson and colleagues evaluated the effect of
cetirizine (10 mg daily), terfenadine (60 mg twice daily), and placebo on eosino-
phil infiltration into nasal secretions and on allergen-induced nonspecific nasal
hyperreactivity after nasal allergen challenge (65). The allergen challenge in-
creased surface eosinophils, which were unaffected by both active drugs. Why
cetirizine prevents the selective recruitment of eosinophils to the skin, but not to
the nasal mucosa, is unknown. A surprising finding was that both antihistamines
inhibited the increased nonspecific nasal reactivity induced by methacholine 24
114 Assanasen and Naclerio
Total nasal symptom score 4.8 ⫾ 0.63 2.2 ⫾ 0.49** 2.13 ⫾ 0.51**
Volume of nasal secretion (mL) 0.3 ⫾ 0.06 0.2 ⫾ 0.05 0.27 ⫾ 0.06
after methacholine challenge
(before allergen challenge)
Volume of nasal secretion (mL) 0.36 ⫾ 0.07 0.25 ⫾ 0.08* 0.27 ⫾ 0.05*
after methacholine challenge
(24 h after allergen challenge)
Fifteen asymptomatic subjects with allergic rhinitis were treated with terfenadine (60 mg twice daily),
cetirizine (10 mg daily), or placebo for 5 days before allergen challenge in a randomized, double-
blind, placebo-controlled trial. Methacholine challenge was performed before and 24 h after allergen
challenge for assessment of nasal hyperresponsiveness. The data are mean ⫾ SEM of 15 subjects.
*p ⬍ 0.05; **p ⬍ 0.01 compared to placebo.
Source: Ref. 65.
h after allergen challenge (Table 2). This study suggests that the allergen-induced
increase in nonspecific responsiveness is a complex phenomenon not dependent
solely on eosinophil influx into the nasal mucosa. In addition, histamine stimula-
tion of the nasal mucosa does not increase the reactivity to methacholine 24 h later
(50), suggesting that histamine released from mast cells after allergen challenge is
not responsible for increased methacholine responsiveness. Thus, the mechanism
by which these two antihistamines reduce nasal hyperresponsiveness is unrelated
to H 1-antagonist activity.
Ciprandi and colleagues investigated the antiallergic activity of cetirizine
in 20 allergic children with allergic rhinoconjunctivitis during the pollen season
(66). Cetirizine significantly reduced clinical symptoms, inflammatory cell in-
filtrates, ICAM-1 expression on nasal epithelial cells, and soluble ICAM-1
(sICAM-1) and ECP in nasal lavages (Fig. 3). In another study comparing lora-
tadine and cetirizine during natural allergen exposure, similar findings were
obtained (67). These data suggest that cetirizine has inhibitory effects on ex-
pression of adhesion molecules, and on cellular influx, as well as on eosinophil
mediators.
Even when asymptomatic, individuals who suffer from house dust mite
allergy have both conjunctival and nasal mucosal inflammation, characterized by
infiltration of inflammatory cells (eosinophils and neutrophils) and by ICAM-1
expression on epithelial cells (16). In one randomized, double-blind, placebo-
controlled, parallel study, Fasci et al. investigated the effect of 2-weeks treatment
with cetirizine on chronic, naturally occurring inflammation in 20 children, all of
whom had allergic asthma associated with mite sensitivity and had been symptom-
Antiallergic Anti-Inflammatory Effects 115
Figure 3 Effect of cetirizine on nasal allergic inflammation during natural pollen expo-
sure. In a double-blind, placebo-controlled, parallel design, 20 allergic children were
treated with either cetirizine (0.15 mg/kg daily) or placebo for 4 weeks during the pollen
season. Nasal lavages were performed before and after treatment. Cell counts and mediator
levels (ECP and soluble ICAM-1) were measured in nasal lavage. Expression of ICAM-
1 on nasal epithelial cells was also evaluated by a five-point rating scale. Individual data
for each parameter are shown. Compared with placebo, cetirizine significantly decreased
eosinophil counts (a), ICAM-1 positivity on nasal epithelium (b), and levels of sICAM-
1 (c) and ECP (d) in nasal lavage fluid. The solid horizontal bars represent median values.
Pre, pretreatment; post, after 4 weeks of treatment. The intragroup comparisons are shown
in the upper part of the each graph (p value, NS). NS, not significant. (From Ref. 66.)
116 Assanasen and Naclerio
free for at least 2 months (68). In contrast to patients treated with placebo, cetirizine-
treated children showed a significant reduction in ICAM-1 on epithelial cells in
nasal scrapings. There was also a trend to a reduction in eosinophil and neutrophil
numbers, consistent with the above finding. It can be speculated that longer treat-
ment might have diminished the inflammatory cell infiltration even further.
A soluble form of ICAM-1 (sICAM-1), thought to consist of extracellular
parts of membrane ICAM-1, has been identified in nasal lavage fluid samples of
patients with allergic rhinitis (69, 70). It is assumed to be generated by local
production in the nasal mucosa, followed by release into nasal secretions. The
cells of origin and the mechanisms for releasing the soluble components of these
adhesion molecules are unknown, but either shedding or enzymatic cleavage from
nasal epithelial cell surface could be involved (71). There is a significant correla-
tion between cell membrane expression of ICAM-1 and of sICAM-1, suggesting
that the measurement of sICAM-1 in secretions reflects the expression of ICAM-
1 at the cell-surface level (66, 72).
In a 2-week study, the effects of cetirizine (10 mg daily) and loratadine (10
mg daily) on the release of sICAM-1 in nasal secretions were compared in patients
with allergic rhinitis during the grass pollen season (73). Cetirizine and loratadine
significantly reduced the sICAM-1 released in nasal secretions, whereas the levels
in the control group of untreated patients were unchanged. In vitro evidence of
inhibitory effects of cetirizine on eosinophil adhesion on human endothelial cells
(74) and on eosinophil chemotaxis (75, 76) supports these findings.
F. Ebastine
Ebastine, a piperidine derivative, and its metabolite, carebastine, are selective
H 1-receptor antagonists devoid of any other known receptor binding (77). Camp-
bell and colleagues studied the antiallergic effect of ebastine in both in vitro and
in vivo models (78). They used nasal polyp cells to examine the effects of ebastine
on the release of LTC4 , LTD4 , and PGD2 in vitro after stimulation by anti-IgE,
and on the spontaneous release of cytokines (GM-CSF, TNF-α, and IL-8). Ebastine
at concentrations ranging from 0.1 to 10 µmol/L significantly inhibited the release
of PGD2 , LTC4 , and LTD4 in a dose-dependent manner. In addition, ebastine at
10 µmol/L significantly inhibited the release of GM-CSF, TNF-α, and IL-8.
The same investigators performed a randomized, double-blind, placebo-
controlled, crossover study comparing the antiallergic effects of ebastine (10 and
20 mg daily) and placebo on the release of inflammatory mediators after allergen
challenge in 12 asymptomatic patients with seasonal allergic rhinitis (78). They
found that ebastine dosages of 10 and 20 mg induced a significant increase in
the mean threshold number of pollen grains required to induce a positive response
compared with placebo. Ebastine significantly reduced the release of GM-CSF
in a dose-dependent manner; however, levels of LTC4 , LTD4 , PGD2 , TNF-α,
Antiallergic Anti-Inflammatory Effects 117
and IL-8 were not significantly affected. These data suggest that ebastine exerts
its anti-inflammatory effect by inhibiting the release of PGD2 , LTC4 , LTD4 , and
cytokines from nasal polyp cells in vitro and by decreasing the release of GM-
CSF in vivo.
G. Fexofenadine
Fexofenadine, the carboxylic acid metabolite of terfenadine, is a new second-
generation antihistamine that is nonsedating and does not cause QT prolongation.
Paolieri and colleagues evaluated the effect of fexofenadine on ICAM-1 expres-
sion of a human continuously cultured conjunctival epithelial cell line (WK) and
a fibroblast cell line (HEL) (79). They found that fexofenadine in a concentra-
tion of 50 µ/mL significantly decreased ICAM-1 basal expression on WK cells,
sICAM-1 levels in IFN-γ-stimulated WK cells, and IFN-γ-induced ICAM-1 up-
regulation on HEL. A dose-dependent decrease of spontaneous IL-6 release was
also observed. This study shows that fexofenadine exerts an anti-inflammatory
effect directly on epithelial cells and fibroblasts, reducing ICAM-1 expression
and sICAM-1.
Abdelaziz and colleagues cultured epithelial cells from nasal biopsy speci-
mens from patients with seasonal allergic rhinitis outside the pollen season and
studied the effect of fexofenadine on eosinophil-induced release of proinflamma-
tory mediators, on eosinophil chemotaxis, and on adherence to endothelial cells
in response to conditioned medium from human nasal epithelial cell (HNEC)
cultures (80). Incubation of HNECs in the presence of eosinophils significantly
increased the release of RANTES, IL-8, GM-CSF, and sICAM-1 from HNECs.
Fexofenadine treatment (10⫺9 –10⫺3 mol/L) significantly attenuated the eosino-
phil-induced release of IL-8, GM-CSF, and sICAM-1 from the HNECs. More-
over, conditioned medium from HNECs significantly altered the activity of eosin-
ophils, as indicated by increased release of ECP, and increased both eosinophil
chemotaxis and adherence to endothelial cells. Addition of 10⫺6 –10⫺3 mol/L
fexofenadine to the conditioned medium significantly decreased eosinophil che-
motaxis and adherence to endothelial cells. In vivo, fexofenadine also modulates
the release of inflammatory mediators, cytokines, and adhesion molecules.
H. Ketotifen
In addition to being a competitive (81) and noncompetitive H 1-receptor antagonist
(82), ketotifen inhibits the release of histamine from rat peritoneal mast cells
(83). It also inhibits both histamine and leukotriene release from human basophil
leukocytes stimulated by both anti-IgE and low concentrations of calcium iono-
phore A23187 (84–86). Majchel and colleagues evaluated the effect of pretreat-
ment with ketotifen (1 and 2 mg twice daily) on the early response to nasal
118 Assanasen and Naclerio
challenge with allergen in a double-blind, crossover trial (87). Six weekly nasal
challenges followed by lavage were performed in 10 allergic subjects after 1 h
and 1, 2, 3, and 4 weeks of ketotifen administration. The number of sneezes
decreased significantly after a single dose of drug with both the 1 and 2 mg doses.
Increasing the duration of drug administration did not improve the results. Neither
dosage significantly reduced levels of histamine and TAME-esterase activity in
recovered nasal lavages. Despite the efficacy of ketotifen in inhibiting sneezing,
it did not block the release of histamine or TAME-esterase activity during the
EPR to allergen challenge. The authors concluded that ketotifen reduces allergic
symptoms by its antihistaminic activities rather than by inhibiting histamine re-
lease from mast cells. They could not exclude the possibility that ketotifen may
selectively inhibit release of other mast cell mediators, since they did not measure
other mediators.
Kato and colleagues investigated the effect of prophylactic treatment with
ketotifen on nasal symptoms, blood eosinophil counts, and serum ECP in subjects
with allergic rhinitis before and after the pollen season (88). Ten subjects who
received ketotifen (orally 2 mg daily) for 4 weeks before the start of the pollen
season (prophylactic treatment group) and 12 subjects who began their medica-
tion 12 days after the start of the season (post-symptomatic treatment group) were
enrolled in this study. Treatment with ketotifen was maintained until the end of
the season. Total subjective symptom scores, blood eosinophil count, and serum
ECP values were significantly higher during the season than during preseason.
There were significant decreases in these three parameters in the prophylactic
treatment group compared to the post-symptomatic treatment group.
The same group of authors demonstrated that prophylactic treatment with
topical ketotifen decreased the total symptom score, blood eosinophil counts, and
serum MBP during the season compared to post-symptomatic treatment (89).
These data suggest that blood eosinophils and levels of ECP and MBP in serum
of allergic individuals were upregulated during the season, and that ketotifen’s
antiallergic properties include inhibiting eosinophil recruitment and its activation
in the blood. It is of interest that topical administration of ketotifen could reduce
blood eosinophils and serum MBP, as plasma concentrations of ketotifen are
undetectable when it is applied intranasally. The decrease in mediator release
from mast cells in the nose by ketotifen might reduce local allergic inflammation,
which subsequently suppressed the systemic allergic response (89).
I. Levocabastine
Levocabastine, a cyclohexyl piperidine derivative, is a selective H 1-receptor an-
tagonist developed for nasal and ocular administration. It is effective and well
tolerated in the treatment of allergic rhinitis (90). It has been shown to reduce
the severity of the immediate nasal response to allergen significantly when admin-
Antiallergic Anti-Inflammatory Effects 119
istered 5 min before the challenge, and its protective effect persists for 24 h after
administration (91).
To study the anti-inflammatory effect of levocabastine on the EPR and LPR
to nasal challenge with allergen in vivo, de Graaf and colleagues evaluated 21
house dust mite-allergic rhinitis patients in a double-blind, placebo-controlled,
two-way crossover study (92). Subjects who had EPR but no LPR on nasal chal-
lenge received either topical intranasal levocabastine (400 µg daily) or placebo
for 1 week. Levocabastine significantly reduced the symptom score, but did not
reduce albumin or tryptase levels in nasal lavage fluid or hyperresponsiveness
to methacholine. In agreement with these data, another study failed to show the
inhibition of an allergen-induced increase in albumin levels by levocabastine (400
µg daily) during the early response to nasal challenge with birch allergen extract
(93). Bachert and colleagues also demonstrated no significant differences in aller-
gen-challenge-induced increments of albumin levels in nasal secretions after
levocabastine (400 µg daily) treatment, compared to placebo (94). These findings
suggest that after allergen challenge the principal effect of levocabastine is its
H 1-antagonist effect.
In a contrasting single-blind, placebo-controlled study, the effect of 8 days
pretreatment with levocabastine (intranasally 800 µg daily) was investigated in
12 asymptomatic subjects with allergic rhinitis (95). There were significant in-
creases in albumin levels and inflammatory cells in lavage fluid after allergen
challenge in the placebo group, but not in the levocabastine-treated group (Fig.
4). Levocabastine significantly decreased nasal symptoms, albumin, and inflam-
matory cell influx (neutrophils, eosinophils, metachromatic cells) after allergen
challenge compared to placebo (Fig. 4). The differences in study population,
methods and levocabastine dosages may explain the apparent discrepancies be-
tween this study and earlier ones.
J. Loratadine
Loratadine is a tricyclic, selective H 1-receptor antagonist without anticholinergic
or sedative properties. In vitro it decreases antigen- and calcium ionophore-
induced histamine and LTC4 release from mast cell lines (96). The antiallergic
activity of loratadine may be mediated by blockade of calcium influx into the
cells (96). To study its antiallergic properties in vivo, Bousquet and colleagues
performed a three-way crossover study comparing the effect of 1-week treatment
with loratadine (10 mg daily), terfenadine (60 mg twice daily), or placebo on
mediator release during the immediate response to nasal challenge with allergen
in 14 individuals allergic to pollen (97). Both active drugs suppressed symptoms
and the release of histamine and PGD2 , suggesting that they affected mast cell
activation. Using a similar model, Andersson showed a significant reduction in
the release of histamine and TAME-esterase activity during the early allergic
120 Assanasen and Naclerio
reaction after loratadine treatment (98). These studies show that loratadine is able
to block the release of mediators during the immediate nasal allergic reaction;
however, loratadine did not significantly inhibit the histamine concentration after
allergen administration to the skin (99, 100).
In a double-blind, placebo-controlled, crossover study in 14 patients aller-
gic to ragweed or grass, loratadine (10 mg daily for 1 week before allergen chal-
lenge) markedly inhibited the sneezing response (101). Release of histamine or
PGD2 was not decreased significantly. Loratadine had some inhibitory effects on
the release of LTC4 , albumin, and kinin, but these were not statistically signifi-
cant. Baroody and colleagues performed another double-blind, placebo-con-
trolled, three-way crossover study comparing the effects of 1 week pretreatment
Antiallergic Anti-Inflammatory Effects 121
Loratadine Cetirizine
In a randomized, double-blind, parallel design, 20 subjects with allergic rhinoconjunctivitis were treated with either loratadine 10 mg daily or cetirizine 10
mg daily for 2 weeks during natural allergen exposure. The parameters were compared before and after treatment. The data are presented as median (range).
Cells and mediators were measured in nasal lavage fluid. ICAM-1, intercellular adhesion molecule-1; ECP, eosinophil cationic protein; EPO, eosinophil
peroxidase; MPO, myeloperoxidase; NS, not significant.
Source: Ref. 67.
123
124 Assanasen and Naclerio
Prechallenge
1st 6.5 (2–25) 6.5 (2–40) NS
5th 0.5 (0–1) 0.5 (0–2) NS
Postchallenge
5 min 4 (1–28) 0.5 (0–3) ⬍0.01
10 min 0.5 (0–5) 0 (0–1) ⬍0.001
20 min 0 (0–2) 0 (0–0) ⬍0.01
30 min 0 (0–1) 0 (0–0) NS
60 min 0 (0–0) 0 (0–0) NS
Ten asymptomatic subjects with allergic rhinitis were treated with loratadine 10 mg daily
and with placebo for 1 week before allergen challenge. Nasal lavages were done before
and after challenge with the relevant allergen after each treatment period. Five nasal la-
vages were performed at 4-min intervals before allergen challenge in order to obtain low
and uniform prechallenge histamine levels (1st: first prechallenge lavage; 5th: fifth pre-
challenge lavage). Nasal lavages were repeated 5, 10, 20, 30, and 60 min after allergen
challenge. Results are histamine levels in nasal lavage fluids (ng/mL) before and after
allergen challenge. The data are median (range) for 10 subjects. NS, not significant.
Source: Ref. 106.
Antiallergic Anti-Inflammatory Effects 125
nism by which an antiallergic drug can inhibit histamine release is through induc-
tion of membrane stabilization (107). It is reasonable to speculate that the
inhibitory effect of loratadine on basophil histamine release is related to its effect
on membrane stabilization, transmembrane Ca 2⫹ influx, and intracellular Ca 2⫹
increase.
K. Mizolastine
Mizolastine, a novel benzimidazole derivative, is highly selective for histamine
H 1-receptors and has no anticholinergic, antiadrenergic, or antiserotoninergic ac-
tivity. At a dosage of 10 mg daily it reduces the symptoms associated with seasonal
and perennial allergic rhinitis (108, 109). Anti-inflammatory properties of mizolas-
tine were demonstrated in animal experiments (110, 111). Levrier and colleagues
studied the antiallergic activities of mizolastine in actively sensitized guinea pigs
and passively sensitized rats (110). Mizolastine significantly reduced allergen-
induced release of histamine from mast cells in bronchoalveolar lavage fluid of
guinea pigs and in the peritoneal fluid of sensitized rats. This study suggests a
potential mast cell inhibitory role for this agent in allergen-induced reactions.
Pichat and colleagues studied the effects of mizolastine, loratadine, terfena-
dine, and pyrilamine on arachidonic acid (AA)-induced edema in the rat paw
(111). Mizolastine significantly inhibited AA-induced paw inflammation in a
dose-dependent manner, whereas other antihistamines failed to inhibit the in-
flammatory action of AA. These data suggest inhibitory effects of mizolastine
on AA-induced inflammation. Mizolastine is one of the newest antihistamines
and there are few published data on its antiallergic effects in humans.
L. Oxatomide
Oxatomide is an H 1-receptor antagonist chemically related to cinnarizine, with
potent antihistaminic activity and inhibitor effects on mast cell degranulation
(112). In addition, oxatomide exerts some antiserotonin, anticholinergic activity,
and anti-slow-reacting substance of anaphylaxis (SRSA) in in vitro and in vivo
models (113). Preincubation of basophils with oxatomide (10⫺7 –10⫺5 mol/L) con-
centration dependently inhibited the immunological release of histamine and
LTC4 before anti-IgE challenge (114). Oxatomide (10⫺7 –10⫺5 mol/L) also re-
duced histamine, tryptase, and LTC4 release from human lung mast cells (HLMC)
activated by anti-IgE.
The efficacy of oxatomide (30 mg daily) in the treatment of seasonal aller-
gic rhinitis and/or conjunctivitis has been demonstrated in a double-blind,
placebo-controlled study (115).
To study the effect of 4 weeks of treatment with azelastine (orally 1 mg
twice a day) and oxatomide (orally 30 mg twice a day) on substance P (SP)
126
Table 5 In Vivo Studies of the Effect of H 1-Antihistamines on Nasal Allergic Inflammation Either After Nasal Challenge with
Allergen or During Natural Allergen Exposure
Hyperresponsiveness
Drug Early phase Late phase in vivo
Azatadine
Togias et al. (39) NCA ↓ Histamine, TAME-esterase, NE NE
kinin
Azelastine
(Intranasal)
Pelucchi et al. (57) NAE No effect: eosinophils —
Ciprandi et al. (54) NCA ↓ Neutrophils, eosinophils, ICAM- ↓ ECP in nasal lavage, neutro- NE
1 expression on nasal epithelial phils, eosinophils, ICAM-1 ex-
cells pression on nasal epithelial cells
Jacobi et al. (59) NCA ↓ Histamine, tryptase NE NE
Cetirizine
Naclerio et al. (60) NCA ↓ TAME-esterase, LTC 4 , albumin NE NE
No effect: histamine, PGD 2
Klementsson et al. (65) NCA NE No effect: eosinophils ↓ increased nonspe-
cific hyperreactiv-
ity to metha-
choline
Ciprandi et al. (68) NAE ↓ ICAM-1 expression on nasal epi- — —
thelial cells
Ciprandi et al. (66) NAE ↓ Neutrophils, eosinophils, ICAM- — —
1 expression on nasal epithelial
cells, sICAM-1, ECP
Assanasen and Naclerio
Campbell et al. (73) NAE ↓ sICAM-1 — —
Ciprandi et al. (67) NAE ↓ Eosinophils, neutrophils, meta- — —
chromatic cells, ICAM-1 expres-
sion on nasal epithelial cells,
ECP, EPO, histamine
Jacobi et al. (59) NCA ↓ Histamine, tryptase NE NE
Ebastine
Campbell et al. 1996 (78) NCA No effect: LTC 4 , LTD 4 , PGD 2 , ↓ GM-CSF -No effect: LTC 4 , NE
GM-CSF, TNF-α, IL-8 LTD 4 , PGD 2 , TNF-α, IL-8
Ketotifen
Majchel et al. (87) NCA No effect: TAME-esterase, his- NE NE
tamine
Kato et al. (88) NAE ↓ Blood eosinophil count, serum — —
ECP
Kato et al. (89) NAE — —
Antiallergic Anti-Inflammatory Effects
tive cells
128
Table 5 (Continued)
Hyperresponsiveness
Drug Early phase Late phase in vivo
NCA, nasal challenge with allergen; NAE, natural allergen exposure; NE, not evaluated; IL, interleukin; LT, leukotriene; TAME, N-alpha-tosyl-L-arginine
methyl ester; GM-CSF, granulocyte macrophage colony-stimulating factor; ECP, eosinophil cationic protein; ICAM-1, intercellular adhesion molecule-1;
SP, substance P; sICAM-1, soluble intercellular adhesion molecule-1; EPO, eosinophil peroxidase; TNF, tumor necrosis factor; PG, prostaglandin; MBP,
major basic protein; HLA-DR, human leukocyte antigen-DR.
Assanasen and Naclerio
Antiallergic Anti-Inflammatory Effects 129
and vasoactive intestinal peptide (VIP) levels in nasal secretions, Shinoda and
colleagues performed a randomized, double-blind, parallel study in 40 subjects
with house dust allergy and 210 healthy subjects (116). Mean values of SP, but
not VIP, were significantly higher in the nasal allergy group than in the control
group. Patients with severe symptoms had significantly higher levels of SP and
VIP in nasal secretions than those in the control group. Oxatomide and azelastine
significantly reduced SP levels in nasal secretions, and VIP levels were sup-
pressed by 70%, although this did not achieve statistical significance.
The mechanism by which oxatomide decreases neuropeptides in nasal se-
cretions is unknown. Eosinophils from human peripheral blood were demon-
strated to contain significantly higher levels of SP and VIP than did neutrophils,
mononuclear leukocytes, and platelets (117). One possible mechanism for the
decrease of the neuropeptides in nasal secretions after oxatomide administration
might be the reduction of eosinophil infiltration into nasal secretions. This hy-
pothesis is supported by the study of Ciprandi and colleagues (118). Using
allergen-specific conjunctival challenge, they demonstrated that oxatomide sig-
nificantly decreased total numbers of inflammatory cells as well as the number
of single cell types (neutrophils, eosinophils, and lymphocytes) during the early-
and late-phase reactions.
M. Terfenadine
From an historical point of view, terfenadine was one of the first H 1-antagonists
to be investigated for antiallergic properties, and was one of the most compre-
hensively studied. Rarely, it caused cardiac toxicity, and regulatory approval
was withdrawn for it in most countries. In addition to its H 1-receptor antagonist
effects it also inhibits the anti-IgE-induced release of histamine, LTC4 , and PGD2
from human lung mast cells in vitro (119). After allergen challenge in subjects
with allergic rhinitis, pretreated with terfenadine, the following have been re-
ported: reduced symptoms, decreased histamine, kinins, albumin and TAME-
esterase activity, decreased inflammatory cell infiltrates and ICAM-1 expression
on nasal epithelial cells, and ECP in lavage fluid (120–125).
V. SUMMARY
Data from in vitro, in vivo, and ex vivo studies suggest that second-generation
antihistamines have a number of antiallergic, anti-inflammatory properties that
appear to be independent of their H 1-blockade activity. First-generation antihista-
mines also have antiallergic, anti-inflammatory properties, as suggested by the
studies with azatadine, chlorpheniramine, mepyramine, and promethazine; most
other first-generation antihistamines have not been studied for these properties.
130 Assanasen and Naclerio
In vitro studies have shown that H 1-antihistamines reduce the release of pro-
inflammatory mediators from mast cells and basophils, the chemotaxis and ac-
tivation of inflammatory cells (especially eosinophils), and the expression of
adhesion molecules induced by immunological and nonimmunological stimuli in
epithelial cell lines. Nasal allergen challenge models have similarly demonstrated
that H 1-antihistamines inhibit mediator release from mast cells and basophils, and
that they decrease inflammatory cell infiltration and the expression of adhesion
molecules on epithelial cells. The results of published studies of the effects of
H 1-antihistamines on nasal allergic inflammation in humans have been summa-
rized in this chapter. Recent investigations indicate that H 1-antihistamines may
modulate airway inflammation by downregulating the activity of airway epithelial
cells, which have an important role in allergic airway inflammation. The modula-
tion of adhesion molecules and of inflammatory cell infiltration by H 1-antihista-
mines may be beneficial during long-term treatment in patients with allergic rhini-
tis. The rationale for this hypothesis is the persistence of inflammation on the
nasal epithelial cells even when patients are symptom-free (16). All of the events
affected by H 1-antihistamines are important in the allergic inflammation cascade.
The underlying mechanisms for such effects remain unclear, but are unrelated
to H 1-antagonist activity. Several studies have demonstrated that H 1-antihista-
mines can form an ionic association with cell membranes and inhibit calcium
ion influx into the mast cell or basophil plasma membrane, or inhibit Ca 2⫹ release
within the cells, and may therefore influence the signal transduction pathways.
However, these effects appear to occur at concentrations higher than those
achieved in therapeutic practice (126–128). It has recently been hypothesized
that the anti-inflammatory activity of H 1-antihistamines may be a consequence
of their ability to influence the activation of genes responsible for the expression
and synthesis of proinflammatory mediators (129).
The contribution of the antiallergic effects of H 1-receptor antagonists to
their clinical efficacy is not fully understood. There have been no data suggesting
that H 1-antihistamines with well-documented antiallergic properties are superior
to the others for which such properties have not been as extensively investigated.
Additional studies are needed to elucidate the mechanisms(s) by which H 1-anti-
histamines exert anti-inflammatory effects. This knowledge might lead to the
development of novel therapies with more potent and specific anti-inflammatory
effects.
ACKNOWLEDGMENTS
This work was supported in part by NIH grant DC 02714 and Anandamahidol
King Scholarship.
Antiallergic Anti-Inflammatory Effects 131
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fen reduces sneezing but not histamine release following nasal challenge with anti-
gen. Clin Exp Allergy 1990; 20:701–705.
88. Kato M, Hattori T, Takahashi M, Yanagita N, Nakashima I. Eosinophil cationic
protein and prophylactic treatment in pollinosis in natural allergen provocation. Br
J Clin Pract 1994; 48:299–301.
89. Kato M, Hattori T, Kitamura M, Beppu R, Yanagita N, Nakashima I. Major basic
protein and topical administration of ketotifen in pollinosis under natural allergen
provocation. Otol Rhinol Laryngol 1995; 57:269–272.
90. Hampel FC Jr, Martin BG, Dolen J, Travers S, Karcher K, Holton D. Efficacy and
safety of levocabastine nasal spray for seasonal allergic rhinitis. Am J Rhinol 1999;
13:55–62.
91. Corren J, Rachelefsky G, Spector S, Schanker H, Siegel S, Holton D, Karcher K,
Travers S. Onset and duration of action of levocabastine nasal spray in atopic patients
under nasal challenge conditions. J Allergy Clin Immunol 1999; 103:574–580.
92. de Graaf-in’t Veld T, Garrelds IM, van Toorenenbergen AW, Mulder PG, Gerth
Antiallergic Anti-Inflammatory Effects 137
I. INTRODUCTION
141
142 Simons and Simons
Figure 2 Continued
CV, coefficient of variation; FL, fluorimetric; GLC, gas–liquid chromatography; HPLC, high-performance liquid chromatography; MS, mass spectrometry;
RIA, radioimmunoassay; UV, ultraviolet; NP, nitrogen phosphorous detector.
a
Can differentiate between parent compound and metabolites.
b
Cannot differentiate between parent compound and metabolites.
c
Not available in the United States at time of publication.
Simons and Simons
Clinical Pharmacology 147
Acrivastine 1.4 ⫾ 0.4 73/4 1.4–3.1 0.26 ⫾ 0.036 0.64 50 0.64/4 59/0
(none)c
Azelastine 5.3 ⫾ 1.6 1.5–12.5 µg-eq/L/4 22–27.6 0.54 ⫾ 0.19 14.5 78–88 47.3–405.9 2(3)/0
(desmethyl- (20.5) (54 ⫾ 15) µg-eq/4 (oral)
azelastine)
Cetirizine (none) 1.0 ⫾ 0.5 257/10 6.5–10 0.06 ⫾ 0.012 0.56 93 2.9/10 60/0
580/20 5.8/20
Desloratadine — 3/7.5 21–31 — — — 104/7.5 —
Ebastined (care- (2.6–5.7) (90–120)/10 (10.3– n/a (90–143 L) (98) (1.75–2.94)/10 (75–95)/0
bastine) (3.6 ⫾ 1.1) 19.3)
Fexofenadine 1–3 290–500/120,80 14.4 1.10 ⫾ 0.144 5.8 ⫾ 0.7 60–70 1.9–3.1/ 12/80
(none) 286/60–180 120,180
Levocabastine 1–2 1.4–2.2 po 35–40 1.8 L/h 1.14 55 — 65–70/20
(none) 0.26–0.29 n, o (po, iv)
33 (n, o)
Loratadine (des- 1.2 ⫾ 0.3 24.3–30.5/40 7.8 ⫾ 4.2 8.52 ⫾ 3.36 119 98 0.04–0.14/40 trace
carboethoxy- (1.5 ⫾ 0.7) (6.7–30.5)/40 (24 ⫾ 9.8) (n/a) (73–76) (0.14–0.39)/40
loratadine)
Mizolastined 1.5 276/10 12.9 0.69 1.4 98 — 0.5/0
(none)
peak plasma drug concentration; t1/2β, terminal elimination half-life; Vd, volume of distribution.
Clinical Pharmacology 149
antagonists being studied, are generally excluded from phase II and III clinical
trials.
B. Pharmacokinetics
1. Extensively Metabolized H1-Antihistamines
Some new H1-antagonists such as azelastine, ebastine, loratadine, and mizolastine
undergo extensive metabolism in the cytochrome P-450 (CYP-450) system in
the liver and/or gastrointestinal tract, which can affect rate and/or extent of ab-
sorption due to gut metabolism, active transport, and first-pass hepatic extraction.
After ordinary single oral doses, the plasma concentration of the parent compound
is low, in contrast with a high concentration of the metabolite(s). Compared with
the values found in healthy young adults, t1/2 β values for these H1-antagonists
may differ in children (10, 11, 77, 115, 116), the elderly (32, 78, 117, 139), in
patients with hepatic dysfunction (34, 80), or renal insufficiency (34, 79, 118),
or those concomitantly receiving macrolide antibiotics, imidazole antifungals,
cimetidine, or other medications eliminated by the CYP-450 system (33, 83, 107,
123–126, 140). A reduction of the dose or an increased interval between doses
may be required (Table 3).
For research purposes, patients who are extensive metabolizers or poor
metabolizers can be identified by phenotyping hepatic enzymes, such as CYP3A4
or CYP2D6 in vitro or in vivo. H1-antagonist metabolism and medication interac-
tions can also be studied in vitro using human liver tissue slices, hepatocytes,
hepatoma cells, microsomal preparations, or purified recombinant fusion proteins
containing CYP-450, with some accuracy in prediction of the in vivo response
(82, 121, 122).
b
Not available in the United States at time of publication.
AUC, area under the concentration–time curve; Cmax , peak plasma drug concentration after single-dose administration; CYP, cytochrome P-450; tmax , time
to reach peak concentration following drug administration; t1/2β, elimination half-life; ↑, increase; ↓, decrease.
Clinical Pharmacology 151
under the concentration–time curve (AUC) is such that dosage adjustments usu-
ally are not necessary (34, 51–54, 95, 96, 106).
Fixed-dose H1-antagonist/pseudoephedrine combination medications are
widely used, and medication interaction studies with H1-antagonists and pseudo-
ephedrine are, therefore, of interest. This is especially true of the H1-antagonists
that are eliminated largely unchanged in the urine, since this is also the primary
route of elimination for pseudoephedrine (23, 113, 120).
C. Pharmacodynamics
1. Wheal-and-Flare Model
Understanding the relationship between plasma H1-antagonist concentration and
the intensity of the H1-antagonist effect is facilitated by objective assessments of
the suppression of the histamine-induced wheal-and-flare response in the skin
(14, 15, 18, 24, 25, 35, 36, 38, 46, 49, 55–59, 77, 85, 93, 98–100, 127–132, 143–
145, 147), or the antigen-induced wheal-and-flare response, to which histamine is
the major contributor. H1-antagonists decrease the size of the wheal directly by
decreasing postcapillary venule permeability and leakage of plasma protein, and
they decrease the size of the flare indirectly by blocking the histamine-induced
axon reflex. Using a standardized wheal-and-flare bioassay, dose–response
curves can be identified for an H1-antagonist. Significant differences in onset,
potency, and duration of activity among H1-antagonists can be identified during
the first 24 h after administration (14, 15) (Figs. 2, 4).
Figure 5 H1-activity on the nasal mucosa produced by intranasal and oral H1-antihista-
mines. In a double-blind, single-dose, crossover study, healthy individuals received either
azelastine nasal spray 0.254 mg/nasal cavity, or oral cetirizine 10 mg, or placebo. Hista-
mine challenges (40 and 400 µg/L) were given 1 h before, and 1, 6, 9, 12, and 24 h after,
treatment. α2-Macroglobulin in the nasal lavage fluid was measured as a marker of in-
creased vascular permeability and exudation of bulk plasma onto the nasal mucosa. From
1 to 12 h after administration, azelastine or cetirizine, but not placebo, decreased the hista-
mine-induced mucosal exudation of plasma, as shown by a significant decrease in the α2-
macroglobulin marker (1 h results shown). (From Ref. 16.)
lites in tissue is probably important, although they have not been directly mea-
sured there.
4, 5). For some H1-antagonists, the duration of action may be even longer in the
elderly and in patients with hepatic or renal dysfunction, and may necessitate a
reduced dosage or dose frequency of some H1-antagonists in these populations
(Table 3).
The residual action of an H1-antagonist is defined as the pharmacological
effects that last for days or weeks after the medication has been discontinued. This
is clinically relevant information because it defines the time during which an H1-
antagonist must be discontinued before allergen skin tests or inhalation challenge
tests with allergen or histamine can be performed with acceptable clinical accuracy.
Most H1-antagonists need to be discontinued 2–7 days before these tests.
Residual
Clinical Pharmacology
Figure 7 H1-activity does not diminish during regular daily administration of an H1-
antihistamine. In a double-blind, placebo-controlled, parallel study in 60 patients with
atopy, mizolastine 10 mg/day was given for 8 weeks. Epicutaneous (puncture) tests with
histamine chlorhydrate 10 mg/mL, codeine phosphate 9%, or allergen (five incremental
concentrations of orchard grass pollen or house dust mite) were performed 2 h after the
mizolastine or placebo dose on 6 test days at least 1 week apart (7 days before the first
dose, immediately before the first dose, and on the 7th, 28th, 42nd, and 56th day of admin-
istration). Suppression of the wheals and flares induced by all three agents was maintained
throughout the study. The figure shows the changes from baseline in patients with allergen-
induced skin reactions during placebo and mizolastine treatment, all concentrations of
both types of treatment being considered together (intergroup comparisons by MANOVA,
p ⫽ 0.0001). The model incorporates treatment, allergen, and interaction. (From Ref. 147.)
158 Simons and Simons
A. Acrivastine
1. Pharmacokinetics
Absorption of acrivastine (19–25) is rapid after oral administration. In healthy
individuals, the mean Cmax is 73 µg/L, achieved at a mean time of 1.4 ⫾ 0.4 h
after administration of acrivastine 4 mg (Table 2). Absorption is not significantly
decreased by the concomitant ingestion of food. During administration of acrivas-
tine three times daily for 7 days, accumulation does not occur (19–23).
The mean apparent Vd is 0.64 and 0.75 L/kg after single and multiple
doses, respectively. Acrivastine is approximately 50% protein-bound.
The principal acrivastine metabolite, a propionic acid analog formed by
reduction of the acrylic acid side chain, accounts for about 10% of the total
plasma concentration and for between 15 and 17% of the dose recovered in the
urine. It is more active than the parent compound in vitro. Unchanged acrivastine
accounts for 59% of the administered dose recovered in the urine. After a single
8 mg dose of [14C]acrivastine, 88% of the ingested radioactivity is recovered in
the urine within 48 h; the remainder is excreted in the feces within 5 days.
After single or repeated doses, the apparent total body clearance is 0.26 L/
h/kg and t1/2 β ranges between 1.4 and 3.1 h. The mean t1/2 β of the metabolite
is 2.3 h (19, 21, 22).
In 36 elderly volunteers (aged 65–75 years) receiving acrivastine 8 mg or
16 mg three times daily for 22 doses, a 25% decrease in clearance, a 35% increase
in t1/2 β and time to Cmax (tmax), and a doubling of the AUC have been reported
(Table 3). There is minimal information about the pharmacokinetics of acrivas-
tine in children or in patients with impaired renal or hepatic function. Acrivastine
is generally formulated in a fixed-dose combination with pseudoephedrine; there
are no pharmacokinetic interactions between the H1-antagonist and the deconges-
tant. There is also minimal information on interactions between acrivastine and
other coadministered medications (19, 23).
2. Pharmacodynamics
After administration of acrivastine, suppression of the histamine-induced wheal
and flare begins within 30 min (Table 4), and peaks at between 1.5 and 2 h (19,
24, 25). The duration of action is shorter than that of any other new H1-antagonist.
Acrivastine 4 mg, but not 2 mg, reduces the response to histamine in nasal chal-
Clinical Pharmacology 159
B. Azelastine
1. Pharmacokinetics
It is not possible to perform pharmacokinetic studies after the administration
of a single dose of the nasal formulation of azelastine (26–39), as the plasma
concentrations of the parent compound and its pharmacologically active major
metabolite, desmethylazelastine, are below 0.25 µg/L, the lowest limit of detec-
tion using the HPLC assay available (Table 1). Using the older radioimmunoas-
say, at steady-state, after intranasal administration of 0.56 mg (4 puffs) daily for
29 days, the Cmax is 0.306 µg/L, the tmax is 2.5 h, and the steady-state plasma
concentration is 0.26 µg/L in healthy individuals and 0.65 µg/L in those with
allergic rhinitis. These plasma concentrations are considerably lower than the
Cmax of 1.5–12.5 µg/L achieved 4–5 h after azelastine 4 mg by mouth (Table 2).
Systemic bioavailability is 40%; after intranasal administration, systemic expo-
sure is estimated as six to eight times lower than after oral administration of
azelastine 4 mg.
Using the new HPLC assay and measuring only the parent compound azel-
astine, the Cmax is 5.9 µg/L, and tmax is 5.3 h.
The Vd of azelastine at steady-state is 14.5 ⫾ 4.0 L/kg and it is 78–88%
bound to plasma proteins.
Azelastine is almost completely metabolized by hepatic oxidation. After
intranasal administration to steady-state, plasma concentrations of desmethyl-
azelastine account for 20–50% of total measurable concentrations of azelastine
and its metabolites. Additional metabolites include the 2- and 7-acid derivatives
formed by oxidation and subsequent azepinyl ring opening. Following adminis-
tration of a single oral dose of [14C]azelastine, 75% of the radioactivity is recov-
ered within 120 h: 50% in the feces and 25% in the urine. HPLC analysis of
urine reveals that 2% of an azelastine dose is eliminated as parent compound
and 3% as desmethylazelastine.
The pharmacokinetics of azelastine are similar when determined after oral
or intravenous administration. In single-dose studies, the t1/2β is 22 ⫾ 4 h for
azelastine and 54 ⫾ 15 h for desmethylazelastine. At steady-state after multiple
oral doses of 4 mg twice daily, the t1/2β is reported as 35.5 h (27, 29–31).
There is minimal information on the pharmacokinetics of the nasal or oph-
thalmic formulations of azelastine in children, in patients with hepatic or renal
dysfunction, or in those concomitantly taking other medications. The pharmaco-
160 Simons and Simons
kinetics of orally administered azelastine have been studied in the elderly (mean
age, 70 years) in whom elimination is decreased, leading to a doubling of plasma
concentrations during multiple doses; a 50% reduction of the oral dose is required
in this population (32) (Table 3). In patients with mild or moderate hepatic or
renal dysfunction, azelastine elimination is not greatly affected and dose reduc-
tions are not considered necessary (34).
2. Pharmacodynamics
Azelastine administered intranasally before challenge with histamine or allergen
decreases sneezing and other symptoms (16, 26, 27, 35–39) and also decreases
α2-macroglobulin concentrations in nasal lavage fluid, providing direct evidence
of histamine blockade on postcapillary venules and prevention of vascular leak
(16) (Fig. 5). Azelastine nasal spray administration, 0.14 mg/nostril twice daily
for 1 week, has no suppressive effect on histamine-induced wheals and flares in
the skin, suggesting that there is little systemic absorption.
Orally administered azelastine has a dose-related suppressive effect on his-
tamine-induced wheals and flares (Table 4), on histamine-induced nasal obstruc-
tion as measured by posterior rhinomanometry, and on histamine-induced bron-
choconstriction in patients with asthma in whom it also has a dose-related
bronchodilator effect. Tachyphylaxis to azelastine has not been reported.
C. Cetirizine
1. Pharmacokinetics
After oral administration of a 10 or 20 mg dose, cetirizine (40–62) is rapidly
absorbed from the gastrointestinal tract, with a mean Cmax of 257 and 580 µg/L,
respectively, achieved in 1 h (Table 2). Concurrent ingestion of food may de-
crease the rate but not the extent of absorption.
The Vd of cetirizine, 0.56 L/kg, is low compared with that of the other
H1-antagonists. At 24 h after a single dose and at steady-state, skin cetirizine
concentrations are similar to, or exceed, serum concentrations (56). Plasma pro-
tein binding is reported to be 93% at plasma concentrations of 25–1000 µg/L.
Approximately 60% of the administered dose is recovered unchanged in
the urine within 24 h. Renal excretion involves an active transport mechanism.
Steady-state concentrations are achieved within 3 days. During long-term admin-
istration, no accumulation occurs and the rate of elimination does not change
(40, 43–45).
After administration of [ 14C]cetirizine, more than 90% of plasma radioac-
tivity is attributed to unchanged cetirizine at 2 h, 80% at 10 h, and 70% at 24
h. Small amounts of a metabolite produced by oxidative O-dealkylation appear
in the plasma at 10 h and in the feces from 24 to 48 h. About 50% of the adminis-
Clinical Pharmacology 161
tered radioactivity is excreted in the urine during the first 24 h after administra-
tion, and a further 10% is excreted in the next 4 days. The major source of urinary
radioactivity is unchanged cetirizine, accounting for 93% of the radioactivity dur-
ing the first 2 h after administration and 83% from 12 to 24 h postdose. The
remaining radioactivity is attributable to small amounts of unidentified metabo-
lites (43).
Mean t1/2β values for cetirizine are 6.5–10 h after a single 10 mg dose in
healthy adults. In children with a mean age of 8 years, the t1/2β is approximately
7 h (Fig. 2); in those with a mean age of 2–4 years, it is 4.9 h; and in infants
with a mean age of 12 months, it is 3.1 h. In infants and children, only 40% of
cetirizine is eliminated unchanged in the urine (46–49).
In the elderly (mean age, 75 ⫾ 11 years), the mean t1/2β of cetirizine is
11.8 h (Table 3); this slight prolongation is associated with significant reduction
in total body renal clearance and apparent nonrenal clearance, and is dependent
on renal function rather than age (50, 51).
In patients of any age with moderate renal dysfunction, the tmax is increased
to 2 h, and the t1/2β is increased to 20–20.9 h. Less than 10% of a dose of cetirizine
is removed by hemodialysis. In patients with impaired hepatic function, the clear-
ance rate is 0.018 L/h/kg (0.3 mL/min/kg), the fraction of the dose excreted
unchanged in the urine (32% after 96 h) is significantly reduced compared with
values obtained in healthy individuals, and the t1/2β is between 13.8 and 14.3 h.
These alterations in the pharmacokinetics are clinically relevant and dose reduc-
tion is suggested in these patients (51–54). Cetirizine elimination is not inhibited
by concomitant administration of other medications such as cimetidine (55).
2. Pharmacodynamics
Cetirizine 10 mg suppresses the histamine- or allergen-induced wheal and flare
response rapidly with a significant effect in 30 to 40 min, and a peak effect 4 to
8 h after administration (14–18, 40, 46, 49, 55–62) (Table 4). Significant suppres-
sion lasts for at least 24 h in adults and children; in infants, it only lasts for 12 h.
The comparative suppressive effects of cetirizine and other H1-antagonists have
been extensively studied (14, 15) (Fig. 4). Cetirizine is more effective than other
antihistamines in suppressing the wheals and flares induced by epicutaneous his-
tamine phosphate 1, 10, or even 100 mg/mL, the concentrations generally used
in this pharmacodynamic model.
Cetirizine also has favorable pharmacodynamics in the upper airway (16,
17) and lower airways (18, 62). It provides dose-dependent protection against
histamine-induced bronchospasm in patients with mild asthma (62).
Patients taking cetirizine regularly should discontinue it 3–4 days before
having skin tests with histamine or allergen. Tachyphylaxis to cetirizine has not
been reported.
162 Simons and Simons
D. Desloratadine
1. Pharmacokinetics
Plasma concentrations of desloratadine (63–72) and its active metabolite 3-hy-
droxy-desloratadine are determined by liquid chromatography/mass spectrometry
with a lower limit of quantitation of 0.025 µg/L (Table 1). Desloratadine has
excellent bioavailability in fasted and in fed subjects (64). It exhibits linear phar-
macokinetics over the dose range 5–20 mg. After a single dose of 7.5 mg and
after multiple dosing with 7.5 mg daily for 14 days, the Cmax is approximately
5.5–10.2 µg/L and the t1/2β is 21–31 h (Table 2). No dosage adjustment is needed
for race or sex (67). Although some increases in the AUC and in Cmax are observed
when desloratadine is administered concomitantly with either erythromycin or
ketoconazole, no clinically important pharmacokinetic changes and no electrocar-
diographic changes are observed (68, 69) (Table 3).
2. Pharmacodynamics
No wheal-and-flare studies with desloratadine have been published to date.
E. Ebastine
1. Pharmacokinetics
After oral administration, ebastine (73–86) undergoes extensive first-pass metab-
olism to its active carboxylic acid metabolite, carebastine. The parent compound
is present in extremely low concentrations in plasma, and pharmacokinetic stud-
ies are based on the measurement of carebastine (Table 1, Fig. 2). After ingestion
of ebastine 10 mg, the carebastine Cmax of 90–120 µg/L was obtained at 2.6–
5.7 h (Table 2), with some variations according to race. The values for the AUC
range from 1.75 to 2.94 mg/L/h. Extrapolating from plasma carebastine concen-
trations, ebastine seems to be readily absorbed and food ingestion increases bio-
availability.
Carebastine has a Vd of 90–143 L, and is 98% bound to plasma proteins.
In human studies, 40% of the radioactivity from labeled ebastine is recovered in
urine and 6% in feces over 24 h, increasing to 71% and 28%, respectively, over
312 h. The t1/2 β of carebastine is 10.3–19.3 h in single-dose studies and in multi-
ple-dose studies over 7 days. The pharmacokinetics of carebastine appear to be
linear following ebastine doses of 10–90 mg. During once-daily multiple-dose
administration of ebastine, the Cmax of carebastine increases 1.6–1.7-fold, but the
AUC24 does not change at steady state, reached by days 3–5 (73–76).
In a multiple-dose study in which ebastine 10 mg was given daily for 9
days to elderly adults age 65–75 years, no significant differences in mean steady-
state pharmacokinetic parameters were found, compared to young adults (Table
Clinical Pharmacology 163
2. Pharmacodynamics
Ebastine has a dose-related suppressive effect (15, 86) on the histamine-induced
wheals and flares over the range of 3–30 mg (61, 73, 77, 85). After a single dose,
the maximum suppressive effect occurs at 6–8 h, and significant suppression is
still present at 24 h (Table 4). The comparative suppressive effects of ebastine
and other new H1-antagonists are shown in Figure 4 (15).
A single oral dose of ebastine 10 mg or 30 mg, administered before bron-
chial challenge with histamine, shifts the dose–response curve 3- to 27-fold.
There is a good correlation between plasma carebastine concentrations and sup-
pression of the histamine-induced wheals and flares, or suppression of histamine-
induced bronchoconstriction. After a short course of ebastine, the residual effect
lasts for 3–4 days. Tachyphylaxis to ebastine has not been reported.
F. Fexofenadine
1. Pharmacokinetics
Fexofenadine (87–102) is readily absorbed when administered orally, with Cmax
reached between 1 and 2.6 h after administration (Table 2). Absorption is not
markedly affected by food (89). Bioavailability is reported as being at least 33%
(90). In equilibrium dialysis studies, 60–70% of plasma fexofenadine is protein-
bound, predominantly to albumin and α1-acid glycoprotein.
During the 24 h after a single dose of fexofenadine 120 mg, and at steady-
state, skin fexofenadine concentrations exceed plasma concentrations (99) (Fig.
6).
The primary pathways of elimination of fexofenadine are biliary and renal
excretion, and there is no evidence of significant biotransformation. In a study
in which healthy volunteers were given fexofenadine 60 mg twice daily for 4
days to achieve steady-state and then received a single 60 mg oral dose of
[ 14C]fexofenadine, 80% of the dose was recovered in an unchanged form in the
feces and 12% in the urine. The only other substances recovered in urine and
feces are azacyclonol, an inactive degradation product, and fexofenadine methyl
164 Simons and Simons
2. Pharmacodynamics
The effectiveness of a single oral dose of fexofenadine (15, 87, 88, 93, 97, 101)
in inhibiting the histamine-induced skin wheal and flare response has been studied
over a dose range of 20–800 mg. Doses of ⱖ40 mg produce significant suppres-
sion of wheals and flares 2 h after administration (Table 4). An 80 mg dose of
fexofenadine is said to be equivalent to a 60 mg dose of the parent compound,
terfenadine. Peak suppression occurs from 3 to 12 h, and suppression is still
significant at 24 h. The comparative suppressive effects of fexofenadine and other
new H1-antagonists are shown in Figure 4 (15). In the skin wheal-and-flare model
and in the nasal challenge model, fexofenadine has a prompt onset of action (98–
101).
When fexofenadine is given for a week and then discontinued, the residual
effect lasts for only 2 days. Tachyphylaxis to fexofenadine has not been re-
ported.
Clinical Pharmacology 165
G. Levocabastine
1. Pharmacokinetics
In healthy individuals, absorption of levocabastine (103–107) from nasal or oph-
thalmic formulations occurs within 1 to 2 h (Table 2) and bioavailability is
between 60 and 80%, and between 30 and 60%, respectively. Swallowed levoca-
bastine may contribute to the overall systemic availability of the nasal spray.
Steady-state plasma concentrations, achieved in 7–10 days, are approximately
10.4 µg/L after two nasal sprays (50 µg/spray) per nostril three times daily, and
1.6 µg/L after application of a 0.05% ophthalmic suspension, 1 drop (15 µg) per
eye three times daily. Steady-state plasma concentrations with the nasal spray
are lower in patients with allergic rhinitis (3.5 to 5.2 µg/L) than in healthy indi-
viduals; this is in contrast to azelastine, which is absorbed to a greater extent by
those with allergic rhinitis.
After application to the nasal mucosa or the eyes in nursing mothers, minute
amounts of levocabastine have been detected in breast milk.
The pharmacokinetics of levocabastine have also been studied after oral
and intravenous administration; these formulations are not used clinically because
of sedative effects. After oral administration, Cmax is attained within 2 h and sys-
temic bioavailability is 100–120%, indicative of a negligible first-pass effect. At
steady-state, intravenously administered levocabastine has a mean Vd of 82 L
(1.14 L/kg). The plasma protein binding is approximately 55%.
Levocabastine undergoes little hepatic metabolism; 65–70% of absorbed
levocabastine is excreted in the urine as unchanged drug and 10–20% appears
unchanged in the feces, probably because of biliary excretion. The remainder is
recovered in the urine as the acylglucuronide metabolite.
After single or repeated doses, the t1/2β of levocabastine is between 35 and
40 h, regardless of the route of administration. In patients with renal impairment,
orally administered levocabastine has an increased t1/2 β of 95 h and a 56% in-
crease in the AUC; urinary excretion of unchanged levocabastine is reduced (Ta-
ble 3). Although hemodialysis removes 10% of a dose of levocabastine, it does
not alter the effect of impaired renal clearance on pharmacokinetics. There is
minimal information on topically administered levocabastine in patients with re-
nal impairment and on levocabastine administered by any route in children, the
elderly, or in patients with hepatic impairment (106). No medication interactions
have been reported (107).
2. Pharmacodynamics
Topically applied levocabastine (103, 104) prevents histamine- or allergen-in-
duced nasal or conjunctival symptoms. Levocabastine nasal spray or levocabas-
tine eye drops administered regularly have no significant suppressive effects on
166 Simons and Simons
H. Loratadine
1. Pharmacokinetics
Loratadine is well absorbed following oral administration (108–126), with peak
plasma concentrations of 24.3–30.5 µg/L occurring 1–1.5 h after ingestion of a
40 mg dose (111–114) (Table 2). Concurrent ingestion of food decreases the rate
but not the extent of absorption. Steady-state is achieved by the fifth day of multi-
ple dosing.
Loratadine has a large Vd of 119 L/kg and is 97–99% plasma protein-
bound. It is extensively metabolized by hydroxylation by the CYP3A4 family to
descarboethoxyloratadine (DCL). After administration of single doses of 20–40
mg, its mean distribution and terminal elimination (t1/2 β) half-life values are 0.9–
1.0 h and 7.8–11 h, respectively. At steady-state, after administration of 40 mg
daily for 10 days, the distribution half-life does not change, and the t1/2 β is 14.4
h; little accumulation occurs. The major metabolite, DCL, has a mean t1/2 β of
17.3–24 h (14.4–18.7 h at steady-state). It is 73–76% protein-bound. It is further
converted to an inactive metabolite excreted primarily in the urine. Like its parent
compound, DCL has dose-proportional pharmacokinetics and does not accumu-
late to any extent during multiple-dose administration.
In children, the t1/2 β of DCL arising from loratadine in vivo is 13.8 h. In
healthy elderly individuals, the mean t1/2 β of loratadine and DCL are 18.2 and 17.5
h, respectively. In patients with impairment of renal or hepatic function, although
there may be increases in Cmax and AUC for loratadine and DCL, the rate of elimina-
tion is not significantly decreased (115–118). Loratadine is one of the few H1-
antagonists for which elimination in breast milk has been optimally investigated:
a 4 kg infant is estimated to receive 0.46% of a 10 mg maternal dose (119).
Potential pharmacokinetic interactions of loratadine and other medications
have been extensively studied (120–126). In the presence of CYP3A4 inhibitors,
loratadine is also metabolized by CYP2D6. Coadministration of ketoconazole
200 mg twice daily for 5 days in 12 healthy volunteers inhibited the metabolism
of a single 20 mg oral dose of loratadine, as did coadministration of erythromycin
or cimetidine; however, these findings are of minimal clinical relevance. The
pharmacokinetics of loratadine are not influenced by concomitant administration
of pseudoephedrine.
2. Pharmacodynamics
Loratadine 10 mg suppresses histamine-induced wheals and flares significantly
within a few hours, and the suppression lasts for 12–24 h (14, 15, 127–130)
(Table 4). The comparative suppressive effects of loratadine and other new H1-
Clinical Pharmacology 167
antagonists are shown in Figure 4 (15). In the wheal-and-flare model, and in the
nasal challenge model (17), significant suppression begins a few hours later after
loratadine than after some other H1-antagonists; however, the data obtained in
studies with a duration of only 24 h are not necessarily reflected in allergic rhinitis
studies lasting several weeks. Loratadine also prevents the bronchoconstrictor
response to histamine or allergen (132, 133).
After a short course of loratadine, the residual effect lasts for less than 1
week. Tachyphylaxis to loratadine has not been reported (131).
I. Mizolastine
1. Pharmacokinetics
Mizolastine is rapidly absorbed with a mean Cmax of 276 µg/L and a median tmax
of 1.5 h (134–142) (Table 2). Bioavailability is 65.5% and is not affected by age
or concomitant ingestion of food or alcohol. Linear dose–response curves are
observed for Cmax and AUC over the dose range 5–20 mg. The Vd of mizolastine
after intravenous administration is 1.4 L/kg, reflecting its low lipophilicity (log
P ⫽ 2.9 at pH ⫽ 7.4). It is 98.4% protein-bound in plasma.
Mizolastine is extensively metabolized, with less than 0.5% of the adminis-
tered dose excreted unchanged in the urine. After administration of [ 14C]mizolas-
tine to humans, 84–95% of the radioactivity is excreted in the feces. The main
metabolic pathway is glucuronidation of the parent compound (66% of the admin-
istered dose). In vitro studies with specific metabolic inhibitors have shown
CYP3A4 and CYP2A6 to be responsible for the oxidation pathways. No active
metabolites have been identified (134, 135).
The distribution half-life is 1.9 h and the t1/2 β is 12.9 h. Systemic plasma
clearance is 0.69 L/h/kg and does not change with repeated once-daily oral ad-
ministration of mizolastine for 5 or 14 days. Steady-state is reached on the third
day of administration and accumulation does not occur (137, 138).
In the elderly (aged 66–77 years), Cmax is lower and apparent t1/2 β slightly
longer than in young healthy individuals (Table 3). In patients with renal disease,
the t1/2 β of mizolastine is prolonged by 47%, but values remain within the
range found in healthy young volunteers, and no dose adjustments are necessary
(139).
Mizolastine is not cleared by hemodialysis. In patients with hepatic cirrho-
sis, tmax is delayed and Cmax is 35% lower than in healthy volunteers, but the
t1/2 β is similar.
Mizolastine has no effect on the pharmacokinetics of theophylline, digoxin,
R⫺(⫹)⫺ and S⫺(⫺)⫺ warfarin or diltiazem. In the in vitro human hepatocyte
model, there are minimal interactions between mizolastine and ketoconazole, and
none between mizolastine and erythromycin; however, incubation of mizolastine
168 Simons and Simons
2. Pharmacodynamics
Mizolastine 10 mg suppresses histamine-induced wheals and flares significantly
within 1 h of administration (Table 4). Peak effect occurs from 3 to 12 h, and
suppression is still significant at 24 h (134, 135, 137, 143–147). Mizolastine has
been measured in skin blister fluid (143). It also produces dose-related bronchodi-
lation and protection against histamine-induced bronchoconstriction.
There is minimal information about the residual effects of mizolastine.
Tachyphylaxis to mizolastine has not been reported. The suppressive effect of
mizolastine on wheals and flares induced by histamine, codeine, or allergen re-
mains highly significant after 3 months of regular administration (147) (Fig. 7).
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178 Simons and Simons
Peter Howarth
University of Southampton, Southampton, England
I. INTRODUCTION
H1-receptor antagonists have been the mainstay of therapy for allergic rhinitis
since they were first introduced for clinical use, following the demonstration by
Staub and Bovet in 1937 that this class of compounds, newly developed at that
time, protected against allergen-induced anaphylaxis (1). The experimental use
of antihistamines in allergic disease was a natural sequel to the suggestion by
Dale that histamine was central to immediate anaphylaxis (2) and the demon-
strated release of histamine following allergen exposure in vitro (3, 4). The rela-
tionship between rhinitis and conjunctivitis symptoms and allergen (grass pollen)
exposure in ‘‘hay fever’’ sufferers was established at the end of the 19th century
(5).
Although observational studies reported symptom relief in allergic rhino-
conjunctivitis with use of the earliest antihistamines, the widespread acceptance
of these medications was limited by their adverse pharmacological effects such
as sedation, dry mouth, and blurred vision. In addition, there was concern that
asthma, a condition often associated with rhinitis, might be worsened by anti-
histaminic therapy (6, 7). This concern was compounded by the reports from
in vitro studies that antihistamines might potentiate mast cell degranulation (8).
Careful subsequent studies, however, did not confirm the bronchoconstrictor
effects of H1-antihistamines. Indeed they suggested that bronchodilatation (9,
10) and the in vitro effects identified only at high (suprapharmacological) con-
179
180 Howarth
B. Conjunctivitis
The cellular changes in allergic conjunctivitis are similar to those identified in
allergic rhinitis, involving mast cells, eosinophils, and T lymphocytes. In the
healthy conjunctiva, although eosinophils are rarely evident, mast cells are a nor-
mal constituent with an estimated 5000–6000 mast cells/mm3, usually found be-
low the basement membrane in the substantia propria (27). Mast cells are not
usually found in the normal epithelium of the bulbar or tarsal conjunctiva (28,
29). In allergic conjunctivitis mast cells increase in number and infiltrate into the
epithelium (29, 30). Eosinophils are also recruited into the conjunctival tissue
and can be identified both in the substantia propria and the epithelium (29). T
lymphocytes are found in the epithelium and substantia propria of normal con-
junctiva (28), consistent with their ‘‘immunological policing role.’’ As in rhinitis,
their levels are only increased in severe chronic disease, such as keratoconjuncti-
vitis (31). T cells, cloned from conjunctival biopsies of patients with vernal kera-
toconjunctivitis, have been shown to have a cytokine profile compatible with a
T helper (Th2) subset (32).
Histamine is present in normal tears (5 ng/mL) and levels are elevated
in vernal keratoconjunctivitis (16 ng/mL), in which there is severe conjunctival
inflammation (33). As in rhinitis, it has been more difficult to detect histamine
increments in milder forms of conjunctivitis or indeed after conjunctival allergen
challenge; however, it has been demonstrated that histaminase is present in hu-
man tears. With inactivation of this enzyme, it has been possible to demonstrate
acute increments in tear levels of histamine following conjunctival allergen chal-
lenge in sensitized individuals (33).
ing immediate nasal itching, sneezing, and rhinorrhea as well as causing nasal
obstruction (34). Following single-nostril application of histamine, the rhinorrhea
is bilateral, indicative of reflex neuronal stimulation. The nasal itching and sneez-
ing are also neuronally mediated, due to stimulation of histamine-sensitive affer-
ent receptors, while nasal obstruction is vascular in origin. Histamine exerts sev-
eral different effects on the nasal vasculature. It increases mucosal blood flow
(35), enhances vascular permeability (36), inducing plasma protein exudation
from fenestrated superficial capillaries, and produces nasal venous engorgement
through its regulatory effects on the nasal capacitance vessels. By increasing
turbinate volume, this latter effect reduces nasal airflow and increases nasal air-
ways resistance.
The neuronal effects of histamine are H1-receptor-mediated: specific H1-
receptor antagonism prevents histamine-induced nasal itch, sneeze, and rhinor-
rhea (37). The receptor regulation of the nasal vascular effects is less precise. H1-
receptor blockade can prevent histamine-induced nasal vascular plasma protein
leakage (Fig. 1), suggesting a specific H1-receptor effect in this regard (36). Hista-
Figure 1 The influence of topical azelastine (0.254 mg per nasal cavity), topical pla-
cebo, and oral cetirizine (10 mg) on histamine- (40 µg/ml and 400 µg/ml delivered in
nasal pool device) induced increments in α2-macroglobulin as an index of induced plasma
protein exudation in 12 healthy subjects. ■, azelastine; , cetirizine; 䊐, placebo. *p ⬍
0.05, **p ⬍ 0.01. Challenge was undertaken 1 h after drug pretreatment. (From Ref.
36.)
184 Howarth
mine H2-receptor antagonism can also partially reduce plasma protein exudation
(38). This effect may be indirect due to a regulatory effect on mucosal blood flow,
however, since within the skin, H2-receptor stimulation causes vasodilatation and
within the nose H2-receptor antagonism reduces the increase in mucosal blood
flow in response to allergen (39). An H2-receptor antagonist, by reducing mucosal
blood flow, would indirectly limit the potential plasma protein exudation from
the superficial mucosal capillaries.
Both H1- and H2-receptor antagonists also modify histamine-induced nasal
obstruction (38). Their combined effects have been reported to be greater than
with either administered alone, although, in general, there is little additional
benefit, particularly in reducing histamine-induced nasal blockage (38, 40).
This limited effect in inhibiting histamine-induced nasal blockage could relate
to the histamine-induced kinin generation shown to occur within the nose (41);
however, since kinins also induce nasal blockage (42) as well as promoting
plasma protein leakage (43), this is unlikely as H1-receptor blockade completely
inhibits plasma protein extravasation (38). More probable is an effect of histamine
on H3-receptors. In rodents, H3-receptors have been identified on presynaptic peri-
vascular nerve terminals, where they regulate sympathetic tone (44). Since the
nasal vasculature is under sympathetic tone, with stimulation inducing constric-
tion, inhibition of this effect by H3-receptor activation would lead to vasodila-
tation and nasal venous engorgement. Thus, the nasal obstruction that is not
H1- or H2-receptor-mediated following nasal histamine insufflation is likely to be
H3-receptor-mediated.
Histamine may also contribute to the recruitment of cells that characterize
allergic mucosal inflammation. In cultured human umbilical vein endothelial
cells, histamine upregulates the expression of the cell adhesion molecule P-selec-
tin (45). It has been proposed that P-selectin, which induces a rolling margination
of leukocytes when upregulated on the vascular endothelium, is critical to tissue
eosinophil recruitment (46). In vivo studies in rodents have demonstrated that
histamine-induced rolling margination is inhibited by a P-selectin antibody and
that the mobilization of P-selectin onto the vascular endothelium by histamine
is mediated by H1- rather than H2-receptors (47). Histamine H1-receptors also
appear to be relevant to the epithelial expression of the adhesion molecule, inter-
cellular adhesion molecule-1 (ICAM-1), since terfenadine has been shown to
reduce epithelial ICAM-1 expression in pollen-sensitive patients during seasonal
pollen exposure (48). In addition to promoting eosinophil–endothelial adherence,
histamine will contribute to eosinophil activation (49). This action is H3-receptor-
mediated: the H3-receptor antagonist thioperamide, but not the H1- or H2- receptor
antagonists pyrilamine or cimetidine, respectively, prevents histamine-induced
eosinophil activation (49). It is thus apparent that histamine can contribute to
many of the features of allergic rhinitis.
Rhinoconjunctivitis 185
B. Conjunctivitis
Instillation of histamine into the conjunctival sac reproduces many of the features
of allergic conjunctivitis. Itching, lacrimation, hyperemia, and conjunctival
edema occur rapidly after histamine instillation. Investigation of the effects of
the topical H1-receptor antagonist levocabastine identified that itching, tearing,
redness, and conjunctival edema are all H1-receptor-mediated (50). In guinea pigs,
the inhibition of histamine-induced conjunctival edema by levocabastine has been
shown to be dose-related (51). Within the conjunctiva there is also an H2-receptor-
mediated effect of histamine on blood flow (52). As such, the hyperemia and
conjunctival edema are in part H2-receptor-determined. No details exist concern-
ing H3-receptors and the conjunctiva. The pertinence of histamine to tissue cell
recruitment and activation in allergic conjunctivitis is as described previously for
rhinitis.
Allergen challenge in sensitized individuals has been used to investigate the ef-
fects of oral and topical antihistamine preparations in both the nose and the eye.
Nasal allergen challenge, either with an aqueous extract or with pollen grains,
induces an immediate response characterized by nasal itch, sneeze, rhinorrhea,
and nasal obstruction. The nasal blockage is often long-lasting but the biphasic
obstructive response that typifies the immediate and late responses in the lower
airways is not as readily discernible in the upper airways. A symptomatic late-
phase response is not a characteristic finding following ocular allergen challenge.
There are, however, biochemical and cellular measures indicative of events ex-
tending beyond the immediate response.
During the immediate nasal response to allergen, an increase in histamine,
tryptase, prostaglandin D2, and kinins is evident, consistent with mast cell degran-
ulation, while further increments in histamine and kinins but not prostaglandin
D2 or tryptase are apparent 6–10 h postchallenge (22). The late changes in hista-
mine, but not the other mast cell markers, is indicative of basophil activation.
Consistent with this, an accumulation of basophils is evident within nasal lavage
during the late response (53), although the most marked cellular change 24 h
post-allergen challenge relates to eosinophil influx (54, 55), which is associated
with concomitant allergen-induced nasal hyperresponsiveness.
A. Onset of Action
Treatment with H1-receptor antagonists modifies the response to allergen chal-
lenge in both the nose and the eye (39, 56). The onset of relief of symptoms
186 Howarth
after a single dose is more rapid with topical than oral medication. Topical levoca-
bastine is reported to afford protection within 5 min of application (56). Oral H1-
antagonists have to be absorbed into the circulation before distribution to the
target organ, in this case the nose and eye, and thus have a slower onset of action.
In pollen chamber challenge studies, in which individuals or groups of individuals
are exposed to a regulated amount of pollen for a prolonged duration, sometimes
with repeated daily priming exposures prior to the actual study, relief of symp-
toms has been reported to be significant within an hour of ingestion for fexofena-
dine (57) and cetirizine (58) but to take longer (3 h) for loratadine (58). A recent
study with one of the active metabolites of loratadine, desloratadine, reveals phar-
macological heterogeneity in the effects of H1-receptor antagonism on the nasal
response to allergen. By implication, this would point to heterogeneity in the
involvement of histamine in the nasal obstructive response to allergen. Fourteen
of 28 subjects (50%) were found to have a major improvement in allergen-in-
duced nasal obstruction (mean 50% reduction at 2 h) with desloratadine in a
pollen chamber challenge study (59); thus allergen-induced nasal obstruction may
only be histamine-dependent in a proportion of rhinitics. When assessed 3 h after
ingestion, cetirizine has been shown to afford greater protection than terfenadine,
loratadine, or astemizole (60). A more rapid onset of effect of cetirizine compared
to loratadine has also been reported from nasal histamine challenge studies (61).
The use of a pollen chamber for group allergen nasal challenge may be a
more sensitive method of evaluation than individual nasal allergen challenge. For
example, one study investigating the protective effect of loratadine and cetirizine
on nasal allergen challenge (62) found these H1-antihistamines to be comparable,
in a placebo-controlled evaluation, in the magnitude of their displacement of the
threshold pollen grain challenge required to induce a positive nasal challenge.
By contrast, a pollen chamber challenge study in which symptoms were induced
and relief evaluated (58), identified a significantly greater effect of cetirizine
(36.7% mean reduction in total symptom scores) than either loratadine (15.4%
reduction) or placebo (12.0% reduction). This study addressed relief after single-
dose therapy, whereas the allergen challenge study referred to above (62) in-
vestigated the protective effect after 7 days of treatment. This study, in which
loratadine and cetirizine were reported to afford comparable protection against
allergen-induced rhinitis, also tested these drugs’ effects on skin wheal responses
to histamine and allergen. Cetirizine had a significantly greater effect on the hista-
mine-induced skin wheal response than loratadine, whereas they had an equal
effect in inhibiting the allergen-induced skin wheal responses. An interpretation
of these findings is that an effect of loratadine on allergen-induced mediator re-
lease makes up for its relative lack of potency as an end-organ H1-receptor antago-
nist. Such an ‘‘antiallergic’’ effect may only be achieved at steady state and may
not be evident in single-dose studies.
Rhinoconjunctivitis 187
Nasal allergen challenge has also been used to investigate the antiallergic proper-
ties of H1-antihistamines in vivo. These investigations are based on the in vitro
findings that H1-antihistamines inhibit anti-IgE-induced histamine release from
human lung fragments at low concentrations, although at high concentrations
they enhance histamine liberation (11). Comparative in vitro studies suggest that
this effect does not relate to H1-receptor antagonist potency but more to the lipo-
philicity of the compound. H1-antihistamines with low lipophilicity have a lesser
effect on histamine liberation than those with greater lipophilicity. This ‘‘antial-
lergic’’ potential of antihistamines has been extended by other in vitro studies
reporting inhibition of LTC4 and leukotriene D4 (LTD4) release from dispersed
human lung cells and from eosinophils, modification of macrophage function,
inhibition of both neutrophil and basophil activation, and alteration in platelet
cytotoxicity (68).
When administered orally at standard clinical doses, the piperidine antihis-
tamines azatadine, terfenadine, and loratadine have all been shown to reduce the
allergen-induced increment in nasal lavage concentrations of histamine and kinins
(69–71). Where measured, this protective effect is also associated with a reduc-
tion in induced increments in albumin. Cetirizine is without effect on histamine
release (63), although it does decrease allergen-induced changes in LTC4 and
LTD4 (80). The interpretation of these findings is complicated: kinins are likely
to be generated in association with plasma protein extravasation (41). Thus the
inhibitory action of antihistamines may reflect purely an H1-mediated action on
Rhinoconjunctivitis 189
vascular permeability, with the inhibitory action on the histamine increase re-
flecting reduced tissue availability of histamine on account of the reduced tissue
fluid exudation. Against such an explanation, however, is the reported lack of
inhibitory effect of cetirizine on the histamine rise in the presence of an inhibition
of the allergen-induced albumin changes (72).
Evidence in support of an additional action for loratadine over and above
end-organ H1-receptor antagonism has been derived indirectly from comparisons
of loratadine with cetirizine in nasal and skin challenge studies (62). In these
studies, cetirizine had greater activity against histamine-induced skin wheal for-
mation than loratadine, but equal activity against allergen-induced skin wheal
and nasal responses. This difference was interpreted as being indicative of a dual
activity of loratadine, involving both end-organ H1-receptor antagonism and inhi-
bition of tissue histamine release. Such an interpretation would be consistent with
the nasal lavage studies (70–71) but is in contrast to a careful skin study using
a microdialysis technique to sample venous blood draining the skin wheal site
directly (73). This placebo-controlled study failed to detect any effect of lorata-
dine on induced histamine release. There may be several explanations for these
discrepant skin and nasal findings. First, there may be target organ differences
in the mast cell sensitivity to the effects of loratadine, although there is no evi-
dence for this. Target site discrepancies may also relate to the inducing stimulus
being stronger in the skin and thus less amenable to inhibition. A third consider-
ation is that the increase in histamine within the nasal lumen following allergen
challenge is, in part, a reflection of basophil activation and that this component,
rather than a mast cell component, is inhibited by loratadine. Consistent with
such a possibility is the failure to detect any significant effect of loratadine on
allergen-induced increments within the nose of tryptase and PGD2 (70), two mast
cell–derived mediators, and the ex vivo identification that loratadine inhibits IgE-
mediated basophil activation (71).
In addition to the assessment of the impact of antihistamine therapy on cell
activation, in vivo studies have investigated the ability of H1-receptor antagonists
to modify plasma protein leakage, eosinophil recruitment and activation, and epi-
thelial activation. Clemastine pretreatment does not modify allergen-induced na-
sal vascular responses (74). No effect on either eosinophil recruitment or eosino-
phil activation has been found with loratadine (70) or cetirizine, either alone or
in combination with the H2-receptor antagonist cimetidine (63), in the allergen
nasal challenge model. A number of H1-antihistamines have, however, been
found to modify epithelial activation. Nasal allergen challenge is associated with
increased epithelial expression of the adhesion molecule ICAM-1 and the appear-
ance in the lavage of the shed form of this, soluble ICAM-1 (sICAM-1). In the
nose, topical azelastine pretreatment has been found to inhibit this response (75)
as has topical levocabastine (76), as well as oral therapy with cetirizine (77),
oxatomide (78), and loratadine (79) in the conjunctiva with topical allergen chal-
190 Howarth
lenge to the eye. These findings have been extended into naturally occurring
disease, with topical azelastine (80) and oral cetirizine (81–83) and loratadine
(81–82). All of these are reported either to downregulate epithelial ICAM-1 ex-
pression or to reduce the recovery of sICAM-1. The relevance of this to the
modification of allergic rhinitis or conjunctivitis is undefined, but increasingly
the epithelium is considered to play an important role in cell recruitment through
the release of chemokines. In vitro, fexofenadine has been found to modify epi-
thelial–eosinophil interactions and the release of the chemokines regulated on
activation, normal T-cell expressed and secreted (RANTES) and interleukin 8
(IL-8), as well as the cytokine granulocyte macrophage colony-stimulating factor
(GM-CSF) and the adhesion molecule ICAM-1 from epithelial cells (84).
These findings have been extended by reports from some workers that cetir-
izine and loratadine can inhibit both eosinophil recruitment and activation in the
nose in naturally occurring disease (82, 83). One of these studies is uncontrolled
(82) and therefore difficult to evaluate. The other, with cetirizine is a placebo-
controlled evaluation in seasonal allergic disease demonstrating a clear effect of
active therapy (83). These findings are compatible with studies in the skin, using
a skin blister model in which cetirizine inhibits allergen-induced eosinophil re-
cruitment (85). Other nasal and skin studies have not identified an effect of cetiri-
zine on either acute allergen-induced eosinophil recruitment or mucosal eosino-
phil accumulation in naturally occurring disease (54, 85, 86). An inability to
identify additional benefit with ‘‘antiallergic’’ antihistamines brings into question
the relevance of these findings to cell recruitment and activation, a difficulty
that is also reflected in naturally occurring disease in which most modern H1-
antihistamines appear equally efficacious when used at standard clinical doses
(see below). Subtle differences between therapies may need very large numbers
of patients to be clinically discernible, due to the variability of the disease expres-
sion. Also, as in some H1-antihistamines, the effect may appear primarily related
to inhibition of histamine release, rather than a broader effect on cell activation,
and consequently no real additional biological benefit is accrued over the H1-
receptor antagonism alone.
60% reduction) since histamine is not the sole contributor to the generation of
these symptoms (91). Oral H1-antihistamines also modify the conjunctival symp-
toms of itch, watering, and redness (92, 93). The effect on conjunctival symptoms
may be less marked than on rhinitis symptoms, possibly on account of a higher
local allergen load in the eye. Topical H1-antihistamines have a similar profile
(94) and while theoretically they may achieve a higher local concentration
(thereby creating a greater effect), comparative trials of topical H1-antihistamine
therapy with oral H1-antihistamine therapy report a similar overall effect in reduc-
ing ocular symptoms (95).
Due to the potential for first-generation H1-antihistamines to cause subclini-
cal central nervous system (CNS) adverse effects, interfering with performance
at work and school, and in some individuals, frank somnolence, these H1-receptor
antagonists are no longer recommended for use, with the second-generation non-
sedating H1-antihistamines being preferred.
Few details will be given regarding terfenadine and astemizole, since these
second-generation H1-antihistamines are no longer approved for use in many
countries because of their potential to cause serious cardiac arrhythmias.
1. Placebo-Controlled Studies
Cetirizine. Cetirizine, a piperazine derivative and carboxylated metabo-
lite of hydroxyzine, is a potent H1-receptor antagonist. Placebo-controlled com-
parative studies of cetirizine 5 mg daily (96), 10 mg daily (96, 97), and 10 mg
twice daily (98) have been conducted and all dosages are found to be effective
in seasonal allergic rhinitis. A subsequent study compared 5 mg, 10 mg, and 20
mg cetirizine dosages with placebo in seasonal allergic rhinitis and found all
active treatments to be effective (Fig. 3), with no significant dose–response rela-
tionship (89). A study using a syrup preparation in children aged 6–11 years
found 5 mg no different from placebo, while the 10 mg dosage was significantly
more effective (99). Cetirizine is marketed at a dosage of 10 mg daily for the
treatment of seasonal allergic rhinoconjunctivitis. In the placebo-controlled trials,
cetirizine, like other H1-antihistamines, is effective for relief of nasal pruritus,
runny nose, and sneezing but less effective for nasal obstruction or lacrimation,
although effects are evident in studies with sufficient power (100). Cetirizine
affords better relief when taken on a daily basis rather than on an as-needed basis
(101).
Desloratadine. Desloratadine is an active metabolite of loratadine that
has been developed for clinical use in its own right. It has a high affinity for H1-
receptor binding. Details in a review article suggest a relative selectivity for the
H1-receptor, with 15–50 times the dosage being required to demonstrate antago-
nism of the H2-receptor or muscarinic receptors (102). A recent abstract does,
however, indicate that the selectivity ratio for H1- to muscarinic M2-receptors is
192 Howarth
Figure 3 The influence of three separate dosages of cetirizine on mean daily symptom
scores, in comparison to placebo, in a double-blind, randomized, parallel-group study de-
sign involving 419 patients with seasonal allergic rhinitis. Treatment was given once daily
for 1 week. Cetirizine was significantly (p ⱕ 0.05) more effective than placebo on all
days, but no dose–response relationship was evident. (From Ref. 89.)
only 5 in comparison to 11 for loratadine and 600 for fexofenadine (103). This
indicates a broader receptor antagonistic profile for desloratadine than either its
parent compound or a comparable H1-receptor antagonist. At the time of writing,
no peer-reviewed original articles relating to desloratadine in allergic rhinitis
were available, although data are available in abstracts from presentations at
meetings, a supplement publication, and a review article (104).
The supplement referred to focused on the effects of desloratadine in reliev-
ing nasal congestion (59). Clinical trials in patients with seasonal allergic rhinitis
identified, in comparison to placebo, that desloratadine not only relieved nasal
itch, sneeze, and rhinorrhea but also improved nasal obstruction. This was re-
ported by the Desloratadine Study Group (105) in a double-blind, randomized
study design involving 346 patients and a 2-week treatment period with deslora-
tadine 5 mg once daily or placebo. Desloratadine treatment led to a 25% reduction
in the nasal congestion score in comparison to placebo ( p ⫽ 0.04). A separate
abstract from the same group reported that this reduction was statistically signifi-
cant, compared to baseline, within 12 h of initial administration (106). A third
abstract from the Desloratadine Study Group reported the influence of treatment
Rhinoconjunctivitis 193
Figure 4 Mean change from baseline in 24-h reflective symptom scores for sneezing,
itchy nose/palate, rhinorrhea, itchy red eyes, and nasal congestion following treatment
with fexofenadine 120 mg once daily (n ⫽ 232, ■), loratadine 10 mg once daily (n ⫽
228, ), and placebo (n ⫽ 225, 䊐) over a 2-week treatment period in seasonal allergic
rhinitis. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.005, ****p ⬍ 0.001, *****p ⬍ 0.0001 in
comparison to placebo; p ⬍ 0.05 for comparison between fexofenadine and loratadine:
itchy red eyes and nasal congenstion. No details of baseline starting score for individual
symptoms are provided in the publication. NS, not significant. (From Ref. 139.)
194 Howarth
whether taken in the morning or in the evening, was superior to placebo. There
was no statistical significance between the 10 and 20 mg treatment groups, but
it has been proposed that 10 mg ebastine be used for mild rhinitis and the higher
dosage for more severe disease (123, 124).
Others. Acrivastine is related to the H1-antihistamine triprolidine. It does
not have advantages over the once-daily nonsedating H1-antihistamines since it
has a short half-life, needing to be taken three times a day (8 mg three times
daily), and has CNS effects (125), especially in association with alcohol (126).
It is effective in the treatment of seasonal allergic rhinitis (127, 128). Emedastine
has been developed for ocular application (129, 130) and tested in a conjunctival
challenge model (131). No placebo-controlled clinical trials have been published
with either this H1-antihistamine or another H1-antihistamine under development,
epinastine (132). Levocetirizine is being developed for clinical use (40), based
on the findings that cetirizine is a racemic mixture of two enantiomers: levocetiri-
zine (R-enantiomer) and dextrocetirizine (S-enantiomer), and that histamine nasal
challenge studies indicate that the H1-receptor antagonistic activity resides with
the R-enantiomer. No trial reports are published as yet relating to its efficacy in
seasonal allergic rhinitis (SAR). A further novel H1-receptor antagonist, rupata-
dine, has been found to be clinically effective in SAR when given at a dosage
of 10 mg once daily (133).
2. Comparative Studies
Comparisons have been made between nonsedating H1-antihistamines and seda-
tive H1-antihistamines such as chlorpheniramine and pheniramine, other nonse-
dating H1-receptor antagonists, and other classes of medication used for allergic
rhinitis.
While sedating and nonsedating H1-antihistamines often have similar clini-
cal efficacy, the two generations of H1-receptor antagonists are clearly distin-
guishable by their sedative adverse effect profile. The nonsedating H1-antihista-
mines have a much more favorable risk/benefit profile. A recent study compared
a sustained-release formulation of brompheniramine with loratadine and found
that brompheniramine 12 mg twice daily was clinically more effective in reliev-
ing nasal and ocular symptoms than loratadine 10 mg once daily (134). This
dosage of brompheniramine was, however, clearly sedative (134). A comparative
evaluation of cetirizine and chlorpheniramine similarly found that while both
treatments were effective in the clinical control of allergic rhinitis, the first-gener-
ation H1-antihistamine chlorpheniramine caused sedation in 40.5% of patients but
only 11.6% of cetirizine-treated patients reported sedation (135). Comparisons of
second-generation H1-antihistamines have, in general, not found any major clini-
cal differences over 1–2 week study periods (100, 110, 118, 124, 136–139).
Rhinoconjunctivitis 197
Figure 6 Influence of intranasal fluticasone 200 µg/day (n ⫽ 121) and oral loratadine
10 mg daily (n ⫽ 119) on symptoms in seasonal allergic rhinitis. Results are presented
as median percentage of symptom-free days for each of the nasal and conjunctival symp-
toms scored over the 4-week treatment period. (From Ref. 144.)
and topical cromoglycate identify that both therapeutic approaches have compara-
ble clinical benefit, although the frequency of treatment regimens differs and
would favor H1-antihistamines on the basis of compliance with regular medica-
tion.
1. Placebo-Controlled Studies
Significant clinical benefit over placebo has been reported with cetirizine 10 mg
daily (150–152), loratadine 10 mg daily (153), and mizolastine 10 mg daily (154).
Symptom improvement can progressively increase during 28 days of treatment
(153) and these trials report the most marked benefit for nasal pruritus, sneezing,
and rhinorrhea, with a lesser effect on nasal obstruction. The lack of benefit on
nasal obstruction was highlighted in one study in which the nasal corticosteroid
beclomethasone dipropionate was administered after the use of regular antihista-
mine treatment. This identified a further reduction in symptoms, in particular,
blocked nose (155). Both cetirizine (152) and mizolastine (154) have, however,
been found to significantly improve nasal obstruction and this symptomatic bene-
fit has also been matched by a significant improvement in rhinoscopic appearance
with mizolastine (154). The improvement in perennial rhinitic symptoms with
cetirizine is associated with an improvement in quality of life (152). In a 26-
week treatment period, a higher dosage of cetirizine (20 mg daily) was found
not only to improve rhinitis, including nasal obstruction, but also to improve
lower airway symptoms, increase peak flow, and reduce the requirement for as-
needed beta-agonist therapy in subjects with coexisting asthma (156). To date,
there are no published placebo-controlled trials of desloratadine, fexofenadine,
or levocetirizine in perennial allergic rhinitis.
A. Rhinitis
Both levocabastine and azelastine administered topically are most effective
against nasal itch, sneeze, and rhinorrhea. In some studies nasal obstruction is
also reduced by azelastine (168–171). There are a number of published placebo-
controlled trials in seasonal allergic rhinitis (172–174), but the majority of studies
report comparison with active medications such as H1-antihistamines (169, 170,
175–177), cromoglycate (172, 178), or nasal corticosteroids (176, 179). One pla-
cebo-controlled study reported no effect of levocabastine on nasal obstruction in
Mountain Cedar-sensitive patients with seasonal allergic rhinitis, when used at
Rhinoconjunctivitis 201
a dosage of 0.2 mg twice daily (1 spray into each nostril twice daily), despite
clear effects on the neurally medicated symptoms of itch, sneeze, and rhinorrhea
(173). In patients with seasonal allergic rhinitis, regular therapy with topical nasal
azelastine is more effective than on-demand use, with effects on nasal inflamma-
tion (ICAM-1 expression on epithelial cells) as well as clinical parameters (80).
Half the standard daily dosage (0.28 mg/day) was also found in this study to be
as effective as the standard dosage (0.56 mg/day), although there was signifi-
cantly greater use of rescue medication in the lower-dosage treatment group.
Azelastine, administered as a nasal spray (180), is more effective than either oral
azelastine or terfenadine in relieving nasal obstruction, while producing compara-
ble relief of other nasal symptoms. Levocabastine is reported to be more effective
than a topical antihistamine/decongestant (antazoline/naphazoline) preparation
(176) or topical cromoglycate (172, 178) in the treatment of seasonal allergic
rhinitis.
The two comparative studies of levocabastine (0.5 mg/mL, two sprays each
nostril four times daily) and cromoglycate (20 mg/mL, two sprays each nostril
four times daily) involving 114 patients over 2 weeks found significantly fewer
symptoms with levocabastine therapy (76% of patients improving vs. 46% on
cromoglycate) (181), which was paralleled by more symptom-free days in the
levocabastine-treated patients (172). An open comparison of the onset of action
of topical levocabastine and nedocromil to both the nose and eye reported that
more than 80% of patients with seasonal allergic rhinitis reported symptom relief
with both medications within 1 h. This amounted to approximately a 50% reduc-
tion in symptom severity (182).
While both levocabastine (176) and azelastine (179) nasal sprays are re-
ported to be as efficacious as topical nasal steroid administration, the comparative
studies are limited and further studies are required before valid comparison can
be made. One study of patients with seasonal allergic rhinitis taking nasal steroids
or oral antihistamines who remained symptomatic after a 1- to 2-week washout
period compared double-dose azelastine (1.1 mg/day) with the combination of
loratadine 10 mg daily and nasal beclomethasone dipropionate 200 µg twice
daily. After 1 week of treatment there was no statistical difference between the
treatments, and azelastine was concluded to be as effective as the combination
therapy (179). Such studies are likely to be misleading: in essence, this represents
predominantly a comparison of azelastine and loratadine, since the effects of the
nasal steroid will not be fully expressed within the timeframe of such a study.
Another study that assessed nasal nitric oxide measurements as a marker of nasal
inflammation, found a significant effect with nasal steroid therapy but not with
topical levocabastine (183).
Studies in perennial rhinitis are limited. One preliminary 2-week study re-
ported improvement in sneezing and rhinorrhea with topical levocabastine, in
comparison with placebo, which could not be improved further by the addition
202 Howarth
B. Conjunctivitis
Levocabastine (0.5 mg/mL, one drop in each eye twice daily) has been shown
to be superior to placebo for the treatment of itchy eyes, runny eyes, and red
eyes associated with seasonal allergic conjunctivitis (185). Relief of symptoms
is rapid, occurring within 15 min of application (168). Topical levocabastine (0.5
mg/mL) appears to be more efficacious than topical cromoglycate (20 mg/mL)
when both preparations are administered four times daily for seasonal allergic
conjunctivitis over a 4-week period (186, 187). Patient diary card recordings
identified fewer symptoms in the levocabastine-treated patients (181). In one of
the studies, the proportion of patients virtually symptom-free on high pollen count
days was greater in the levocabastine (33%)- than in the cromoglycate (6%)-
treated patients (187).
The use of medication for treatment of a condition is based both on its beneficial
effects and on its adverse effects potential. The major advantage of the second-
generation oral H1-antihistamines, which considerably improved their risk/benefit
profile, was their absence of CNS sedative effects when used at standard clinical
dosages. With loratadine, fexofenadine, mizolastine, and ebastine, the reported
side effects of tiredness and drowsiness are no different from placebo at the rec-
ommended dosage level (188–190). This clinical reporting is substantiated by
laboratory assessment incorporating reaction time analysis, the performance of
complex sensorimotor tasks such as simulated car driving, sleep latency studies,
and electroencephalographic (EEG) monitoring (191–198). The topical H1-antag-
onist levocabastine has also been shown to be devoid of adverse CNS effects by
using such methods (199). When the dosage of loratadine and mizolastine is
increased above the standard 10 mg once daily, there are reports of cognitive
or psychomotor performance test impairment (190). Cetirizine is labeled as a
nonsedating H1-antihistamine in Europe and as a sedating antihistamine in the
United States. Many studies with cetirizine show no difference from placebo in
the reporting of drowsiness or sleepiness, although some do at the standard dos-
age (reviewed in 190) and there are reported EEG abnormalities (200).
Rhinoconjunctivitis 203
B. Other Combinations
The addition of regular therapy with a nedocromil sodium nasal spray to oral
therapy with astemizole has been found to provide improved control in ragweed
seasonal allergic rhinitis, despite greater use of rescue medication in the astemi-
zole-treated group (218). In patients with perennial rhinitis (both allergic and
Rhinoconjunctivitis 205
C. Common Cold
Nasal lavage studies in the common cold have failed to demonstrate histamine
release and nonsedating H1-antihistamines have not been found to be effective
(220, 221). One study of loratadine-D vs. placebo has, however, reported that
loratadine-D, administered twice daily, is more effective than placebo in relieving
symptoms, with improvement not only in nasal obstruction, as might be antici-
pated with pseudoephedrine, but also in sneezing and rhinorrhea (222). In view
of the previous lack of effect of H1-receptor antagonism alone, assessment of
pseudoephedrine alone administered by the same method is now required to as-
sess whether modification of nasal obstruction itself may modify other sequelae,
or whether such a combination is essential for benefit.
206 Howarth
D. Nonallergic Rhinitis
Some patients with rhinitis who are skin-test negative have nasal eosinophilia
(NARES) and may benefit from H1-antihistamine therapy. So may individuals
who experience cold air–induced rhinorrhea, as in these individuals there is evi-
dence of mast cell degranulation (223, 224). Clinical trials have thus reported
some benefit with H1-antihistamines in nonallergic rhinitis patients. Subanalysis
reveals that patients in whom sneezing is the most prominent symptom respond
best to this mode of therapy (155, 225).
X. SUMMARY
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7
H 1-Antihistamines in Asthma
I. INTRODUCTION
221
222 Lordan and Holgate
high-risk atopic infants and the potential role of H 1-antagonists in the continuing
management of patients with chronic asthma.
A. Mast Cells
In 1953, Riley and West identified the mast cell as a major source of histamine
(3). Stimuli that increased the numbers of mast cells in tissues were also noted
to result in increased release of histamine. The identification of circulating IgE
and the discovery of high-affinity IgE (FcεRI) receptors on mast cells supported
the hypothesis that allergen cross-linkage of IgE receptors on mast cells resulted
in mast cell degranulation, histamine release, and the characteristic bronchocon-
striction of asthma (4).
In healthy and asthmatic subjects, the airways have been shown to contain
numerous mast cells, which originate from CD34 ⫹ precursor cells, and are pre-
dominantly of the tryptase only phenotype (MC T ), as distinct from chymase-
positive, tryptase-positive mast cells (MC CT ) found in other tissues (5). The polar-
ization of airway mast cells to the MC T type is promoted by the presence of mast
cell growth factors derived from infiltrating Th2-type lymphocytes (interleukin
[IL]-3, IL-4, and IL-9), and stem cell factor released by the bronchial epithelium
and adjacent fibroblast/myofibroblast layer (6). Although some investigators have
not noted any difference in mast cell numbers in endobronchial biopsies (5, 7) or
bronchoalveolar lavage (BAL) fluid (8) between asthmatics and healthy subjects,
others have confirmed increased numbers in BAL fluid of stable asthmatics (9),
and endobronchial evidence of a further rise in mast cell numbers in parallel with
the extent of the late allergic response to allergen challenge (10, 11). In patients
with asthma, some mast cells show ultrastructural evidence of degranulation,
which is not found in healthy subjects, and become localized to the bronchial
epithelium after allergen challenge, where they are more likely to encounter in-
haled allergens or be activated by other noxious stimuli (12). Consistent with the
hypothesis of increased activation of mast cells in asthma is the observation that
mast cell mediator levels such as histamine, tryptase, and leukotrienes are in-
creased in BAL fluid in asthmatics after allergen challenge (13). Flint et al.
Asthma 223
B. Basophils
Until recently, it has been difficult to differentiate between mast cells and baso-
phils in tissues, since both cells contain metachromatic granules and stain posi-
tively for FcεRI receptors. Similar to mast cells, airway and circulating basophils
are derived from CD34 ⫹ cells. Upon activation by IgE-dependent or IgE-indepen-
dent mechanisms, basophils release a number of potent mediators, including his-
tamine, leukotrienes, proteoglycans, and cytokines such as IL-4 and IL-13 (18–
22). Earlier studies have applied morphological criteria including cell surface
expression of FcεRI receptors, the presence of metachromatic granules staining
negatively for trypsin, and multilobular nuclei to identify basophils in tissues.
Using these indirect criteria, increased numbers of basophils have been described
in the sputum of asthmatics during exacerbations. After subsegmental allergen
challenge with ragweed antigen in sensitized allergic asthmatics, Guo et al. re-
ported a 20- to 200-fold increase in the numbers of IgE-bearing, histamine-con-
taining cells in BAL fluid, 95% of which were considered to be basophils (23).
McFarlane and colleagues have recently developed a monoclonal antibody
(BB1) that stains antigens specific to basophils (24) and have used this antibody to
assess the role of basophils in the allergic airway responses of asthma. They have
confirmed increased numbers of basophils in bronchial biopsies of atopic asthma-
tics compared to healthy controls, atopic nonasthmatics, or even nonatopic asthma-
tics. They noted a further increase in the numbers of BB1-positive basophils at 24
hours after allergen challenge, coincident with the late allergic response, with a
proportion of these cells showing evidence of degranulation. The influx of basophils
into the airways was significantly lower than the numbers of eosinophils recruited,
suggesting that although basophils contribute to the development of the late allergic
response (LAR), eosinophils play a more important role.
224 Lordan and Holgate
The initial isolation of histamine in 1907 by Windaus and Vogt (25), and the
recognition that anaphylactic challenge of lung tissue resulted in histamine re-
lease, stimulated the search for mediators involved in airflow dysfunction in pa-
tients with asthma (26). Early studies by Weiss et al. observed that the administra-
tion of intravenous or intramuscular histamine to patients with bronchial asthma
precipitated attacks of breathlessness associated with bronchial obstruction as
measured by decreased vital capacity (27). It was recognized that the bronchocon-
striction induced by histamine was unique to asthmatic subjects, was not observed
in healthy subjects, and could be abrogated by pretreatment of asthmatic subjects
with an early histamine receptor antagonist, β-dimethylaminoethyl-benzhydryl-
ether hydrochloride, which had shown effectiveness in animal studies and in aller-
gic rhinitis (28, 29).
It has been well documented that histamine is released in airway inflamma-
tion in asthma and it is possible to detect histamine or its metabolites in airway
fluids, peripheral blood, or urine of asthmatic subjects. In the circulation, hista-
mine release was initially localized to the granulocyte fraction of blood (30), and
it was later confirmed by Ishizaka et al. that basophils were responsible for hista-
mine release from blood stimulated in vitro with an anti-IgE antibody (31).
Barnes et al. showed that plasma histamine levels were increased in asthmatics
compared to healthy controls, atopic nonasthmatics, or chronic bronchitic sub-
jects (32). Plasma histamine release is noted to increase in atopic asthmatics
after allergen challenge, and in asthmatic subjects experiencing an exacerbation,
compared to stable asthmatics. The levels of histamine found correlate with the
severity of underlying disease (23). Patients receiving effective treatment for
asthma have also been shown to release lower levels of histamine than asthmatic
subjects with poorly controlled disease (33).
Figure 2 The allergen-induced reduction in FEV 1 during the early and late allergic
response to inhaled allergen in 12 asthmatic subjects after 1 week of treatment with pla-
cebo (open circles), zafirlukast 80 mg twice daily (closed circles), loratadine 10 mg twice
daily (open squares), or a combination of zafirlukast and loratadine (solid squares). The
pulmonary function is expressed as a percentage of the postdiluent FEV 1. (From Ref. 61.)
(Fig. 2). Roquet and colleagues noted that pretreatment of asthmatic subjects with
the selective cysteinyl leukotriene LT 1 receptor antagonist zafirlukast (80 mg
twice daily) reduced the extent of the EAR by 62% and the LAR by 55% (61)
(Fig. 2). The H 1-antagonist loratadine (10 mg twice daily) had a lower efficacy
and reduced the EAR and LAR by 25 and 40%, respectively. The combination
of the two agents was most effective, suppressing the EAR and LAR by 75 and
74%; however, a recent study by Dahlen et al. showed that high-dose loratadine
alone offered less protection against exercise-induced bronchoconstriction
(⫺9%) than high-dose zafirlukast alone (57%), or the combination of loratadine
and zafirlukast (65%) (62). Although it does appear that leukotrienes play a more
important role than histamine in the development of allergen- or exercise-induced
bronchoconstriction, these studies support the view that a combination of an anti-
histamine and an antileukotriene in high doses may represent a novel strategy
for the treatment of asthma.
Mast cells and basophils Inhibition of mediator release (histamine, leukotrienes, and
PGD 2)
Eosinophils Suppression of influx to airways after allergen challenge
Reduced chemotaxis
Reduced mediator release (superoxide radicals)
Neutrophils Reduced chemotaxis
Reduced release of mediators
Vascular endothelium Reduced expression of leukocyte adhesion molecules
(ICAM-1, VCAM-1) on vascular endothelium
Reduced NF-κB expression
Bronchial epithelium Reduced expression of activation markers, HLA-DR, and
ICAM-1
Reduced release of RANTES, IL-16, and soluble ICAM-1
Reduced expression of NF-κB
Antigen-presenting cells Possible reduction of antigen-presenting/antigen-processing
activity by APCs
ICAM-1, intercellular adhesion molecule-1; RANTES, regulated upon activation, normal T expressed
and secreted; HLA-DR, human leukocyte antigen-DR; NF-κB, nuclear factor kappa B; APC, antigen
presenting cell; VCAM-1, vascular cell adhesion molecule-1.
Asthma 229
to the hypothesis that H 1-antihistamines may inhibit the activation of genes re-
sponsible for the synthesis of proinflammatory mediators (64).
B. Mediator Release
The potential of various antihistamines to inhibit the generation of proinflamma-
tory mediators has been widely studied. Church et al. observed an inhibition of
anti-IgE-induced histamine release from human lung fragments by antihistamine
compounds at low concentrations, but a paradoxical increased release at higher
concentrations independent of the challenge used (65), suggesting inhibitory ef-
fects by mechanisms independent of the H 1-histamine receptor. Ketotifen has
shown poor inhibitory actions on histamine release by human lung mast cells,
but was noted to antagonize effectively the release of slow-reacting substance of
anaphylaxis (SRSA) (66). Azelastine has also been shown to inhibit histamine
and leukotriene release from human lung mast cells at concentrations of 3 µM
(67–69) while loratadine reduces leukotriene but not histamine release (70).
Ketotifen also inhibits the release of superoxide radicals by human neutro-
phils. In addition, inhibition of oxygen free radical production has been described
for ketotifen in human alveolar macrophages, and for azelastine, oxatomide, lora-
tadine, and cetirizine in human eosinophils. Of interest, the actions of cetirizine
were more pronounced in cells obtained from atopic subjects, with effective inhi-
bition of mediator release at lower concentrations in eosinophils obtained from
atopic donors than from nonatopic controls (71).
The airway epithelium is an important source of autacoid mediators, cyto-
kines, and chemokines, and plays an important role in regulating the inflamma-
tion, repair, and remodeling process in asthma (72). In vitro studies involving
the culture of bronchial epithelial cells transformed by virus 12-SV40 cells
(BEAS-2B) have confirmed that histamine is capable of activating the airway
epithelium with increased accumulation of intracellular calcium, an effect that
can be abrogated by the antihistamine diphenhydramine (73). Vignola et al. also
showed that histamine exposure increases the expression of the activation mark-
ers HLA-DR and ICAM-1 and the production of fibronectin by airway epithelial
cells, which can be inhibited by either the H 1-receptor antagonist pyrilamine or
the H 2-receptor antagonist ranitidine (74). More recently, it has been shown that
histamine augments the release of IL-16 (a potent chemokine for CD4 ⫹ lympho-
cytes and eosinophils) from airway epithelial cells in culture, particularly after
priming by IL-1β and TNF-α (75). These effects were inhibited by the protein
synthesis inhibitor cyclohexamide, and by dexamethasone, suggesting de novo
synthesis of IL-16 by mechanisms involving the activation of transcription fac-
tors, such as NF-κB (75). Bayram and colleagues observed an increased release
of IL-8, RANTES, and soluble ICAM-1 by primary bronchial epithelial cell
cultures after exposure to the air pollutant nitrogen dioxide (NO 2, 400 ppb),
and inhibition by loratadine or its metabolite SCH34117 (desloratadine) (76, 77)
230 Lordan and Holgate
(Fig. 3). Arnold et al. also confirmed that the release of IL-8 from bronchial
epithelial cells (A549) in response to TNF-α or phorbol 12-myristate 13-acetate
(PMA) exposure was inhibited by pretreatment with cetirizine, and was associ-
ated with a decreased amount of accessible DNA-binding sites of NF-κB as deter-
mined by flow cytometry automated cell sorting (FACS) analysis, providing fur-
ther evidence for the anti-inflammatory effects of H 1-antagonists (78).
Figure 3 The release of (a) RANTES and (b) sICAM-1 by primary bronchial epithelial
cell cultures after 24 h in vitro exposure to 400 ppb NO 2 in the presence or absence of
loratadine (0.25–25 µM). Expressed as median and range, n ⫽ 6 in each group. RANTES,
regulated upon activation, normal T expressed and secreted; sICAM-1, soluble intercellu-
lar adhesion molecule. (From Refs. 76, 77, and 122.)
232 Lordan and Holgate
little effect on morning peak expiratory flow (PEF), evening PEF, or FEV 1. Seda-
tion was noted more frequently in the active treatment group compared to those
receiving placebo, and additional side effects of weight gain, altered taste, head-
ache, and dry mouth were recorded.
The second-generation H 1-antihistamines have many advantages over the
first-generation H 1-antihistamines in terms of specificity, safety, and side effect
profile. Similar to H 1-receptor effects in the upper airways and skin, there is no
evidence of tachyphylaxis to bronchodilator effect in the lower airway (96–105),
and no increase in asthma symptoms has been documented with continued use
of antihistamines (106, 107).
Some authors have suggested that antihistamines may have a corticoste-
roid-sparing effect in asthma (102) (Fig. 5a), but this has not been consistently
shown (103) (Fig. 5b).
A. Cetirizine
Cetirizine, a carboxylated metabolite of hydroxyzine, is a potent antihistamine
with documented bronchodilator and anti-inflammatory properties (108) and no
effect on calcium channels, serotoninergic, muscarinic, or dopaminergic receptors
(109). In a study of symptomatic grass pollen–sensitive asthmatics, treatment
with cetirizine 15 mg daily for 2 weeks led to a reduction in asthma symptoms,
and allowed a reduction in the concomitant use of β 2-agonists and inhaled cortico-
steroids (ICS) compared to placebo (110). Bousquet and colleagues reported that
cetirizine (10 or 15 mg twice daily) was more effective than terfenadine (60 mg
twice daily) in the control of asthma in 97 grass pollen–allergic subjects with
mild seasonal symptoms of recent onset. Spector et al. also confirmed a significant
bronchodilator effect of cetirizine in a DBPC trial of 13 patients with mild-to-
moderate asthma. After three different doses of cetirizine (5, 10, or 20 mg), they
noted a bronchodilator effect that was additive to, and lasted longer than that of,
salbutamol (101).
B. Azelastine
Azelastine has been shown to inhibit the release of both histamine and leuko-
trienes from human lung mast cells (71), and may also have some suppressive
effects on antigen processing or presentation (89). The efficacy of azelastine in
the management of persistent asthma has been assessed in a number of studies
(97, 102). In a DBPC trial of 24 asthmatic subjects by Gould et al. (97), treat-
ment with azelastine for 7 weeks resulted in a reduction in symptoms of cough
and wheeze, associated with improvements in peak flow readings, and a reduc-
tion in the use of rescue bronchodilator therapy. Busse et al. also noted that
azelastine reduced the requirements for inhaled corticosteroids in adults with
chronic asthma (102). In this study of 193 adults with asthma, subjects received
either azelastine 6 mg twice daily or placebo in combination with beclometha-
sone dipropionate 6–16 inhalations per day. The inhaled corticosteroid was then
reduced until maximum reduction or discontinuation was achieved and main-
tained for a 12-week period. The authors noted a significantly greater overall
median reduction in corticosteroid dose in the azelastine group compared with
placebo (4.9 puffs per day for azelastine compared to 3.1 puffs per day for pla-
cebo, p ⬍ 0.01), indicating a mild glucocorticoid-sparing effect of azelastine in
asthma (Fig. 5a).
C. Ketotifen
Studies assessing the role of ketotifen in asthma have shown variable efficacy, but
excessive drowsiness has been consistently reported. In a 1-month randomized
placebo-controlled study of ketotifen (1 mg and 2 mg) involving 50 atopic asth-
matics, Dyson and colleagues showed no improvement in PEF; also, there was
a significant reduction in reliever β 2-agonist use in the subgroup of patients not
maintained on ICS, but no improvement in patients requiring ICS therapy (111).
Fourteen percent of subjects either withdrew from the study or reduced the dose
of ketotifen due to excessive sedation. A 7-month DBPC study of ketotifen was
performed in 138 children aged 5–17 years with chronic asthma (112). After 10
Asthma 237
D. Loratadine
Loratadine has been variably successful in asthma treatment. Kroll et al. per-
formed an uncontrolled study of 25 patients with asthma and showed an improve-
ment in lung function, associated with a reduction in asthma symptoms and bron-
chodilator use after 6 weeks treatment with loratadine 10 mg daily (114);
however, the same dose of loratadine failed to show any effect on peak flow or
symptoms in a DBPC crossover trial involving 17 subjects with moderate asthma
(115).
Allergic rhinitis and asthma are both relatively common disorders and the two
conditions commonly coexist. The upper and lower airways share a number of
epidemiological, physiological, immunopathological, and pharmacological simi-
larities, yet also exhibit distinct features as summarized by Simons (Table 2).
Poorly controlled allergic rhinitis has been shown to sustain asthma-like symp-
toms (116), and has been associated with a worsening of asthma control. Nasal
allergen challenge in subjects with allergic rhinitis and mild asthma results in
increased bronchial hyperreactivity to methacholine, which is reduced by prior
treatment with cetirizine (10 mg daily) (117). An improvement in symptoms of
allergic rhinitis and asthma has been documented for patients with coexistent
rhinitis and pollen-sensitive asthma after treatment with cetirizine at dosages as
low as 10 mg daily, in comparison with terfenadine (60 mg twice daily) which
only improved allergic rhinitis symptoms (118). Grant et al. performed a 6-week
randomized DBPC clinical trial of 186 patients with seasonal allergic rhinitis and
238 Lordan and Holgate
Table 2 Links Between the Upper and Lower Airways in Allergic Rhinitis and
Atopic Asthma
IL-4, interleukin 4; GM-CSF, granulocyte macrophage colony stimulating factor; RANTES, regulated
upon activation, normal T expressed and secreted.
Source: Adapted from Ref. 94.
asthma (105) (Fig. 6). They reported a worsening of symptoms in the placebo
group during the study, whereas the patients treated with cetirizine (10 mg daily)
showed improvements in rhinitis and asthma symptoms. Although the use of
reliever bronchodilators was reduced, there was no significant improvement in
lung function in the cetirizine-treated group. More patients in the cetirizine-
treated group completed the trial, suggesting that cetirizine was safe, well toler-
ated, and effectively relieved symptoms in upper and lower airways disease, at
doses commonly used for the treatment of allergic rhinitis (105). These effects
Asthma 239
Figure 6 Effects of H 1-antihistamines in seasonal allergic rhinitis and mild asthma. (a)
There was a significant reduction in rhinitis symptoms from week 1 and during the pollen
season in cetirizine-treated patients. (b) Cetirizine significantly reduced asthma symptoms
during weeks 1, 2, 4, 5, and 6 of the study, but no significant improvements in PEF or
FEV 1 were noted. (From Ref. 105.)
240 Lordan and Holgate
of H 1-antagonists on upper and lower airways disease have also been confirmed
by Corren and colleagues in a DBPC trial in which they gave a combined prepara-
tion of loratadine 5 mg and pseudoephedrine sulfate 120 mg twice daily (104).
Compared to placebo, the combination was shown to improve pulmonary func-
tion and symptoms of allergic rhinitis and asthma in 193 patients with seasonal
allergic rhinitis and asthma.
There has been considerable recent interest in the early-life origins of asthma.
Management strategies have been devised to prevent the later onset of asthma
in infants considered at high risk of asthma due to atopic status or positive history
of asthma in one or both parents. Allergen avoidance in early life has been advo-
cated as a possible strategy but is difficult to achieve and may not be effective.
Of particular interest are the results of studies suggesting that antihistamine ther-
apy may delay the subsequent development of asthma. Placebo-controlled studies
by Iikura et al. and Bustos et al. of 1 and 3 years’ duration, respectively, in infants
with atopic dermatitis, positive family history of asthma, and/or elevated IgE
levels suggest that ketotifen may delay the onset of asthma (119, 120). The Early
Treatment of the Atopic Child (ETAC) study reported similar effects with cetiri-
zine, which was shown to prevent the onset of asthma when administered to
grass- or house dust mite–sensitized infants (121). Although the precise mecha-
nisms involved in this process are not yet clear, it has been suggested that in-
flammatory mediators released from a primary site of atopy (e.g., the skin in
atopic dermatitis) may have distant actions on a secondary organ to upregulate
the expression of adhesion molecules on the pulmonary vascular endothelium,
priming the airways for the recruitment of inflammatory cells to the lungs, and
the later development of bronchial asthma. It is possible that cetirizine may act
to downregulate the activation state of the pulmonary vascular endothelium by
downregulating adhesion molecules through mechanisms involving NF-kB ex-
pression, and may prevent the airway inflammation from the outset (63).
X. SUMMARY
to play a more prominent role in these responses in asthma. The improved speci-
ficity, tolerability, and safety profile of the second-generation H 1-antagonists as-
sociated with anti-inflammatory activities and bronchodilator activities, may con-
tribute to relieve the symptoms of the upper and lower airways in patients with
coexistent mild seasonal asthma and allergic rhinitis. Considering the global rise
in the prevalence of allergy and asthma, the suggestion that H 1-antagonists may
delay the onset of asthma in infants is of considerable interest and merits further
assessment. Although it is unlikely that monotherapy with most currently avail-
able H 1-antagonists will provide significant clinical benefit in asthma, the poten-
tial of combined antihistamine and antileukotriene therapy may prove useful,
particularly in subjects with poor compliance to inhaled corticosteroid therapy.
ACKNOWLEDGMENTS
Dr. Lordan is a clinical research fellow funded by a program grant from the
Medical Research Council, UK. Professor Holgate is MRC Clinical Professor of
Immunopharmacology. The authors thank Evelyn Lordan for her assistance and
support in preparation of the manuscript.
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Asthma 247
Malcolm W. Greaves
National University of Malaysia, Kuala Lumpur, Malaysia
I. INTRODUCTION
249
250 Kobza Black and Greaves
II. PATHOPHYSIOLOGY
fusion, skin chamber, and suction blister techniques. In the skin, histamine reacts
with H 1- and H 2-receptors to induce erythema and whealing, but H 1-receptors
are predominantly responsible for the flare and itching (8). So far no H 3-receptors
have been identified in human skin (9). Because there is subsensitivity to the
effects of histamine in the skin after 30 min (10) and wheals persist for many
hours, other mediators are also involved in the urticarial process. Upregulation
of the vascular adhesion molecules E selectin and VCAM occurs in chronic urti-
carial wheals and in delayed pressure urticaria (11), enabling leukocytes to tra-
verse the blood vessel walls in response to mast cell-derived chemoattractants
such as IL-6 and IL-8. The ensuing dermal inflammatory cells can release their
own repertoire of proinflammatory mediators, thus prolonging and amplifying
the whealing process.
In physical urticarias (except delayed pressure urticaria), wheals are short-
lived, often for less than 1 hour, and the reaction appears to be predominantly
mediated by histamine although other inflammatory mediators are also involved.
Urticarial vasculitis is usually considered to be due to immune complex
deposition in the skin and other organs (3).
III. PROGNOSIS
A detailed history is vital (12) for categorizing the type of urticaria, and for
elucidating a cause, if one can be found, and aggravating factors, if any.
It is helpful to identify patients with physical urticarias, urticarial vasculitis,
and contact urticaria since their management will differ from that of the larger
group of patients with ordinary ‘‘idiopathic’’ chronic urticaria.
In patients with physical urticarias it is important to reduce the exposure
to precipitating factors. H 1-antihistamine therapy is generally helpful, except in
delayed pressure urticaria, which can be very resistant to this and other treat-
ments.
The suspicion of urticarial vasculitis must be confirmed by examination
of a biopsy specimen of a wheal, which shows a perivascular dermal inflamma-
tory cell infiltrate rich in neutrophils, with leukocytoclastic (fragmentation of the
nucleus of neutrophils), red cell extravasation, and fibrinoid necrosis of mi-
Urticaria and Angioedema 253
General measures
Avoid cause, if known
Avoid aggravating factors: NSAIDs, tight clothes
Reduce heat, stress, alcohol
Provide explanation and reassurance
Drug therapy
Second-generation low-sedation H 1-antihistamines: treatment of choice
Sedating antihistamine at night (on an empirical basis)
H 2-antihistamine for trial period
Mast cell stabilizers: terbutaline, nifedipine (usually disappointing)
Oral corticosteroids
Acute exacerbations of chronic ordinary urticaria
Exacerbations of delayed pressure urticaria
Urticarial vasculitis
Avoid long-term administration for chronic urticaria, if possible
Anabolic steroids for prophylaxis of hereditary C1 esterase deficiency
Immunomodulation: For severe cases not responding to conventional therapy, admin-
istered in specialized units
Oral cyclosporin
Intravenous high-dose immunoglobulin
Plasmapheresis
to an anxious patient. Patients will expect that their urticaria is due to a food
allergy, but in chronic urticaria this is seldom the case.
In many patients with acute urticaria and the vast majority of those with
chronic ordinary urticarias, no external cause can be found. Although urticaria
is distressing and unsightly, usually it does not harm general health.
Because the main mediator is histamine, H 1-antihistamines have been and
remain the symptomatic treatment of choice for urticaria and angioedema until
there is spontaneous remission. Patients are worried about the long-term use of
antihistamines; therefore, the benefits, possible side effects, and the relatively
good long-term safety record of the second-generation drugs must be explained.
The place of antihistamine therapy is set in context of the overall manage-
ment of urticaria in Table 2.
V. TREATMENT TRIALS
A. Design
First, the pharmacodynamics of histamine-induced wheal-and-flare suppression
are studied. This is useful for ascertaining onset, potency, and duration of action;
however, in one study, an H 1-antagonist administered at a dosage that totally
suppressed histamine-induced whealing only caused 60% improvement in spon-
taneous urticarial wheals (13).
The objective assessment of H 1-receptor antagonist treatment of urticarias
has been difficult. Because urticaria is a heterogeneous group of conditions,
which may vary in response to therapy, the treated group should be defined pre-
cisely as to whether they have chronic ordinary or physical urticaria. This has
not been done in all studies. Urticaria occurs in patients of all ages, but most
studies have been performed in adults.
The course of chronic urticaria is notoriously unpredictable, with a ten-
dency to improvement. This makes crossover studies unreliable. As there is a
marked placebo effect, a placebo should always be incorporated into the design.
Trials should clearly identify the response of individual symptoms and
signs of urticaria (itching, erythema, whealing) in addition to a global response.
There is no direct objective method to assess itching, one of the most distressing
aspects of urticaria, but it can be evaluated subjectively using a point scale of
severity or a visual analog scale. Indirect objective assessments based on
scratching are rarely included. Whealing is evaluated by various methods includ-
ing reduction in the numbers of wheals (grouped on a point scale), percentage
of patients in whom urticaria cleared or was greatly improved, or a point scale
of global improvement scored by subject/and or investigator. Assessments of the
effect of treatment on systemic symptoms and quality of life should be included.
The challenges involved in designing clinical trials of antihistamine treat-
Urticaria and Angioedema 255
Acute urticaria may follow a viral upper respiratory tract infection, may be due
to an IgE-mediated reaction to food or drugs such as penicillin, or may be an
anaphylactoid (pseudoallergic) reaction to a nonsteroidal anti-inflammatory med-
ication. These aspirin-like drugs divert prostaglandin production by the cyclo-
oxygenase pathway into leukotriene production via the lipoxygenase pathway.
In a hospital setting, a cause is found in fewer than 50% of patients with acute
urticaria (15).
The optimal treatment of acute urticaria is with second-generation low-
sedation antihistamines, but there are no controlled trials comparing these medi-
cations. Epinephrine treatment of severe angioedema with localized difficulty
breathing or swallowing or widespread urticaria is described in Chapter 9 on
anaphylaxis.
One study compared the treatment of acute urticaria with either loratadine
10 mg/day or prednisolone 40 mg/day for 3 days in 109 patients (15). All patients
were evaluated until remission. Complete remission occurred in 94% of patients
after prednisolone therapy compared to 66% after loratadine treatment. As a prac-
tical step, however, low-sedation antihistamines are begun at the same time as
a short course of oral steroids, and continued as long as acute urticaria persists.
pressure urticarias), and less than 24 hours (differentiating them from the wheals
of urticarial vasculitis, which last individually longer than 24 hours according to
generally accepted criteria). Normally the wheals of CIU leave no marks on the
skin except for those caused by rubbing. Delayed pressure urticaria occurs con-
currently with CIU in about 40% of patients (16). The well-recognized treatment-
resistant character of delayed pressure urticaria may at least partly explain the
seemingly poor response of some patients with CIU to antihistamine therapy.
The wheals of delayed pressure urticaria, in addition to persisting for 36–48
hours, are often painful, occur at pressure sites such as the palms, soles and
waistbands, and may be indurated on palpation, which may lead to the erroneous
diagnosis of urticarial vasculitis. Histological examination of a skin biopsy of
a wheal can facilitate the correct diagnosis. Other physical urticarias, such as
symptomatic dermographism and cholinergic urticaria, may coexist with CIU.
About 40% of patients with CIU have associated angioedema, which affects
skin and mucus membranes (1). Pruritus is an invariable feature of CIU, although
it may be a lesser or greater cause of disability in different patients. Itching may
occur at any time but is most prevalent in the evening and at night (2).
Systemic symptoms are not very common in CIU and, when they occur,
should raise the possibility that the correct diagnosis is urticarial vasculitis. Joint
pains are common in patients with CIU in whom delayed pressure urticaria is a
feature. The natural history of CIU is poorly documented. The best data, available
on 554 hospital patients, suggest that 50% of patients with urticaria alone will
have achieved remission within 6 months to 1 year and 50% of those with associ-
ated angioedema within 2–5 years. In some patients urticaria can be persistent
and up to 20% can still be affected in 20 years (1).
A. Pathophysiological Mechanisms
The underlying pathophysiology of CIU is noncontroversial. The numbers of
dermal mast cells are not increased. Promiscuous activation of these cells leads
to the release of histamine and other mediators, which cause vasodilation and
perivascular accumulation of eosinophils, neutrophils, and mononuclear cells,
aided by increased adhesion molecule expression in the postcapillary venules.
The cause of the unwanted dermal mast cell activation is less clear.
Most patients with CIU, their relatives, and very often their physicians as
well, believe that dietary factors are causative. In contrast to acute urticaria, how-
ever, food items can rarely be implicated as culprits of CIU (17) and exclusion
diets rarely lead to remission of hives (18). Chronic infections and infestations
including candidiasis (19), bacterial sinusitis (20), and most recently Helicobacter
pylori infection (21) have been proposed to be causative. The weight of evidence,
recently comprehensively reviewed, is against a direct role for these agents (22);
however, the possibility that H. pylori could play an indirect role in genetically
Urticaria and Angioedema 257
B. Diagnosis
A careful history is important. If the diagnosis of a physical urticaria has been
made, further investigation should focus only on the physical urticaria and need
not involve tests for circulating autoantibodies or food additive reactivity. In some
patients without physical urticaria, it may be worthwhile carrying out a placebo-
controlled food additive challenge, which is the gold standard for diagnosis of
food additive reactivity (33, 34). An autologous serum skin test can be carried
out to screen patients for autoimmune urticaria (antiFcεRI or anti-IgE), but it is
time-consuming and needs to be interpreted by someone experienced in per-
forming the test (35). Positive results need to be confirmed by demonstrating in
vitro histamine release from basophils of low- and high-IgE occupancy donors,
with inhibition by human recombinant FcεRIα or monoclonal IgE (26). Some
laboratories use Western blotting or enzyme-linked immunosorbent assays
(ELISAs) (29, 32), but since these methods also detect immunoreactive but non-
functional anti-FCεRI autoantibodies, false-positive results may occur in auto-
immune connective tissue and immunobullous disease (32).
The cause of CIU remains elusive in at least 40% of all patients despite
investigations along the lines recommended here. As discussed previously,
searching for infections, infestations, and food allergies is usually not helpful;
however, it is worthwhile to identify histamine-releasing autoantibodies in se-
verely affected patients in whom plasmapheresis or intravenous immunoglobulin
therapy may be indicated.
258 Kobza Black and Greaves
B. First-Generation H 1-Antihistamines
There is no precise definition of first-generation antihistamines, but members
of the group were generally licensed before 1981 and characteristically cause
marked drowsiness and atropine-like (anticholinergic) side effects, leading to
260 Kobza Black and Greaves
1. Hydroxyzine
Like other members of its class, hydroxyzine penetrates the endothelial lining of
the capillaries of the central nervous system (CNS) and causes marked sedation.
It also has marked atropine-like (anticholinergic) activity. Nevertheless it remains
one of the most widely used H 1-antihistamines in the treatment of CIU, since it
is potent, inexpensive, and its soporific effect can be put to good use. It has an
elimination half-life of 14 to 20 hours in adults. Hydroxyzine is best given in
the evening to allay nocturnal pruritus. The dosage is 25–75 mg (one to three
25 mg tablets). The sedative action assists in providing patients with a full night’s
sleep and also allays anxiety associated with severe protracted urticaria and angio-
edema. The patient must be warned that computer skills and car driving may be
impaired in the morning from the evening dose of hydroxyzine, and that
consumption of alcohol must be avoided. Hydroxyzine plasma levels and wheal-
suppressive activity increase significantly when it is coadministered with cimeti-
dine.
2. Chlorpheniramine
Chlorpheniramine has, like hydroxyzine, marked sedative and anticholinergic
side effects, low cost, and rapidity of action. It is prescribed orally for adults at
a dosage of 4 mg (one tablet every 6 hours). By injection it can be prescribed
at a dose of 10–20 mg. The cautions with its use are the same as for hydroxyzine.
3. Doxepin
Tricyclic antidepressants, including doxepin, were introduced as antihistamines
although they were rapidly ‘‘adopted’’ for psychiatric use owing to their mood-
elevating properties. Doxepin is a potent H 1-antihistamine with a high affinity
for H 1-receptors. It also possesses significant H 2-antihistaminic activity (47). In
a double-blind, crossover study of 50 patients with CIU, doxepin 10 mg three
times a day conferred a more favorable response than diphenhydramine 25 mg
three times a day (48). The dosage can be gradually increased up to 75 mg a day
in divided doses; however, because it has a half-life of 19 hours, doxepin is best
used as a single evening dose of 10–75 mg in adults. On an empirical basis, it
is sometimes combined with a morning dose of a low-sedation antihistamine such
as loratadine, fexofenadine, or mizolastine (see below). It is very useful in pa-
tients with severe CIU that is unresponsive to low-sedation antihistamines alone.
Urticaria and Angioedema 261
Such patients frequently become anxious and depressed, and respond to doxe-
pin’s anxiolytic and mood-elevating actions. Doxepin is also available in a topical
cream formulation in a concentration of 5%, but its topical use in CIU presents
no real advantages over systemic antihistamines, since drowsiness due to percuta-
neous absorption is common. Doxepin needs to be used cautiously. It has sedative
and anticholinergic side effects. Concurrent alcohol consumption should be
avoided. Doxepin should not be coadministered with any other medication that
potentially prolongs the QT interval (e.g., cimetidine), as this may lead to cardiac
arrhythmias. Doxepin enhances the hypertensive actions of epinephrine and other
sympathomimetics and should not be used with monoamine oxidase–inhibiting
drugs. It should not be used during breast feeding. Doxepin is not recommended
in children.
4. Ketotifen
Pharmacologically this compound has a range of interesting actions. In addition
to its ability to produce H 1-blockade, it inhibits release of histamine and other
mediators from mast cells and basophils in vitro (49). Its mast cell and basophil
stabilizing-action may be at least partly due, at the molecular level, to inhibition
of transmembrane calcium transport. Ketotifen causes a number of side effects,
including sedation and atropine-like effects (dry mouth, blurred vision, constipa-
tion). Whether its mast cell–stabilizing properties are clinically significant is un-
clear. We were unable to demonstrate any reduction of urinary excretion of hista-
mine or its metabolites in patients with cutaneous mastocytosis treated with
ketotifen (50); however, plasma histamine levels have been demonstrated to be
reduced in patients with physical urticarias (51).
There have been a number of studies of its usefulness in chronic urticaria.
A Japanese study compared ketotifen 1 mg daily, clemastine (a first-generation
H 1-antihistamine) 2 mg, and placebo in 305 patients with chronic idiopathic
urticaria in a double-blind trial (52). Significantly greater relief of pruritus and
whealing was observed in patients receiving ketotifen than clemastine or placebo.
The frequency of side effects (20–21% of patients) was the same in the ketotifen-
and clemastine-treated patients. A number of other reports, mainly anecdotal,
also support its use in the treatment of chronic idiopathic urticaria (53).
1. Cetirizine
Cetirizine is the carboxylated metabolite of the first-generation H 1-antihistamine
hydroxyzine (see above). It is long-acting (up to 24 hours) with a rapid onset
and potent activity at the H 1-receptor. It possesses significant antiallergic activity,
especially in inhibiting eosinophil chemotaxis (54), although the clinical rele-
vance of this action of cetirizine in patients with CIU is unclear. It has no cardiac
toxicity. In adults, the licensed dosage is 10 mg daily or 5 mg twice daily. There
is an oral solution (5 mg/mL) for children 2 years and older.
Several studies of the efficacy of cetirizine in CIU have been published.
An early multicenter double-blind study in 219 patients compared cetirizine 5–
20 mg daily with hydroxyzine 25–75 mg daily and placebo (55). The results
showed equivalence with hydroxyzine in terms of clinical efficacy and superiority
with regard to severity of side effects, which with cetirizine were no greater than
placebo. It is a criticism of this and most other clinical studies of antihistamines
in CIU that the criteria for diagnosis of CIU are not clearly set out, and the
question arises as to how many patients recruited actually had predominantly
physical urticaria. A subsequent smaller placebo-controlled study in which 30
patients with CIU received 10–20 mg cetirizine daily also showed a significant
benefit (56). Cetirizine is as effective as another low-sedation antihistamine, lora-
tadine, as suggested by a double-blind placebo-controlled study of 116 patients
with chronic urticaria (57). These results are summarized in Table 3.
2. Loratadine
Loratadine is a long-acting minimal-sedation H 1-antihistamine with little or no
affinity for cholinergic or alpha-adrenergic receptors and no cardiotoxicity. It is
widely used in the treatment of CIU because of its efficacy and low frequency
of adverse reactions, leading to a high degree of patient compliance. In addition
to its H 1-antagonist activity, it has antiallergic action independent of the H 1-recep-
tors. This action includes ‘‘stabilization’’ of the mast cell membrane, leading to
reduced secretion of mast cell–derived mediators including eicosanoids, suppres-
sion of adhesion molecule expression, and inhibition of vasopermeability (58).
There is convincing evidence that loratadine in therapeutic dosages suppresses
mediator release into nasal secretions in patients with seasonal allergic rhinitis
(59). To what extent these actions form a part of the therapeutic response to
loratadine in the skin of patients with CIU, at least at a therapeutic dosage of 10
mg daily, is uncertain.
Urticaria and Angioedema 263
3. Mizolastine
Mizolastine, a relative newcomer to the ranks of the so-called second-generation
low-sedation H 1-antihistamines, has no anticholinergic and minimal sedative ef-
fects. It is also claimed to have anti-inflammatory action independent of its affin-
ity for the H 1-receptor. In the rat, it inhibits transformation of arachidonic acid
to its lipoxygenase transformation products, the pro-inflammatory leukotrienes
and related fatty acids (64). To what extent this is relevant to the actions of the
drug in humans is uncertain. A recently published report (65) in 247 patients
with CIU compared mizolastine 10 mg daily with loratadine 10 mg daily and
placebo. Mizolastine was more effective in suppressing symptoms and signs of
CIU than placebo and equivalent to loratadine. Angioedema, when present, was
similarly ameliorated. Adverse effects were no different from those occurring
with placebo for either active drug.
A smaller study involving 56 patients with CIU compared mizolastine with
placebo (66). The results showed that mizolastine produced a greater decrease
in itching, whealing, and erythema than placebo. Drowsiness and anticholinergic
side effects were not significantly different between mizolastine and placebo.
Further details of these studies are summarized in Table 3. Overall, mizolastine
appears to be equally, but not more, effective than loratadine and cetirizine in
the management of CIU.
4. Fexofenadine
Fexofenadine is an effective low-sedation antihistamine. It has no cardiotoxic
side effects, causes no drowsiness or impairment of cognitive function, and can
be safely administered with cytochrome P-450-inhibiting drugs. Its pharmacolog-
264
Cetirizine 10 mg 219 Randomized, double- P, E, W, ordinal Cetirizine ⬃ hy- Severe somnolence: Was double-blinding 55
daily, hydroxyzine blind, parallel, 4 scale, symptoms, droxyzine ⬎ pla- Placebo 3% compromised?
25–75 mg daily, wks VAS cebo Cetirizine 6%
placebo Cetirizine more effec- Hydroxyzine 15%
tive on itch than
wheal size
Cetirizine 10 mg 30 Double-blind, cross- P, E, W, ordinal Cetirizine more effec- Small numbers 56
daily, placebo over, 4 wks tive than placebo
Cetirizine 10 mg, lor- 116 Randomized, double- P, E, W, size of W, Cetirizine and lorata- Dizziness, drowsiness: Loratadine signifi- 57
atadine 10 mg, pla- blind, parallel, 4 ordinal dine ⬎P1 Cetirizine 20% cantly more rapid
cebo; all daily wks At 4 wks free of Loratadine 16% in action than cetir-
symptoms: Placebo 8% izine
Loratadine 63%
Cetirizine 45%
Placebo 13%
Fexofenadine 60, 222 Randomized, double- P, W, ordinal: overall Fe 180, 240 mg ⬎P1 Drowsiness and 68
120, 180, 240 mg blind, parallel, in total other side effects:
daily; placebo 6 wks symptom score fexofenadine ⬃
daily All doses ⬎ decrease placebo
pruritus
Kobza Black and Greaves
Fexofenadine 20, 60, 439 Randomized, P, W, ordinal All doses of fexofena- Frequency of seda- Quality-of-life indi- 69
120, 240 mg twice multicenter, dou- dine ⬎ placebo for tion not stated ces also showed
daily or placebo ble-blind, parallel, P and mean total improvement on
twice daily 4 wks symptom score fexofenadine
Loratadine 10 mg 187 Randomized, double- P, E, W, ordinal, over- Loratadine ⬎ terfena- Active drugs had mini- 60
daily, terfenadine a, blind, parallel, 4 all improvement dine ⬎ placebo mal side effects, no
60 mg twice daily, weeks Marked relief: greater than pla-
placebo Loratadine 64% cebo
Terfenadine 52%
Placebo 25%
Loratadine 10 mg 172 Randomized, double- P, W, ordinal, overall Loratadine ⬃ hy- Sedation: Hydroxyzine caused 63
daily, hydroxyzine blind, parallel, 4 efficacy droxyzine ⬎ P1 Loratadine 7% marked drowsiness
Urticaria and Angioedema
25 mg three times weeks At 4 wks patients with Hydroxyzine 49% and dry mouth; lora-
daily, or placebo marked relief: Placebo 3% tadine caused ⬃ se-
Loratadine 65% dation to placebo.
Hydroxyzine 66% Was double-blind-
Placebo 41% ing compromised?
Mizolastine 10 mg, 247 Randomized, P, number and size of Mizolastine ⬃ loratad- Drowsiness more fre- 65
loratadine 10 mg, multicenter, dou- W, ordinal ine; sig more quent with mizolas-
placebo; all daily ble-blind, parallel, effective than tine than loratadine
4 wks placebo or placebo
Mizolastine 10 mg 56 Randomized, two- P, E, W, ordinal Mizolastine sig more Slightly more drowsi- 66
daily, placebo center, double- effective than pla- ness with mizolas-
blind, parallel, 4 cebo tine
wks
a
Terfenadine has been withdrawn in most countries. VAS, visual analog scores; Pl, placebo; ⬎ significantly better; ⬃ essentially equivalent; P, pruritus,
E, erythema, W, wheal; sig, significantly; Nos, number of participants; Fe, fexofenadine.
265
266 Kobza Black and Greaves
ical and pharmacokinetic properties have recently been reviewed (67). In the
treatment of CIU, fexofenadine is administered at a dosage of 180 mg (one tablet)
daily. It is licensed in some countries for children under the age of 12 years. In
a dose-ranging study, daily fexofenadine doses of 60 mg, 120 mg, 180 mg, and
240 mg were compared to placebo (68). Two hundred and twenty-two patients
with CIU were randomly allocated to one or another of these daily dose regimens
on a double-blind basis. The 180 mg and 240 mg doses produced significant
improvement in total symptom score. Lower doses caused an improvement in
scores for itching. As a result of this study, the authors recommended the 180 mg
daily dose for the patients with CIU. Adverse side effects were trivial and no
greater than with placebo at any of the dosages used.
In another randomized, double-blind, placebo-controlled, dose-ranging
multicenter study, the fexofenadine doses given were 20, 60, 120, or 240 mg
twice daily (69). All four doses were more effective than placebo with regard to
amelioration of pruritus, whealing, and total symptom score (Fig. 1). It is interest-
ing that patients receiving fexofenadine experienced less drowsiness than those
receiving placebo. The authors concluded that dosages of fexofenadine of 60 mg
twice daily or more were most effective. Quality-of-life indices were measured
and showed an overall improvement in fexofenadine-treated patients in whom
urticaria interfered significantly less with daily activities and with sleep than it
did in placebo-treated patients.
Overall, fexofenadine appears to be an effective H 1-antihistamine with a
very low frequency of unwanted side effects and no sedation or cardiotoxicity.
D. H 2-Antihistamines
Studies on the responses of human skin blood vessels led to the conclusion that
H 2- as well as H 1-receptors were present on these vessels (8, 36, 37). Activation
of H 1- and H 2-receptors induced erythema and whealing, but H 2-activation had
little effect on flare and itching. Cimetidine, an H 2-receptor antagonist, in combi-
nation with chlorpheniramine, caused a significantly greater inhibition of hista-
mine-induced erythema than either drug alone (38). This raised the possibility
that the combination of H 1- and H 2-antihistamines might be more effective than
either drug alone in the treatment of urticaria.
The earliest study of H 1- and H 2-antihistamines in urticaria by Commens
and Greaves included 19 patients with chronic idiopathic urticaria who were
allocated on a randomized, double-blind basis to three consecutive treatments for
2 weeks consisting of a combination of chlorpheniramine 4 mg and cimetidine
400 mg each four times a day, chlorpheniramine 4 mg four times a day, and
placebo four times a day (39) (Table 4). There was a significant reduction in
whealing and itching with chlorpheniramine treatment, alone and when combined
Urticaria and Angioedema 267
daily for 7–10 days, in sequential combination with placebo, terbutaline 2.5 mg
four times daily, cyproheptadine 4 mg four times daily, chlorpheniramine 4
mg four times daily, or cimetidine 300 mg four times daily. The hydroxyzine–
cimetidine combination significantly improved itching and number of wheals
compared to all other combinations (71).
Combination treatment with H 1- and H 2-antagonists was studied in 15 se-
lected patients with chronic urticaria in a randomized, crossover, double-blind
study. Chlorpheniramine 4 mg four times daily, chlorpheniramine 4 mg and ci-
metidine 400 mg four times daily in combination, and placebo were administered
for 4 weeks with a 1 week washout period. The number and persistence of wheals
and the presence of itching were scored daily on an ordinal scale. The group as
a whole showed no difference in number and persistence of wheals between the
antihistamine- and placebo-treated groups; however, four patients fared signifi-
cantly better on combined antihistamine therapy, so the authors suggested that
the combined H 1- and H 2-antihistamine treatment might show modest benefit in
some patients (72).
A study by Cook and Shuster assessed the severity of 20 patients with
chronic idiopathic urticaria without therapy (73). They were then allocated in
a double-blind randomized manner to three blocks of 2 weeks’ treatment with
cimetidine and placebo, chlorpheniramine and placebo, and cimetidine and chlor-
pheniramine. Both H 1-receptor blockade alone and in combination with H 2-
receptor blockade produced a significant reduction in whealing and itching, but
there was no significant difference among the treatments.
In a multicenter study, 120 patients with chronic idiopathic urticaria were
treated with chlorpheniramine for 6 weeks, commencing at 4 mg four times daily.
The dosage was increased until symptoms were controlled, or to the maximum
tolerated. Forty-three patients did not respond, but chlorpheniramine was contin-
ued in all. Forty were randomly allocated to receive in addition either cimetidine
400 mg four times a day or placebo four times a day, and assessed for 8 weeks.
The most important change was reduction in total symptom score compared to
baseline. Chlorpheniramine and cimetidine in combination were significantly
more effective than chlorpheniramine alone at both 4 and 8 weeks (74).
These studies do not demonstrate any consistent efficacy of a combination
of an H 1- and H 2-antihistamine over an H 1-antihistamine alone. It has been sug-
gested that any modest improvement with the combination may not only have
been due to the blockade of H 2-receptors on blood vessels, but also to increased
levels of chlorpheniramine or hydroxyzine, which could have occurred because
cimetidine inhibits the enzyme complex cytochrome P-450, which metabolizes
chlorpheniramine and hydroxyzine and elevates the H 1-antihistamine plasma and
tissue concentrations (40).
In another study, however, 25 patients with chronic urticaria were treated
with the low-sedation antihistamine terfenadine (subsequently withdrawn) in
Urticaria and Angioedema 271
A. Dermographism
Symptomatic dermographism is the most common physical urticaria (Table 5).
It is an abnormal itching, whealing response to moderate friction of the skin (78).
A reproducible stimulus can be quantified by using a calibrated spring-loaded
stylus (dermographometer), stroked firmly along the skin of the back, and measur-
ing the width of the wheal produced. In symptomatic dermographism, itching and
whealing occur within minutes below a 36 g/mm 2 setting of the stylus. Patients
generally have very itchy uncomfortable skin, and show wheals, often linear,
within minutes of scratching. Dermographism is usually idiopathic and not asso-
ciated with systemic disease.
In symptomatic dermographism, the reproducible whealing response can
be assessed objectively, so this has been used to test whether a combination of
H 1- and H 2-antihistamines was superior to H 1-antihistamines alone; however, the
results obtained may not be applicable to ordinary chronic urticaria.
A double-blind trial in 33 patients with symptomatic dermographism
showed that hydroxyzine 75 mg daily decreased whealing to a significantly
greater degree than chlorpheniramine 12 mg daily, and was preferred by patients
(79).
A double-blind, randomized trial of antihistamine therapy using chlor-
pheniramine 4 mg, cimetidine 400 mg, and their combination four times daily
in successive 2-week periods was carried out in 10 patients with dermographism
(80). The mean diameters induced by the stylus at 49.0 and 73.5 g/mm 2 after 10
min were measured after each treatment period. There was significant overall
improvement with the combination treatment, but chlorpheniramine given alone
produced no benefit. A similar study showed that only the combination of cimeti-
dine and chlorpheniramine significantly reduced dermographometer-induced
wheal and flare compared to either H 1- or H 2-antihistamine alone or to placebo
(81). In another study, a single low dose of chlorpheniramine (4 mg) successfully
reduced dermographometer-induced wheals (82); therefore, the combination of
H 1- and H 2-antihistamine was not necessarily superior to the H 1-antihistamine
chlorpheniramine.
Table 5 H 1- and H 2-Antihistamine Treatment of Physical Urticarias
Study design
Treatments Nos and length Assessments Results Side effects Reference
Dermographism
Hydroxyzine 75 mg 33 Double-blind, 2 wks Dermographometer Hy ⬎ Ch 79
daily, chlorphe- wheal widths
niramine 12 mg
daily
Chlorpheniramine 4 16 Randomized, double- Dermographometer Ch ⫹ Ci ⬎ Ch 80
mg qid, cimeti- blind, sequential, wheal widths ( p ⬍.025)
dine 400 mg qid, 2 weeks Ci worsened
Urticaria and Angioedema
combination
Chlorpheniramine 4 12 Randomized, double- Dermographo- Hydroxyzine: the Trimeprazine and 78
mg qid, mepyra- blind, crossover, 5 meter wheals most effective cyproheptadine
mine 50 mg tid, days treatment, 2 most sedating
promethazine 50 days washout
mg nocte, ketoti-
fen 1 mg bid, cy-
proheptadine 4
mg qid, trimepraz-
ine 10 mg tid, pre-
treatment
Chlorpheniramine 4 19 Randomized, double- Dermographometer Ch ⫹ Ci ⬎ Pl 81
mg qid, cimeti- blind, crossover; wheal widths ( p ⬍ 0.01)
dine 400 mg qid, each combination,
combination, 48 h, 5 days free
placebo
Chlorpheniramine 4 20 Randomized, double- Whealing response Ch ⫹ Ci ⬎ Ci 82
mg, cimetidine blind, sequential to dermogra-
400 mg, or combi- phometer
273
nation 2 h before
assessment
274
Study design
Treatments Nos and length Assessments Results Side effects Reference
Cy, cyproheptadine; Hy, hydroxyzine; Pl, placebo; Te, terfenadine; ke, ketotifen; ⬎, significantly better; ⬃, equivalent response; p, probability; VAS, visual
analog score; h, hours; Nos, number of participants; bid, twice daily; tid, three times daily; qid, four times daily; nocte, at night.
276 Kobza Black and Greaves
B. Cholinergic Urticaria
Cholinergic urticaria (heat bumps, prickly heat) (86) (Table 5), another common
type of urticaria grouped with the physical urticarias, occurs in up to 10% of
young adults. Within minutes, a rise in core body temperature caused by heating
induced by a hot bath, exercise, or stress induces multiple itchy small monomor-
phic wheals surrounded by a flare. The hives usually last less than 1 hour. Se-
verely affected patients may develop angioedema or a form of exercise-induced
anaphylaxis.
Challenge tests include exercise or a hot bath to induce the characteristic
wheals. The reproducibility of whealing after challenge is not as consistent as
dermographometer-induced whealing in dermographism; however, wheal counts
in a predefined area have been used as an objective measurement of the severity
of cholinergic urticaria.
Ten patients with cholinergic urticaria were tested in a randomized, double-
blind, crossover, placebo-controlled trial with hydroxyzine 20 mg three times
daily. Each treatment was taken for 5 days with a 3-day washout. There was a
significant reduction in the number of exercise-induced wheals with hydroxyzine
compared to placebo. One patient in each group reported drowsiness (87).
Cetirizine in doses of 10 mg and 20 mg was studied in a double-blind,
placebo-controlled, crossover trial involving 3-week treatment periods in 24 pa-
Urticaria and Angioedema 277
tients with cholinergic urticaria (88). Evaluation of the patients’ daily symptom
scores based on itching, erythema, and whealing showed a high level of improve-
ment with cetirizine, with only whealing showing a greater improvement at the
higher dose.
Although antihistamines are moderately effective in many patients with
cholinergic urticaria, some severely affected patients may not benefit signifi-
cantly. A controlled trial of danazol 200 mg three times a day significantly con-
trolled whealing in patients with cholinergic urticaria (89). Although this is an
unlicensed indication for this drug, it may be an option for short-term treatment
of the most severely affected patients.
C. Cold Urticaria
The most common form is acquired cold urticaria in which contact with cold air,
water, or objects induces itching, erythema, and wheals localized to the contact
site (90). Wheals develop within minutes and resolve within 1 hour. Exposure
of large areas of the body to cold, such as swimming in cold water, can induce
massive histamine release with risk of histamine shock and drowning. Patients
with cold urticaria must avoid such situations and have epinephrine available.
Confirmatory challenge testing is by application of a melting ice cube in
a plastic bag against the skin for 20 min, resulting in whealing at the site.
The condition usually occurs in children and young adults. It is idiopathic
in over 90% of cases. Rarely, it may be secondary to cold-reactive proteins such
as cryoglobulins, which should be measured especially if there are unusual associ-
ated features such as Raynaud’s disease or purpura. Some patients have cryoglo-
bulinemia secondary to lymphoproliferative malignancy.
Treatment of idiopathic cold urticaria is with H 1-antihistamines (Table 5).
Early studies showed that cyproheptadine was effective in cold urticaria; how-
ever, it is sedative and can cause headaches and inappropriate weight gain. Other
H 1-antihistamines with fewer side effects are as, or more, effective. For example,
a double-blind, crossover study in six children with cold urticaria showed that
ketotifen, a somewhat less sedating antihistamine, was as effective as cyprohepta-
dine (91). A double-blind comparison of cyproheptadine 4 mg, doxepin 10 mg,
cinnarizine 10 mg, and hydroxyzine, all administered three times daily, showed
similar efficacy of these H 1-antihistamines assessed by suppression of the ice
cube test. Doxepin was subjectively the most effective and, although sedating,
had the fewest side effects (92).
Another second-generation antihistamine, acrivastine, was more effective
in treating cold urticaria than cyproheptadine and was less sedating (93). Twelve
patients with cold urticaria were tested with an ice cube before and 4 hours after
administration of cetirizine 10 mg. The whealing response was abolished in five
patients and reduced in the others (83). These studies suggest that second-genera-
278 Kobza Black and Greaves
D. Solar Urticaria
This is a rare condition in which itching, erythema, and whealing occur within
minutes in areas exposed to ultraviolet radiation and/or visible light. The wheals
resolve within 1 hour. Confirmation is an immediate whealing response to natural
sunlight or a solar simulator, but the monochromator, available in special photo-
biology units, will demonstrate the specific wavelengths responsible. Treatment
is difficult, but some patients respond to low-sedation H 1-antihistamines (94).
In a placebo-controlled, double-dummy, crossover study in six patients with so-
lar urticaria, terfenadine 60 mg twice daily (now withdrawn) or cetirizine 10 mg
daily was given for 2 days with a washout period of 7 days. Monochromator-
induced whealing was assessed 2 hours after the last dose of medication. At the
doses used, cetirizine and terfenadine were equally effective in raising the thresh-
old whealing response in four patients, but two patients failed to respond to either
(95) (Table 5). This is in keeping with the variable response to antihistamines
in solar urticaria (94). Treatment of patients failing to respond to H 1-antihista-
mines in combination with sunblocks includes photochemotherapy with ultravio-
let A (PUVA) (96) or even plasmapheresis (97) supervised in specialist photobi-
ology centers.
F. Urticarial Vasculitis
Usually a cause cannot be identified for urticarial vasculitis (3). In a few patients
it may be due to an infection such as hepatitis B or C, or to a collagen vascular
disease such as lupus erythematosus or Sjögren’s disease. Investigation for pul-
monary, renal, or other systemic involvement should be undertaken.
There are no controlled trials of therapy. Most patients respond poorly to
H 1-antihistamine therapy; however, because the lesions are itchy these medica-
tions are usually continued and other medications added. The response is unpre-
dictable. Nonsteroidal anti-inflammatory drugs, such as dapsone 50–100 mg
daily, colchicine 0.5 mg twice to three times daily, and antimalarials have all
been used. Long-term oral corticosteroids may be necessary, but the dosage re-
quired for control may exceed prednisone 30 mg daily. Azathioprine can be used
for a steroid-sparing effect.
X. SUMMARY
ber, size, and duration of urticarial lesions. Relief of whealing, flaring, and ery-
thema may be incomplete as the vascular effects of histamine are mediated to
its action at H 2-receptors as well as at H 1-receptors, and other vasoactive sub-
stances may also be involved.
In randomized, prospective, placebo-controlled, double-blind studies, the
new low-sedating H 1-antihistamines have been found to be effective and safe in
urticaria. Sedating antihistamines, although effective, place patients at risk for
adverse effects, including decreased psychomotor performance. The response to
H 1-antihistamines in some types of urticaria, for example, in urticarial vasculitis,
is unsatisfactory. An H 2-antihistamine administered concurrently with an H 1-anti-
histamine may modestly enhance relief of itching and wheal formation in some
patients with urticaria refractory to treatment with an H 1-antihistamine alone.
The available evidence does not justify the routine addition of H 2-antihistamine
treatment to H 1-antihistamine treatment.
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9
Histamine and Antihistamines
in Anaphylaxis
Stephen L. Winbery
Methodist Central Hospital Teaching Practice,
Memphis, Tennessee
Philip L. Lieberman
University of Tennessee College of Medicine,
Memphis, Tennessee
I. INTRODUCTION
287
288 Winbery and Lieberman
Table 1 Continued
duced mast cell and basophil degranulation. The approximate incidence of ana-
phylaxis and anaphylactoid reactions is provided in Table 2.
The same vasoactive and inflammatory mediators, including histamine and
tryptase play a role in both types of clinical events. Measurement of serum tryp-
tase levels for mast cell degranulation may differentiate IgE-mediated from non-
IgE-mediated reactions but as yet are not widely used (26–28).
Penicillin
1–5 reactions per 10,000 patient treatments Idsoe et al. (1)
Cephalosporins
3–7% of patients with a history of penicillin allergy Saxon et al. (2)
and a positive skin test
N-acetylcysteine for acetaminophen overdose
50 patients in 17 months at one pediatric hospital Bailey and McGuigan (3)
Radiocontrast media
Estimated 2667 reactions with 500 deaths to hyperos- Cohan et al. (4)
molar agents
Severe reactions in 0.04% of patients receiving lower Katayama et al. (5)
osmolar agents
Plasmapheresis and cryofiltrationa
Plasmapheresis: 2 of 21 patients with 497 procedures Siami et al. (6)
Cryofiltration: 4 of 28 patients with 680 procedures
Drugs used during perioperative period
Penicillin, analgesics, nonsteroidal anti-inflammatory van der Klauw et al. (7)
drugs (NSAIDs)
Anesthetics—1: 13,000 Laxenaire (8)
Muscle relaxants—1: 6500
Australia: frequency between 1: 5000 and 1: 25,000 Fisher and More (9)
with mortality of 3.4%
France—1:4500 cases Hatton et al. (10)
MMR
28 patients reported since 1980 Kelso et al. (11)
Insect stings
0.4–3% of population is sensitive Golden (12)
Estimated 25–50 deaths per year Barnard (13)
39 of 138 patients with a previous history upon re- van der Linden et al. (14)
challenge
1: 2000 individuals is severely allergic Maher et al. (15)
Aspirin and NSAIDs
Anaphylactoid reactions occur in as many as 0.9% of Settipane et al. (16)
patients taking aspirin
35: 51,797 patients taking NSAIDs experienced shock Strom et al. (17)
Most common agent causing anaphylaxis in a series Kemp et al. (18)
of 267 adult cases
Allergen-specific immunotherapy
1: 100,000–1: 1,000,000 doses Klimet (19)
a
All patients who had reactions were taking ACE inhibitors.
MMR, measles, mumps, rubella; NSAID, nonsteroidal anti-inflammatory; ACE, angiotensin-con-
verting enzyme.
Anaphylaxis 291
C. Modulation by Histamine
Histamine may play a role in modulating anaphylaxis, as it binds to H 2-receptors
on basophils and mast cells, leading to inhibition of further histamine release by
the cyclic adenosine 3′,5′–monophosphate (cAMP)-dependent mechanism (39–
41). H 2-receptor agonists cause a dose-dependent inhibition of antigen-induced
histamine release from sensitized guinea pig hearts. This suggests histamine feed-
back inhibition of antigenic histamine release via H 2-receptors (42). In theory,
if histamine modulates the anaphylactic response via H 2-receptors, H 2-receptor
antagonists could have a detrimental effect on the treatment of anaphylaxis. This
has been reported with the use of H 2-antagonists alone in clinical settings (43).
As discussed below, the addition of H 2-antagonists may be of benefit in the treat-
ment or prevention of anaphylactic episodes and some authors have suggested
the addition of cyclo-oxygenase inhibitors when treating anaphylaxis (44).
A. Histamine Receptors
Histamine stimulates H 1-, H 2-, and H 3-receptors to produce its characteristic re-
sponses (Table 4). Many of the actions of histamine are local and tissue-depen-
dent. H 1-receptor stimulation results in the breakdown of the second-messenger
inositol phosphate and calcium mobilization, and H 2-mediated responses are
mostly due to activation of adenylate cyclase; however, there is considerable
‘‘cross talk’’ between second messenger systems (54). The mechanisms responsi-
ble for many actions of histamine such as vascular smooth muscle dilation are not
understood and may involve release of epithelial factors. Histamine can stimulate
endothelial cells to produce nitric oxide, a smooth muscle relaxant factor (55,
56). In guinea pig lung tissue, histamine binds to H 1-receptors to produce a phos-
pholipase-C-dependent calcium mobilization that stimulates the conversion of
L-arginine to nitric oxide. Nitric oxide activates guanylate cyclase, leading to
production of 3′,5′-cyclic guanosine monophosphate (cGMP) (57).
The H 3-receptor is identified pharmacologically by its antagonist, thiopera-
mide. These receptors have been located on presynaptic nerve endings both per-
ipherally and in the central nervous system. H 3-receptors control acetylcholine
release at the level of the myenteric plexus in the guinea pig intestine (58), modify
peripheral neuropeptide release, modulate airway reactivity (59), and control his-
tamine synthesis in brain and lung tissue. H 3-receptors are on presynaptic termi-
nals of sympathetic effector nerves that innervate heart and systemic vasculature.
The H 3-receptor modulates norepinephrine release from systemic nerves and, in a
296 Winbery and Lieberman
2. Nerves
Histamine directly stimulates nerve endings to produce pruritus. Local inflamma-
tion nonspecifically stimulates nerve endings to release neurotransmitters and
neuropeptides that can perpetuate and potentiate the actions of histamine and
other inflammatory mediators.
4. Respiratory System
Histamine acts via H 1-receptors in the lower airways to constrict bronchial
smooth muscle, dilate or constrict vascular smooth muscle, cause microvascular
leak, and activate sensory nerves. In healthy individuals, histamine does not cause
significant bronchoconstriction, but patients with asthma and other lower airway
disorders are hypersensitive to its bronchoconstricting effects. H 1-receptors also
mediate an increase in airway fluid and electrolyte secretions and increased mu-
cous viscosity. In awake sheep, bronchial vasodilation is mediated primarily by
histamine acting on H 1-receptors (66). In experimental models, H 2-receptor stim-
ulation may actually relax constricted bronchial smooth muscle. This is probably
not clinically significant, since patients with asthma tolerate H 2-antagonists well
(67). Although most reports indicate that cimetidine and ranitidine do not cause
or potentiate bronchoconstriction in normal and asthmatic patients, in one study,
bronchoconstriction increased in 4 of 24 asthmatic patients treated with cimeti-
dine. In addition, isolated basophils from H 2-antagonist-treated asthmatic patients
showed enhanced histamine release (68). H 3-receptors in the lungs modulate chol-
inergic neurotransmission, neuropeptide release, and bronchoconstriction (59, 69).
5. Gastrointestinal System
Histamine plays a physiological role in stimulating gastric acid secretion through
H 2-receptors, and H 2-antagonists have been widely used to decrease gastric acid
secretion. Histamine also produces gastrointestinal smooth muscle contraction
and relaxation. These responses are caused by direct actions on smooth muscle
H 1- and H 2-receptors and indirect actions leading to release of several active
substances from the gut’s own intrinsic nervous system.
to be measured more accurately and quickly than ever before. Histamine begins
to rise in 5–10 min and may remain elevated for up to 60 min. Urine histamine
and histamine metabolites may stay elevated longer and are more stable (70).
Analysis of the histamine metabolite methylhistamine in urine can be valuable
in diagnosing anaphylaxis (71), especially when combined with the measurement
of tryptase concentrations (26).
IV. ANTIHISTAMINES
H 1-receptor antagonists were introduced into therapeutic use 60 years ago. Bind-
ing of the H 1-antagonist to the H 1-receptor does not produce a response but,
rather, blocks the actions of endogenous histamine at H 1-receptors. For the most
part, H 1-antagonist binding is competitive and reversible, with the exceptions of
astemizole, terfenadine, and loratadine. Antihistamines may be ranked on the
basis of potency; however, equal efficacy can usually be obtained by giving a
relatively larger dose of the less potent drug. Potency may be relevant when
considering the limitations of the effects of these agents beyond histamine recep-
tor blockade (72).
A. Second-Generation H 1-Antihistamines
The newer H 1-antagonists such as cetirizine, fexofenadine, and loratadine are
highly selective for the H 1-receptor and are generally well-tolerated at doses that
produce high levels of antihistaminergic activity. At the present time, none of
the second-generation H 1-antagonists is available for injection, but in one study
several of the agents were given intravenously to squirrel monkeys (73). These
newer agents have not yet been widely used for the treatment or prevention of
anaphylaxis in humans; however, like their predecessors, they prevent anaphy-
lactic death in experimental animal models. The improved selectivity and addi-
tional antiallergic properties of these drugs may be of benefit in the treatment of
anaphylaxis (73–76). Two of the new H 1-antagonists, terfenadine and astemizole,
are no longer used in most countries due to potential cardiac toxicity (72) (see
Chap. 12).
H 1-receptor but also inhibit cell mediator release (77, 78), basophil migration
(79), and eosinophil recruitment (80). In therapeutic concentrations, H 1-antago-
nists such as chlorpheniramine, mepyramine, ketotifen, promethazine, diphenhy-
dramine, cyclizine, and oxatomide can inhibit IgE-induced histamine release (81).
At supratherapeutic concentrations, the H 1-antagonists can release histamine by
an antigen-independent direct cytotoxic effect on mast cells. The antiallergic ef-
fect to inhibit release of histamine from mast cells and basophils has been shown
with the second-generation H 1-antagonists as well, including terfenadine, loratad-
ine, cetirizine, azatadine, azelastine, ketotifen, and oxatomide (82–84). Their an-
tiallergic effects vary depending on the source of the mast cells and the stimulus
used (compound 48/80, IgE-antigen, substance P, Con A, or a calcium iono-
phore). The exact mechanism of inhibiting histamine release is unknown, but
may be due in part to the lipophilic and cationic nature of the H 1-antagonists.
Many H 1-antagonists are lipophilic, cationic drugs and may dissolve into the cell
membrane and produce stabilization to sodium ion and calcium ion flux; however,
there is imprecise correlation between lipophilicity and inhibition of histamine
release (82).
Several other antiallergic effects have been observed with the second-gen-
eration antihistamines including inhibition of allergen-induced eosinophil, baso-
phil, and neutrophil migration and inhibition of PAF-induced eosinophil accumu-
lation in the skin. There is a definite need for characterization of the antiallergic
properties of H 1-antagonists using double-blind, placebo-controlled human stud-
ies with strict criteria for measurement of plasma concentrations, standardization
of mediator assays, and reproducibility. The role of antiallergic effects of antihis-
tamines in the treatment of anaphylaxis, if any, has not been established and
further clinical investigation is warranted. The effects are reviewed in Chap-
ter 4.
V. ANTIHISTAMINES IN ANAPHYLAXIS
A. The Adjunctive Role of Antihistamines in Treatment
of Acute Anaphylaxis
It is important to emphasize early diagnosis of anaphylaxis along with prompt
treatment with epinephrine and volume expansion, realizing that antihistamines
are an adjunctive treatment (85). Histamine is only one of a number of mediators
that contribute to the pathophysiology of anaphylaxis, and H 1-antagonists are not
effective as single agents for the treatment of anaphylaxis.
Before the discovery of the H 1- and H 2-receptors, histamine was thought
to be the mediator of anaphylaxis because agents such as diphenhydramine
blocked or reversed histamine-induced hypotension and bronchospasm; however,
H 1-antihistamines alone were clinically ineffective in reversing all the symptoms
Anaphylaxis 301
phylactic signs and symptoms for patients in group 3 compared with the other
groups: the combination of an H 1- and H 2-antagonist was superior to an H 1-
antagonist alone. Although not all anaphylactic reactions were suppressed, there
were no severe reactions (103). In a third study involving 100 patients with previ-
ous reactions to RCM, the addition of an H 2-antagonist did not alter the results
of prophylaxis. Combined glucocorticoid–antihistamine treatment prevented the
majority of patients from having reactions and none had severe reactions (104).
At best, the results are inconclusive as to whether an H 2-antagonist is an effective
adjunctive agent to diphenydramine, prednisone, and ephedrine (105), therefore,
the use of an H 2-antagonist should be left to the discretion of the physician manag-
ing the patient.
The protocol for prevention of reactions to RCM in patients at risk should
be followed regardless of the route of administration of the RCM or the procedure
being performed. Reactions have been reported after hysterosalpingograms, my-
elograms, and retrograde pyelograms (106). The introduction of nonionic and
low-osmolar RCM has decreased the frequency, but not the severity, of adverse
events (107).
The risk of reactions to RCM in patients with previous reactions decreases
to 1% with the use of the prophylactic regimen plus the use of a low-osmolar
agent (105). The antihistamine/prednisone prophylactic regimen has been so suc-
cessful that it has been adopted for prevention of other anaphylactic reactions in
patients at risk in the following settings: plasma exchanges (108), general anes-
thesia (109), fluorescein administration (110). It has also been used in patients
with cold urticaria who must undergo bypass surgery (111). Based on studies in
ragweed-sensitized dogs, there has been some suggestion that the addition of
cyclo-oxygenase inhibitors to the RCM prophylactic regimen may be useful (44).
This prophylactic regimen has been demonstrated only to prevent anaphy-
laxis and anaphylactoid episodes. In two reported instances, it failed to prevent
304 Winbery and Lieberman
2. Volume Expanders
A combination of H 1- and H 2-antagonists with a corticosteroid effectively pre-
vented reactions to urea-linked gelatin solutions used as volume expanders in
two studies. In one study, volunteers received intravenous infusions of the plasma
expander. Fifteen of 50 had anaphylactic symptoms compared to 0 of 50 in the
pretreated group. In the other study, 27 of 150 orthopedic patients had significant
reactions when pretreated with only intravenous saline. When pretreated with
dimethindene and cimetidine, 4 of 150 patients had reactions; in those pretreated
with chlorpheniramine plus cimetidine, 9 of 150 patients had reactions (114).
3. Plasma Exchange
Patients undergoing plasma exchange may experience anaphylactic reactions due
to multiple causes. Pretreatment using a modification of the program established
for the prevention of RCM reactions has been successful in preventing repeat
reactions (108). These reactions seem much more likely when patients are treated
concurrently with angiotensin-converting enzyme (ACE) inhibitors (6).
4. Fluorescein
Fluorescein is commonly employed as an intravenous microvascular contrast
agent by ophthalmologists and optometrists. In patients with previous reactions
to fluorescein, the incidence of reaction with subsequent exposure can be nearly
50% (115). A modification of the treatment regimen for RCM reactions has been
used to prevent recurrent reactions. The modification includes a 3-day regimen
of oral prednisone followed by 50 mg diphenhydramine with 400 mg cimetidine
1 h before the test (110).
5. Idiopathic Anaphylaxis
Even after exhaustive searches for avoidable provoking factors for anaphylaxis,
some triggers remain undetected. Patients with mild episodes of idiopathic ana-
phylaxis that occur fewer than three or four times per year probably do not need
preventive therapy. For moderate or severe episodes occurring more frequently,
the combination of an H 1- and H 2-antagonist should be considered on a daily
basis. The second-generation, nonsedating H 1-antagonists should be used in pref-
erence to potentially sedating drugs. When patients are refractory to antihistamine
therapy, glucocorticoids, albuterol, cromolyn, and ephedrine may be empirically
added (116). Adult and pediatric patients with idiopathic anaphylaxis have similar
clinical profiles and should be treated in a similar way (117).
Anaphylaxis 305
6. Anaphylaxis to Latex
Exposure to latex is widespread. Sources include condoms, balloons, gloves,
bladder catheterization with rubber tubing, intravenous injection ports and tubing,
ventilator tubing, electrocardiogram pads, and latex-cuffed enema tubes. In pa-
tients with latex allergy, perioperative prophylaxis with corticosteroids, H 1- and
H 2-antagonists, and ephedrine has been recommended; however, such a prophy-
lactic regimen, while useful, has not been as successful in preventing reactions
to latex as it is in preventing reactions to RCM in at-risk individuals, perhaps
due to differences in the inducing or causative mechanisms between RCM and
latex (118).
7. Exercise-Induced Anaphylaxis
Exercise-induced anaphylaxis was first described by Sheffer and Austen in 1980
(119). The mechanism responsible for anaphylaxis appears to be non-IgE-medi-
ated mast cell activation. Successful prophylaxis with antihistamine therapy is
not always achieved (120, 121). Of almost 300 patients, 56% reported improve-
ment with H 1-antagonist prophylaxis compared to 44% who improved by
avoiding extreme temperatures and 37% who improved by avoiding certain food
co-triggers (24).
9. Morphine
Morphine is used for preoperative analgesia and induction of anesthesia. Philbin
and associates investigated the relationship between plasma histamine levels, sys-
temic vascular resistance, and diastolic blood pressure in patients given 1 mg/
kg intravenous morphine before cardiac bypass surgery. In patients undergoing
bypass, intravenous morphine causes significant histamine release. Four groups
of 10 patients each were studied. Group 1 received placebo; group 2 received
cimetidine; group 3 received diphenhydramine; group 4 received both the H 1-
and H 2-antagonist. Patients in both groups 3 and 4 had significant decrease in
morphine-related reactions, but the combination therapy was more effective than
treatment with the H 1-antagonist alone. Thus, pretreatment with antihistamines
can attenuate the hemodynamic complications of intravenous morphine adminis-
tered to patients undergoing cardiac bypass (129).
In a postmortem study of heroin-related deaths, 32% of the decedents had
elevated mast cell tryptase levels. This suggests that a significant proportion of
heroin-related deaths are, at least in part, due to anaphylactoid reactions (130).
10. Vancomycin
Intravenous injection with vancomycin or polymixin causes non-immune dose-
dependent degranulation of mast cells and basophils leading to anaphylactoid
reactions. The reaction to vancomycin can be prevented by pretreatment with an
antihistamine (131).
11. Protamine
Protamine is being used increasingly in cardiac catheterization, cardiothoracic
and vascular surgical procedures, dialysis, and leukopheresis. It is also found in
some insulin preparations. Reactions to protamine can be IgE-mediated (132).
The incidence of reaction to protamine during cardiac bypass can be as high as
Anaphylaxis 307
10.7% (133). Patients with known sensitivity to protamine who must undergo
procedures in which hexadimethrine bromide cannot be substituted should be
pretreated with the prophylactic regimen used for reactions to RCM.
12. Chymopapain
Chymopapain, used topically for enzymatic debridement of surface lesions, is
known to induce anaphylactoid reactions. Antihistamines have been shown to be
effective in the prophylaxis of chymopapain-induced anaphylaxis. In a retrospec-
tive review of an uncontrolled trial, the combination of an H 1- and an H 2-antago-
nist was more effective than an H 1-antagonist alone for prevention of reaction
to chymopapain (134).
13. N-Acetylcysteine
N-acetylcysteine (NAC) is an antidote for acetaminophen overdose and in much
of the world, although not in the United States, is available for intravenous admin-
istration. In one study there were 50 cases of anaphylactoid reactions of varying
severity to NAC over 17 months in a pediatric hospital. The incidence of anaphy-
lactoid reactions to NAC has prompted clinicians to review the indications for
its use. Reactions to NAC can probably be prevented with H 1-antagonists (3).
1. Experimental Evidence
In pentobarbitone-anesthetized rats, compound 48/80 produces an anaphylactoid
response that includes decreased mean arterial blood pressure, decreased left ven-
tricular pressure, and increased frequency of ventricular tachycardia and fibrilla-
tion. Either cimetidine or diphenhydramine reduced the frequency of ventricular
tachycardia and fibrillation, but only the combination of the H 1- and H 2-antago-
nists completely inhibited hypotension and decreased left ventricular pressure
and ventricular arrhythmia. (137). Numerous studies have shown that H 1- and
308 Winbery and Lieberman
VI. SUMMARY
Anaphylaxis and anaphylactoid reactions are potentially fatal. These disorders are
sometimes iatrogenic, and increase with increased exposure to drugs, synthetic
substances, and medical procedures. Non-IgE-mediated anaphylactoid reactions
are common in medical settings and are clinically indistinguishable from anaphy-
laxis. These reactions may be unrecognized if a rigid classic definition of anaphy-
laxis is used.
Histamine is a primary mediator of anaphylaxis and signs and symptoms
of anaphylaxis can be reproduced by histamine infusion. Histamine triggers a
cascade of inflammatory mediators and modulates its own release.
H 1-antihistamines are adjunctive treatment therapy for acute anaphylaxis
and anaphylactoid reactions, in which many mediators of inflammation are in-
Anaphylaxis 309
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Anaphylaxis 317
Michael S. Blaiss
University of Tennessee Center for the Health Sciences
College of Medicine, Memphis, Tennessee
I. INTRODUCTION
With the increasing emphasis on economics in health care there has been an
incentive to develop new ways to assess the value of health care treatment. This
has led to the development of the field of pharmacoeconomics, which can be
defined as the identification and measurement of the comparative value of differ-
319
320 Blaiss
Cost-Identification
Costs are compared among different programs or treatments.
Cost-Benefit
Costs are compared to benefits from a program or treatment as defined by society.
Cost-Effectiveness
Costs are compared to clinical effects produced by different programs or treatments.
Cost-Utility
Costs are compared to quality-adjusted life years attained among different programs
or treatments.
Cost-Effectiveness 321
ysis compares costs when the safety and efficacy of any two or more treatments
are assumed to be equal. This technique should not be used if there is any question
of differences in outcomes observed with the different treatment modalities. A
common use of cost-identification analysis would be comparing a brand-name
drug with its generic equivalent.
Cost–benefit analysis is a comparison of costs and the accompanying out-
comes on a monetary basis (4). This technique requires placing a dollar value
on the outcomes produced, which could be very difficult depending on who is
setting the value of the benefits obtained. An example of cost–benefit analysis
would be a case in which one treatment that costs $500 a year produces outcomes
valued by society at $1500, while a second treatment that costs $250 a year
produces outcomes valued by society at $1000 per year. The second treatment
would have the highest cost–benefit for the outcomes obtained, since for each
dollar spent there was a $4 benefit ($1000 outcomes/$250 costs), while the first
treatment had a $3 benefit ($1500 outcomes/$500 costs). Difficulties from this
type of cost evaluation arise when one tries to put a monetary value on years of
life saved or improvements in psychosocial outcomes (2).
The cost-effectiveness analysis compares the costs of alternative treatments
in monetary units with the clinical results obtained with treatment (6). This analy-
sis uses a natural unit or health outcome such as life-years gained, symptom-free
days, or number of cures obtained for assessing outcomes. This method allows
for the development of the cost-effectiveness ratio: the cost to achieve a particular
outcome. An example would be one treatment that costs $1000 for 5 patients
and increases symptom-free days by 50% and a second treatment that costs $1500
for 5 patients and increases symptom-free days by 90%. Treatment A has a cost-
effectiveness ratio of 20 (1000/50) while treatment B’s ratio is 16.7 (1500/90).
Even though the second treatment is more costly, it is more cost-effective due
to the higher increase in symptom-free days for each dollar spent. In using cost-
effective analysis in comparing two treatments, there are four possible outcomes
(7) (Fig. 1). Quadrant I shows that treatment A is more effective and costs less
than treatment B. In this case treatment A is truly cost-effective. In quadrant III,
the scenario illustrates that treatment A is more costly and less effective than
treatment B; therefore, treatment B is more cost-effective. The next possibility,
quadrant II, shows that treatment A is less costly and less effective than treatment
B. In this scenario, treatment A may or may not be the most cost-effective de-
pending upon the particular clinical situation and resources available for treat-
ment. One would need to analyze the cost-effectiveness ratio to determine the
optimal therapy. Quadrant IV, the last possibility, shows that treatment A is more
costly and more effective. Again it would depend upon the clinical situation,
resources available, and assessment of the cost-effectiveness ratio, in determining
which treatment produces the best value.
The last method of assessing pharmacoeconomics costs is cost-utility anal-
322 Blaiss
Allergic
Healthy adults rhinitis patients
Health domain (n ⫽ 116) (n ⫽ 111)
* p ⬍ 0.0001.
†
p ⬍ 0.0005.
Source: Adapted from Ref. 2.
pets or dust mites (12) and found that, in all but one health domain, patients with
perennial allergic rhinitis had significantly poorer quality of life than the healthy
controls (Table 2). Specific instruments used in the evaluation of quality of life
are usually focused on one particular interest such as a disease state, a distinct
patient population, or certain functions or problems. An example in allergic rhini-
tis is the Rhinitis Quality-of-Life Questionnaire (RQLQ) (13, 14) (Table 3). It
is scored on a six-point scale with a lower score indicating better quality of life.
Meltzer et al., using the RQLQ, showed that patients with rhinitis have impaired
quality of life compared to the healthy population (15).
1. Activities
2. Sleep
3. Nonspecific symptoms: fatigue, thirst, reduced productivity, tiredness, poor concen-
tration, headache, worn out
4. Practical problems: need to rub and blow nose/eyes repeatedly, inconvenience of
having to carry handkerchief
5. Nasal symptoms
6. Eye symptoms
7. Emotional problems: frustrated, impatient or restless, irritable, embarrassed by symp-
toms
Up to 40% of the population suffers from allergic rhinitis (16, 17). A majority
of patients with allergic rhinitis are children, adolescents, and young adults (18).
Because patients are rarely, if ever, hospitalized, rarely require surgery or other
sophisticated interventions, and do not have their day-to-day survival threatened
by this entity, allergic rhinitis may be seen as a minor nuisance. It is now being
recognized as a costly condition in the health care arena. Costs of allergic rhinitis
can be classified into two major categories: direct and indirect. Direct costs are
monies spent in the care of the patient, while indirect costs are monies lost due
to the disease. An important aspect of allergic rhinitis costs is that this disease
can lead to or complicate other high-cost disorders such as asthma, sinusitis, otitis
media with effusion, and nasal polyposis. These conditions lead to an important
cost category: ‘‘hidden’’ direct costs. Table 4 illustrates the direct, ‘‘hidden’’
direct, and indirect costs associated with allergic rhinitis.
Direct costs
Physician/provider consultation
Laboratory testing: allergy skin tests, RAST, etc.
Costs of specific allergy therapy: environmental control, prescription and OTC medi-
cations, and immunotherapy
‘‘Hidden’’ direct costs
Costs for antibiotics, radiographs for diagnosis and emergency department visits for
sinusitis
Surgical costs for nasal polyposis and sinusitis
Medical and surgical costs for otitis media with effusion
Costs of worsening asthma and frequent upper respiratory infections
Orthodontic costs
Evaluation and treatment of ocular symptoms
Indirect costs
Sleep disorders and neuropsychiatric abnormalities
Activity limitation due to symptoms and effects of first-generation H 1-antagonists
Decreased decision-making capacity
Impaired psychomotor function
Poor concentration
Irritability
Fatigue
Decreased functioning at work and school
Increased motor vehicle accidents and school and workplace injuries
show direct costs of allergic rhinitis of $4.48 billion and indirect costs of $3.37
billion.
Ray et al. assessed direct expenditures for treatment of allergic rhinocon-
junctivitis in 1996, along with calculating the ‘‘hidden’’ direct costs of rhinitis,
such as sinusitis, asthma, acute upper respiratory tract infection, pharyngitis and
tonsillitis, nonatopic conjunctivitis, and chronic otitis media and eustachian tube
disorders (24). These investigators found that the primary diagnosis of rhinitis
led to direct costs of $1.9 billion (in 1996 dollars). Costs were estimated for
rhinitis as a secondary diagnosis and found to be $4.0 billion (Table 5). Although
all these studies took distinct approaches and used different methods in determin-
ing costs related to allergic rhinitis, it is clear that this disease has a significant
economic impact on the health care system.
The mainstays of pharmacological therapy for allergic rhinitis are oral H 1-antago-
nists and intranasal corticosteroids. Table 6 lists some first- and second-genera-
tion H 1-antagonists and their costs per day calculated from their average whole-
sale price and recommended frequency of daily dosing (25). The average
wholesale price is used to keep the data uniform in this analysis. It is important
to note that the true cost of the H 1-antagonist for the patient may vary because
certain health plans may have arrangements for discounts from pharmaceutical
companies and certain pharmacists charge more or less for a particular medica-
tion. Also, in many countries most H 1-antagonists, including the new nonsedating
ones, are available on a nonprescription basis. First-generation H 1-antagonists
have been in use for many years. These drugs are all effective in decreasing the
symptoms of allergic rhinitis such as rhinorrhea, sneezing, nasal itching, and
ocular symptoms and are the least expensive daily pharmacological therapy in
the management of allergic rhinitis (Table 6). They may not be the most cost-
effective, however, because many patients experience significant side effects that
may impair productivity (Chap. 11). These H 1-antagonists cross the blood–brain
barrier and may cause significant central nervous system sedation, impairment
of psychomotor function, and depression (26, 27). This sedation may be imper-
ceptible. In many states it is illegal to operate heavy machinery or a motor vehicle
while using these medications. Internationally, civilian and military aviation au-
thorities prohibit their use. The first-generation sedating H 1-antagonists have been
shown to have a detrimental effect on learning in children (28–30). Fireman
determined from pharmacy data from a health maintenance organization (HMO)
Second-generation a
Fexofenadine (60 mg) $2.07
Loratadine (10 mg) $2.44
Cetirizine (10 mg) $1.92
First-generation
Diphenhydramine (50 mg) $0.56
Clemastine (2.68 mg) $1.35
Chlorpheniramine (8 mg) $0.21
Nasal spray
Azelastine $1.99
a
Costs in United States reflect prescription-only status of these
H 1-antihistamines.
Source: From Ref. 25.
328 Blaiss
group. Other clinical studies have shown that adults and adolescents with seasonal
allergic rhinitis had significantly better improvement with fluticasone nasal spray
than loratadine tablets (44, 45). Kozma compared cost-efficacy ratios for intrana-
sal fluticasone and terfenadine tablets within a sample of patients with seasonal
allergic rhinitis symptoms due to mountain cedar allergy (46). Costs measured
were the direct costs of the drugs used for therapy; efficacy was assessed using
patient ratings of symptoms and their overall assessment of response to treatment.
The cost-efficacy ratios for intranasal fluticasone once daily were more favorable
than the ratios for terfenadine 60 mg twice daily. Two cost-effectiveness studies
from Canada found fluticasone to be 2.5 times less costly daily than terfenadine
and 5.7 times less costly daily than loratadine (47).
Other intranasal corticosteroids and second-generation H 1-antagonists
have been compared in assessing clinical efficacy. Bernstein et al. conducted a
multicenter, double-blind, parallel-group study in 239 patients randomized to re-
ceive either triamcinolone nasal spray or astemizole tablets (48). Overall, triam-
cinolone spray was more effective than astemizole in reducing total nasal symp-
toms, nasal stuffiness, nasal itching, and sneezing. Schoenwetter et al. compared
the safety and efficacy of intranasal triamcinolone with oral loratadine in reliev-
ing symptoms of ragweed-induced seasonal allergic rhinitis (49). Improvement
in all rhinitis symptoms was significantly greater with triamcinolone than with
loratadine. Physicians’ global evaluations indicated that 78% of patients taking
triamcinolone had moderate to complete relief, compared with 58% of loratad-
ine-treated patients ( p ⱕ 0.0001). Schulz compared quality of life in patients
with allergic rhinitis using triamcinolone nasal spray or loratadine (50). At day
14, the patients using triamcinolone spray were significantly better ( p ⬍ 0.05)
in several different components of quality of life and overall quality of life as-
sessment. Ratner assessed use of loratadine tablets alone, fluticasone nasal spray
alone, and the combination in the management of seasonal allergic rhinitis. In
all aspects, fluticasone alone showed more clinical and quality-of-life improve-
330 Blaiss
ment than loratadine tablets. There was no added benefit to the combination of
loratadine tablets and fluticasone nasal spray compared to fluticasone nasal
spray alone.
Weiner performed a meta-analysis of articles comparing intranasal cortico-
steroids and nonsedating H 1-antagonists in the management of allergic rhinitis
(51). The conclusions gained from this study point out the greater improvement
in allergic rhinitis symptoms with intranasal corticosteroids, except in eye symp-
toms, for which both agents were equal. The authors were not truly able to analyze
cost-effectiveness from the studies, but did compare the mean daily cost of oral
corticosteroids in Australia (by asking pharmacists in four Australian states) with
the mean daily cost of intranasal corticosteroids. Their surveillance data found
that second-generation H 1-antagonists were 4.5 times more expensive daily than
intranasal corticosteroids. Stempel did an evidence-based analysis comparing
these agents in allergic rhinitis management and came to the same conclusion
(52). A study in South Africa found that intranasal corticosteroids were the least
costly in the management of allergic rhinitis (53).
In summary, these studies indicate that the intranasal corticosteroids are
more cost-effective than the second-generation H 1-antagonists in the management
of allergic rhinitis. It is important to remember that convenience and compliance
are deciding factors in chronic use of medication. Oral medications have a higher
compliance rate than inhaled agents (54). Also, these studies were primarily effi-
cacy-based, involving patients using the medications during short-term clinical
trials. In ‘‘real life’’ many patients only use these agents on an as-needed basis.
Informing patients of the pros and cons of each type of medication and allowing
them to participate in deciding on their pharmacological management may be
the best approach for highest compliance.
Allergen immunotherapy (vaccinations) is the administration of low, and
then sequentially increasing, dosages of allergens by subcutaneous injection in
patients with IgE-mediated diseases, such as allergic rhinitis, allergic asthma, and
insect sting anaphylaxis (55). It has been shown to be efficacious in the treatment
of patients with allergic rhinitis (56, 57). Sullivan reported that the average direct
costs for immunotherapy at Emory University were $800 for the first year and
$170 for next 2–4 years (58). The estimated costs for immunotherapy based on
the Medicare payment schedule are $1640, which includes 24 injections to main-
tenance dose, followed by monthly injections for 3–5 years and allergen extract
preparation for 10 allergens (59).
In determining the cost-effectiveness of allergen immunotherapy, Kumar
looked at costs of treatment and quality of life in patients with allergic rhinitis
prior to allergen immunotherapy and then assessed these variables yearly for 3
years of immunotherapy (60). The cost of care was $1129 ⫾ 321 in the year
prior to immunotherapy and $950 ⫾ 352 for the third year of allergen immuno-
therapy. This study suggests that allergen immunotherapy is no more costly by
Cost-Effectiveness 331
the third year than allergy treatment without immunotherapy, with significant
improvement in quality of life. Direct comparisons of cost-effectiveness of immu-
notherapy and H 1-antagonists are not available.
Urticaria and angioedema (Chap. 8) can have a marked effect on the patient’s
quality of life. O’Donnell used a generic quality-of-life instrument, the Notting-
ham health profile, and showed that patients with delayed pressure urticaria had
scores showing restriction in the areas of mobility, sleep, and energy, and demon-
332 Blaiss
strated high scores in pain, social isolation, and altered emotional reactions (63).
H 1-antagonists are the first-line therapy for patients with both acute and chronic
urticaria and angioedema. First-generation agents are effective for many forms
of urticaria and angioedema, and recent studies have documented the value of
the second-generation H 1-antagonists in controlling symptoms (64–66). Research
is lacking in comparing the cost-effectiveness of H 1-antagonists in this condition
compared to other medications, although it is clear that their safety and efficacy
outweigh such treatments as corticosteroids, tricyclic antidepressants, and immu-
nosuppressive therapy, such as cyclosporine. At present there are no studies as-
sessing cost-effectiveness between the first- and second-generation H 1-antago-
nists in controlling urticaria and angioedema. As with all chronic diseases treated
with first-generation H 1-antagonists, one needs to weigh the decreased cost of
these agents compared to second-generation agents against the sedative and other
adverse effects seen with first-generation agents that can increase indirect costs.
IX. ASTHMA
X. ANAPHYLAXIS
XI. SUMMARY
apy. H 1-antagonists are widely used in the treatment of many atopic disorders,
especially allergic rhinitis. This review has pointed out cost-effectiveness and
quality-of-life studies comparing the different H 1-antagonists among themselves,
and with other treatments used in allergic rhinitis, such as intranasal corticoste-
roids and allergen immunotherapy. Cost-effective analyses among H 1-antagonists
in other allergic diseases, such as atopic dermatitis, urticaria and angioedema,
and asthma, are lacking at this time.
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11
H 1-Antihistamines and the Central
Nervous System
F. Estelle R. Simons
University of Manitoba, Winnipeg, Manitoba, Canada
I. INTRODUCTION
337
338 Welch et al.
Alkylamines Piperidines
Brompheniramine (Dimetane) Azatadine (Optimine)
Chlorpheniramine (Chlor-Trimeton) Cyproheptadine (Periactin)
Dexchlorpheniramine (Polaramine) Phenindamine (Nolahist)
Ethanolamines Piperazines
Carbinoxamine (Clistin) Hydroxyzine hydrochloride (Atarax)
Clemastine (Tavist) Hydroxyzine pamoate (Vistaril)
Dimenhydrinate (Dramamine) Meclizine (Antivert)
Diphenhydramine (Benadryl)
Doxylamine (Unisom)
Ethylenediamines
Tripelennamine (PBZ)
a
U.S. brand names are given in parentheses.
Effects on CNS 339
Fexofenadine Allegra
Loratadine Claritin
Cetirizine Zyrtec
Acrivastine Semprex D Available only as a combination
antihistamine-decongestant
Ebastine NA
Mizolastine NA
Ketotifen Zaditor Available only as ophthalmic drops in USA
Azelastine Astelin Available only as nasal spray and ophthalmic drops
in USA
Levocabastine Livostin Available only as ophthalmic drops
a
U.S. brand names are given.
The blood–brain barrier, formed by endothelial cells lining CNS capillaries, has
evolved to provide a stable chemical environment for neurons. Endothelial cells
in CNS capillaries are characterized by tight junctions, with cell membranes being
fastened along the length of their contact. The capillaries are encased by
astrocytes. Lipid-soluble molecules travel freely across these endothelial mem-
branes, but other chemicals need the help of pinocytosis, receptors, or specific
transport mechanisms (20).
Most first-generation H 1-antagonists readily penetrate the blood–brain bar-
rier (21). The variable propensity of these medications to cause somnolence and
other CNS effects now limits their use in the treatment of allergic disorders. In
other patient populations, some of these CNS effects are considered to be thera-
peutic; for example, the use of nonprescription dimenhydrinate for the treatment
of motion sickness and diphenhydramine or doxylamine as medications for in-
somnia.
The mechanisms by which the first-generation H 1-antagonists cause useful
and adverse CNS effects are still being elucidated. The role of histamine as a
neurotransmitter is now firmly established. Histamine has important neuromodu-
latory influences on CNS electrophysiology that determine normal thalamocorti-
cal function in the brain (22). The histaminergic system seems to be concerned
with mechanisms that favor vigilance during the wakeful state and the balance
Effects on CNS 341
between wakefulness and slow-wave activity during sleep (23). Histamine also
functions as a neuroregulator for higher brain functions (e.g., cognition, memory),
with deficits of the histaminergic system having been implicated as playing an
important role in major diseases such as Alzheimer’s, schizophrenia, and Down
syndrome (24–26). Histaminergic pathways are widespread. They originate from
the reticular formation and project diffusely to the cerebral cortex. Most first-
generation H 1-antagonists in therapeutic dosages lead to the occupation of a major
fraction of the cerebral H 1-receptors; hence, central effects in humans are thought
to be predominantly mediated by a blockade of endogenous histamine (22).
Yanai, (27) using positron emission tomography and comparing the histamine
H 1-receptor occupancy between chlorpheniramine and terfenadine, demonstrated
that first-generation H 1-antagonists in recommended doses occupied almost all
H 1-receptors in the brain and that the full occupancy of H 1-receptors was closely
related to their unwanted central side effects. Further proof that somnolence and
CNS dysfunction arise from H 1-antagonism alone within the CNS is based on
studies demonstrating that subjective and objective measurements of drowsiness
and performance are limited to H 1-antagonist enantiomers with a high affinity
for CNS histamine H 1-receptors. For example, (⫹)-chlorpheniramine (chlorphen-
amine) and (⫺)-dimethindene enantiomers produce sleepiness, decrease daytime
sleep latency, and impair digit–symbol substitution tests, whereas the enantio-
mers (⫺)-chlorpheniramine and (⫹)-dimethindene, both of which have low af-
finity for the H 1-receptor, do not differ from placebo in their subjective or objec-
tive CNS effects (28). Other mechanisms may play a role in the central effects
of some H 1-antagonists, such as their known ability to inhibit the metabolism of
histamine by N-methyltransferase, and the additional ability of some to block
cholinergic, alpha-adrenergic, and serotonin receptors in the brain.
The idea that peripheral and central H 1-receptors differ (29) is no longer
accepted; however, H 1-receptor subtypes possibly exist (30). Also, in contrast to
earlier views (31), it is now believed the H 1-antagonists probably have similar
affinity for peripheral H 1-receptors and for central H 1-receptors (32). The precise
structural requirements for receptor selectivity and affinity are still being eluci-
dated (33).
Most of the second-generation H 1-antagonists penetrate poorly into the
CNS, which accounts for their relative nonsedating properties. The proportional
contribution of factors such as large molecular size, electrostatic charge, lipo-
philicity, binding to serum albumin, and small volume of distribution to this phe-
nomenon is either unknown or is still being elucidated (34, 35). The addition of
a chemical group that is ionized at physiological pH will convert a potentially
sedating H 1-antagonist into a less sedating one. For example, the oxidation of
the terminal alcohol group of hydroxyzine to a carboxylic acid group results in
cetirizine, which is less sedating than its parent compound. The second-genera-
tion H 1-antagonists also have much less affinity for muscarinic cholinergic and
342 Welch et al.
serotoninergic receptors than their predecessors do, and this, too, contributes to
their relative lack of adverse CNS effects (31, 36–38).
CNS effects after oral H 1-antagonist administration have been assessed subjec-
tively (self-reported impairment) and objectively (investigator-measured impair-
ment) (12, 39) (Table 3). One common source of subjective assessment is from
clinical trials of H 1-antagonists in large numbers of patients with chronic allergic
rhinitis or urticaria (15, 40). Adverse CNS effects in these trials are usually unso-
licited: patients are asked to simply state if they had any problems while taking
the medication being studied. The data obtained in these multiple-dose studies
reflect ‘‘real-life’’ conditions (the disorder being treated, as well as the treatment
itself ) and are thus helpful. Subjective information is also obtained in a more
direct and quantifiable way by having patients self-rate CNS symptoms such as
somnolence, impairment of concentration, or fatigue, using a simple scoring sys-
tem, a standardized score such as Stanford Sleepiness Scale, Leeds sleep evalua-
tion score, Epworth Scale, the Profile-of-Moods Questionnaire, or a linear or
visual analog rating scale.
In objective studies (Table 3), usually performed in healthy volunteers,
performance tests and several electroencephalographic (EEG) tests are used to
assess CNS function. Drowsiness can be objectively measured through the use
of the EEG, such as with continuous 24-hour EEG monitoring. The multiple sleep
latency test measures the time needed to induce EEG signs of stage 1 sleep in
individuals given repeated opportunities to fall asleep. The EEG, in particular
the P300 (or P3), a positive auditory EEG response, can also be used as an objec-
tive and sensitive measure of sustained attention and cerebral processing speed.
Its latency depends on the amount of time required for evaluation of the stimulus.
Medications that cause cognitive impairment can prolong P300 latency. Objective
EEG tests are useful in that they are not influenced by subjects’ motivation, per-
formance strategy, task familiarity, boredom, memory, or amount of practice.
Objective assessment of the effects of H 1-antagonists on performance
and learned tasks involves sensorimotor coordination, memory, CNS arousal/
information processing, and psychomotor tests. Most investigators use a battery
of standardized tests which, although influenced by a number of patient variables
that are difficult to control fully, are believed to be representative of real-life
functions. The relative sensitivity of the various performance tests in identifying
persons susceptible to CNS dysfunction from H 1-antagonists is not well docu-
mented. The critical flicker fusion (CFF) test, a task of cognitive capacity, and
the choice reaction time (CRT) test, a measure of sensorimotor performance, are
both thought to be sensitive indicators of impairment with H 1-antagonists.
Effects on CNS 343
Subjective
Adverse event reporting in clinical trials (unsolicited; multiple-dose, real-life condi-
tions)
Scoring systems (volunteers asked specifically about somnolence or impairment)
Stanford Sleepiness Scale (SSS)
Leed’s sleep evaluation score
Profile-of-moods status questionnaire
Linear analog rating scale (LARS)
Visual analog rating scale (VARS)
Objective
Electroencephalogram (EEG) tests
Continuous EEG monitoring
Multiple sleep latency (time to stage 1 EEG sleep when subjects are given re-
peated opportunities to sleep under standardized daytime conditions)
P3 or P300 event-related potential (time-locked electrical field potential reflecting
active cognitive processing of information)
Performance Tests
Sensorimotor coordination
Critical tracking test (using a control stick to keep an oscillating vertical line in
the center of a television screen)
Adaptive tracking
Pursuit meter or rotor
Trials B maze
Visuomotor coordination
Reaction time
Simple
Choice
Auditory
Memory
Waking
Visual
Short-term, long-term
Sensory
Attention task
Auditory vigilance
Continuous performance task
Spatial perception
Dynamic visual acuity (determining the orientation of gaps in rings as the images
sweep by)
CNS arousal information processing
Mental arithmetic
Visual screening
Digit-symbol substitution (filling in blank spaces with the appropriate symbol indi-
cated by a code)
344 Welch et al.
Table 3 Continued
Color test
Stroop test
Critical flicker fusion (defining the frequency at which a group of flickering lights
appears steady)
Motor ability
Glass bead picking test
Dexterity tests
Psychomotor
Computerized simulated car driving
Computerized flight simulator
Actual car-driving tests (steering, weaving and gap acceptance; usually computer
monitored)
The Digit Symbol Substitution Test, a simple pencil and paper test, believed to
measure integration, speed, and accuracy of visual and fine motor skills, is also
employed in a large number of studies and appears to be a reliable indicator
of sedation (41). Actigraphy, the process in which one continuously measures
movement (the motor component of behavior throughout the day) has been used
to detect impairments in performance and to overcome the problems associated
with testing at fixed time intervals. Tests involving complex sensorimotor activi-
ties (e.g., application of learned strategy, car tracking, simulated driving or flying
tests, or, where permitted by law, computer-monitored on-the-road driving tests)
have also been utilized, and are believed to be more representative than simple
tests of reaction time or memory (41). In a few performance studies, a school
environment (42, 43) or a work environment (44–46) has been simulated.
Most of the objective performance and EEG studies have been conducted
following a single H 1-antagonist dose in healthy volunteers, using a double-blind,
crossover study design. Multiple-dose studies, studies in patients with allergic
disorders such as rhinitis or urticaria, and dose–response studies are less common.
In an ideal situation, a new H 1-antagonist is compared not only with placebo but
also with an H 1-antagonist known to be sedating, so that the sensitivity of the tests
being used to identify CNS dysfunction can be assessed. If an old H 1-antagonist
comparator either is not given or is given but does not produce impairment of
CNS function, it cannot be ascertained if the tests being used have the required
sensitivity. Tests are usually performed at baseline and at one or more additional
preselected intervals, almost always including tests 2–3 h postdose, at the time
of anticipated peak serum concentrations, and presumably peak CNS effects. In
some studies, attempts have been made to relate CNS effects to peripheral H 1-
blockade and/or to serum H 1-antagonist concentrations (47–58). This is helpful
Effects on CNS 345
in the interpretation of test results and prevents the problem of mistakenly identi-
fying an H 1-antagonist as being nonsedating when, in fact, the dose administered
was too low to produce adequate peripheral H 1-blockade and was, therefore, clini-
cally irrelevant.
In EEG and performance studies, after H 1-antagonist administration there
is generally good correlation among the objective tests (56, 59–65). The relation-
ship between performance and subjective feelings of somnolence, however,
seems to be more complex and less well understood. Sleepiness/alertness level
provides a basic capacity (or incapacity) for performance. Performance, therefore,
should be lowest when alertness is lowest and sleepiness is highest; however, it
can be modified by factors such as motivation and task familiarity. In most studies
in which subjective and objective measures are used, patients who report somno-
lence or show EEG evidence of decreased sleep latency also have performance
impairment on psychomotor tests or driving tests. Various researchers, however,
have reported an inconsistent correlation between the symptoms and measures
of drowsiness and H 1-antagonist-induced mental impairment. The most common
type of discrepancy between subjective and objective measures of sedation occurs
when the patient shows impairment on psychomotor tests but does not report a
for somnolence) (12, 49). It has also been postulated that the time course and
pattern for induction of sleepiness and performance impairment in the day do
not coincide, resulting in a potential poor correlation between the two types of
CNS effects (41). Finally, it has been suggested that self-assessments of perfor-
mance and sleepiness are basically unreliable and easily influenced by a multitude
of factors, while performance-based and objective measures are superior to sub-
jective ones, although also affected by changing performance strategies and/or
motivation levels (41). Whatever the mechanism, both subjective and objective
tests should be conducted in order to determine the potential for CNS impairment,
because either one alone may underestimate the CNS effects of an H 1-antagonist.
V. FIRST-GENERATION H 1-ANTIHISTAMINES
(1.25–10 mg), chlorpheniramine (4–8 mg), and clemastine (1–3 mg) (42, 44–
50, 52, 53, 55–57, 59, 61, 64, 65, 67, 69–73, 79, 81, 84–118). Impairment has
also been documented to occur after ingestion of azatadine, brompheniramine,
dimethindene, mequitazine, promethazine, trimeprazine, and tripelennamine (66,
70, 90, 96, 100, 108, 119–130).
First-generation H 1-antagonists are still commonly used for treatment of
symptoms of allergic disorders in children, since some of the newer nonsedating
H 1-antagonists are not available in pediatric formulations in many countries, and
because of the former’s low-cost nonprescription availability. Few objective eval-
uations of their adverse CNS effects have been performed in young subjects (42,
55, 131, 132). When diphenhydramine and hydroxyzine were studied in children
ages 6–12 years using objective (P300 latency test) and subjective (visual analog
scale) measures, CNS impairment was seen in much the same manner demon-
strated in adults with these measures of sedation (132). The elderly population
as a special group has also been studied in a limited fashion in terms of sensitivity
to H 1-antagonists. Results showed that first-generation H 1-antagonists such as
chlorpheniramine and diphenhydramine impair cognitive processing and cause
subjective somnolence in a way similar to young adults (58). (See Chapters 14 and
15 for more details regarding effects of H 1-antagonists in the young and elderly).
Diphenhydramine and other older H 1-antagonists were used in the past
for induction of sleep EEGs, and are still commonly used as a remedy by self-
medicating insomniacs (133–136). Six hours postdose, diphenhydramine (50 mg)
has a sedative effect comparable to that of alcohol and triazolam (137). Hydroxy-
zine continues to be used as a preoperative sedative and anxiolytic (138, 139).
Several strategies have been suggested for minimizing the sedative effects of H 1-
antagonists when used for the treatment of allergic rhinitis, allergic conjunctivitis,
or chronic urticaria. One strategy is to use a first-generation H 1-antagonist in a
single large dose at bedtime. Since the patient will be sleeping during the night,
sedation or impairment of CNS function might not cause any problems. This
strategy is based on the assumption that the sedative effects are limited to the
hours of sleep and that symptom relief from peripheral H 1-blockade lasts through-
out the next day. Goetz (69) studied this idea prospectively and found that patients
given hydroxyzine (50 mg) at bedtime maintained peripheral H 1-blockade for up
to 24 h, based on suppression of histamine-induced wheals and flares, but subjec-
tive drowsiness was also increased significantly the morning after the nighttime
dose. In another study using the Multiple Sleep Latency Test and the Stanford
Sleepiness Scale, the sedating effects of pm dosing with chlorpheniramine and am
Effects on CNS 349
dosing with terfenadine were investigated. Results demonstrated that the CNS-
depressant effects of evening administration of a sedating H 1-antagonist persisted
throughout the following day (140) (Fig. 3). Similar findings of daytime sleepi-
ness following evening dosing with chlorpheniramine were obtained using the
new technique of functional magnetic resonance imaging as a tool to assess levels
of brain activation (141). Carryover effects are most likely a result of the long
elimination half-lives of sedating antihistamines, which for hydroxyzine, brom-
pheniramine, and chlorpheniramine are 20–24 h (13) (Chap. 5).
Some physicians advise regular daily use of a first-generation H 1-antagonist
with the expectation that tolerance to the CNS adverse effects will occur after a
few days. It is known that tolerance to the peripheral H 1-blockade effects of
H 1-antagonists (e.g., skin test suppression) does not develop (52, 68, 89, 142).
Tolerance to H 1-antagonist-induced drowsiness and sedation has been reported
by some, but not all, investigators. Volkerts (65) treated volunteers with triproli-
dine 5 mg twice daily or placebo for 4 consecutive days and conducted testing
on the first and fourth treatment day. Triprolidine significantly reduced scores
on the various tests done on the first day, including self-assessment rating, objec-
tive sleep latency test, cognitive performance test, and an actual driving test. By
the fourth day, the subjective (self-rating) and objective (sleep latency) measures
of drowsiness, as well as the speed performance in the driving test, were no
longer statistically different between the triprolidine-treated and placebo groups.
In contrast to this evidence for the development of tolerance, some of the cogni-
tive studies and the lateral weaving part of the driving test continued to show
statistically significant differences between groups, perhaps implying partial tol-
erance. Schweitzer (114) treated subjects with diphenhydramine (50 mg three
times daily) for 3 days and measured multiple sleep latency, a simulated assem-
bly-line task, and sleepiness ratings by visual analog scale on day 1 and day 3.
Diphenhydramine produced marked impairment and drowsiness only on the first
day of treatment; no difference between diphenhydramine and placebo was noted
on the third day, suggesting that tolerance occurred. Manning (142) using diphen-
hydramine, and Bye (89) using triprolidine, also reported tolerance to the CNS
effects of these first-generation H 1-antagonists; however, the development of tol-
erance is not universal or predictable. Volunteers given hydroxyzine 25 mg twice
daily for 5 days did not develop tolerance to the CNS effects, as evidenced by
continued drowsiness and prolongation of reaction time (95). Similarly, Brook-
huis (143) gave volunteers triprolidine 10 mg/day for 5 days and tolerance to its
adverse effects on a car-driving test was not observed. Kay (98) tested various
measures of sedation after dosing with diphenhydramine 50 mg on day 1, and
then on days 3 and 5 after continual dosing with 25 mg four times daily. Fatigue
and sleepiness were reported, and scores were reduced on the measures of divided
attention, working memory, and vigilance on day 1. On days 3 and 5, the amount
of fatigue had decreased but was still significantly greater than it was for subjects
receiving loratadine 10 mg daily or placebo. Furthermore, subjects on day 5 re-
ceiving diphenhydramine continued to have significantly greater psychomotor
impairment than those receiving placebo or loratadine. Given these conflicting
findings, using a first-generation H 1-antagonist and hoping the patient develops
tolerance to the adverse CNS effects appears to be unwise, as tolerance is an
inconsistent and unpredictable phenomenon.
The two aforementioned strategies to avoid the sedating effects of first-
generation H 1-antagonists are not currently recommended. Physicians should be
aware of the recommendations made by the Joint Task Force on Practice Parame-
ters in Allergy, Asthma, and Immunology (1998):
Sedation and performance impairment are undesirable and potentially dan-
gerous side effects of first-generation antihistamines. Consequently, second-
generation antihistamines that are associated with less risk or no risk for
these side effects should usually be considered before sedating antihistamines
for the treatment of allergic rhinitis, and are even mandated in some segments
of the transportation industry. Studies have demonstrated that many patients
Effects on CNS 351
the same findings (43). Spaeth used a visual analog scale to measure vigilance
in patients with untreated symptomatic seasonal allergic rhinitis (152). Their
baseline scores were below normal, but improved after treatment with either a
second-generation oral or topical H 1-antagonist. The exact mechanisms by which
CNS impairment occurs with symptomatic allergic disease are not known. Sleep
disturbance may be playing a role (153), as patients with allergic rhinoconjunctiv-
itis often report difficulty initiating or maintaining sleep (154) and sleep
disruption/deprivation is known to cause excessive daytime sleepiness, cognitive
difficulties, and poor school academic performance (155). Whatever the mecha-
nisms, the above studies point out the importance of controlling for the presence
or absence of allergic symptoms when conducting research on the effects of new
H 1-antagonists on mental function.
Information regarding CNS effects can be obtained from results of clinical trials
conducted primarily to evaluate the efficacy and safety of the second-generation
H 1-antagonists in patients who have symptomatic allergic disease (e.g., allergic
rhinitis, urticaria), or from results of studies specifically performed with objective
tools to measure sedation and/or impairment, usually carried out in healthy volun-
teers. Clinical trials almost always involve multiple dosing over days to weeks,
with adverse effects such as somnolence being self-reported and unsolicited by
the investigator. Conclusions from these studies may be difficult since some lack
a placebo group, the percentage of patients reporting any adverse events is some-
times low, and/or statistical analysis of the difference between groups may not
be performed with regards to adverse effects. Nevertheless, results of these clini-
cal trials have shown, in general, that patients taking loratadine and fexofenadine
and the now unavailable terfenadine and astemizole, report somnolence at a rate
not significantly different than patients treated with placebo (see US package
inserts for each agent). However, findings from clinical trials evaluating acrivas-
tine, ketotifen, ebastine, mizolastine, cetirizine, and topical azelastine are more
variable, with one or more studies showing self-reported somnolence with use
of these agents to be higher than with placebo, even at the usual recommended
therapeutic dosage (14, 18, 75, 156–159).
In objective, single-dose studies in healthy volunteers, the incidence of
somnolence and impairment of CNS function associated with manufacturers’ rec-
ommended daily dosages of many of the second-generation H 1-antagonists is
similar to that produced by placebo and significantly lower than that produced
by first-generation H 1-antagonists such as triprolidine, diphenhydramine, chlor-
pheniramine, clemastine, or hydroxyzine. The first of the second-generation H 1-
Effects on CNS 353
antagonists, terfenadine, has been studied most extensively (47, 53, 55, 57, 59,
60–62, 65, 69, 71, 85, 90, 94, 95, 99, 101–106, 111, 112, 120, 160, 161). Another
early second-generation H 1-antagonist, astemizole, has also been well studied
with similar findings to terfenadine (51, 57, 79, 104, 105, 123, 162–165). As
noted previously, both terfenadine and astemizole have been removed from the
market in many countries throughout the world because of adverse cardiac ef-
fects; however, they remain historically important because they were the first H 1-
antagonist agents to demonstrate an absence of sedation and performance impair-
ment properties.
Other well-studied second-generation H 1-antagonists that are widely avail-
able include cetirizine (46–48, 50, 52–54, 56, 57, 63, 65, 67, 72, 73, 93, 114,
160, 166, 167) (Table 4), loratadine (42, 44, 45, 54, 57, 63, 64, 86, 93, 98, 106,
111, 120, 168) (Table 5), and fexofenadine (41, 73, 115, 150, 169–171, 178)
(Table 6). These second-generation agents produce significantly less somnolence
and mental impairment than their first-generation predecessors (Fig. 4).
Less well-studied and less widely available oral second-generation H 1-an-
tagonists include ebastine (97, 116, 143, 172, 173) (Table 7) and mizolastine (99,
107, 117, 174, 175) (Table 8). Information from studies so far show that both of
these H 1-antagonists, when used at their usual therapeutic dosage, have objective
sedative profiles similar to placebo.
There are few studies of acrivastine (91, 92, 110) and ketotifen (68, 70,
176–178), both of which have been considered second-generation H 1-antago-
nists. Unlike the other agents in the second-generation category, acrivastine and
ketotifen have been shown to cause more somnolence and impaired performance
than placebo (Table 9), although not consistently in all tests.
Gengo et al. (48) 12 db, pc, co C 10, 20 CFF; Stroop; VAS; PHB 0.5, 1, 2, 4, 6, 8, 12, H, but not C, ↓ CNS function
H 25 24, 36
P
Doms et al. (166) 36 db, pc, co C 10 Psychomotor; learning, mem- Not stated Results for C ⫽ P; Alc im-
P ory, attention; concentration; paired all tests except one
Alc 0.6g/kg (positive coordination; VAS; anxiety
control)
Pechadre et al. (53) 9 db, pc, co C 10 EEG spectrum analysis; VAS; 3, 6 C did not affect EEG; T inhib-
T 60 PHB ited EEG at 6h; C, T or P
P did not cause subjective feel-
ings of impairment; no posi-
tive control
Alford et al. (47) 14 db, pc, co C 10, 20 qd EEG; LARS; PHB 1.5 (LARS) continuous C 10 & 20, T 60 and P pro-
T 60 bid (EEG) duced ⬍20% total EEG seda-
Ch 4 tid tion; Ch & Tr produced
Tr 5 tid ⬎40% EEG sedation. Sig-
P nificant subjective sedation
seen only with Tr
De Roeck (93) 16 db, pc C 20 DSS; MSLT; SSS Every 2 hrs ⫻ 5 D ↓ sleep latency in 1h and
L 20 this effect differed signifi-
D 50 ⫻ 2 cantly from L and P, but not
P C; similar trends were seen
in performance and subjec-
tive data
Gengo et al. (50) 15 db, pc, co C 5, 10, 20 DSS; Trails B maze; driving 2, 4, 6, 8, 24 D, but not C, ↑ reaction time
D 50 simulator and produced significant
Welch et al.
P drowsiness
Seidel et al. (67) 60 db, pc, pa C 5, 10, 20 MSLT; EEG ⫹ eye move- 2, 4, 6, 8, 10 (MSLT, H, but not C, affected MSLT,
H 25 ments; RT; SSS; POMS SSS); 2.5, 8.5 (RT); EEG and eye movement
P 4.5 (POMS) tests, but no subjective im-
pairment was reported in any
group
Betts et al. (160) Not stated pc T 120, 240 Actual slow driving; EEG vi- Not stated C 20, but not C 10, T 120, T
C 10, 20 sual evoked potential 240, produced impairment
Effects on CNS
P
Levander et al. (52) 12 db, pc, co C 10 ⫻ 7d Psychological tests; VAS; PHB 4 (after AM dose on d1 H, but not C, ↓ CNS function
H 20 ⫻ 7 d and d7) after single dose; no differ-
P⫻7d ence between C and H at
steady-state
Pechadre et al. (54) 10 db, pc, co C 10 Quantified EEG; VAS; PHB 2, 6 C and P did not affect EEG; L
L 10, 40 10 and 40 produced slight
P EEG changes at 2 h; no posi-
tive control
Ramaekers et al. 16 db, pc, co C 10 Actual driving; EEG; 0.5–5 C alone and L, C, or P ⫹ Alc
(63) L 10 subjective affected EEG, driving (weav-
P ing, speed), and subjective
⫾ Alc drowsiness. Alc had a
greater effect than C. L had
no effect on any of measures
Volkerts et al. (65) 27 db, pc, co C 10 daily ⫻ 4d Actual driving; computerized 1, 2, 2.5, 3.5, 6 C 10 mg, T 120 mg, and P did
T 60 bid ⫻ 4d memory tasks; sleep latency not affect any tests. Tr ↓
T 120 qd ⫻ 4d driving and psychometric
Tr 5 bid ⫻ 4d tests and reduced sleep la-
P tency; tolerance to Tr by day
4; T 60mg bid ↓ psychomet-
ric performance after sub-
chronic treatment
Walsh et al. (46) 12 db, pc, co C 10 Simulated assembly line task 0.5, 1.5, 2.5, 3.5, 5.5, Pretrained to minimum correct
H 25 with seven variables; 8 ⫻ 50 6.5, 7.5, 8.5 response rate; H, but not C,
P min tasks; subjective ↓ performance and ↑ sleepi-
ness; H & C did not differ
subjectively
355
356
Schweitzer et al. 12 db, pc, co C 10 qd ⫻ 3d MSLT; simulated assembly line 1, 3, 5, 7, 9 (MSLT); D, not C, adversely affected all
(114) D 50 tid ⫻ 3d task; actigraphy; subjective VAS 1.5, 3.5, 5.5, 7.5 objective tests and increased
P (VAS) (assembly line task) subjective sleepiness by day
on days 1 and 3 1. No effect by D seen at
day 3.
Simons et al. (56) 20 db, pc, co C 10 P300; VAS; PHB 3 H and D but not C or P ↑
H 50 P300 latency
D 50
P
Patat et al. (175) 18 db, pc, co C 10 qd ⫻ 7d 1) Driving (actual and simu- 1) 4, 7.3 (actual); 3.2, M and C had no effect on driv-
M 10 qd ⫻ 7d lated) 6.5 (simulated) ing or CFF; both did cause
P 2) CFF, adaptive tracking, di- 2) 1.5, 2.6, 4.5, 6, 7.8 minimal but significant
Alc or P, single vided attention changes in tracking and di-
dose, d 5 or 7, 2h vided attention tasks at cer-
post dose of M, C, tain time points post-dose.
or P Alc caused significant detri-
mental effects in all psycho-
motor and driving tests
Welch et al.
Sannita et al. (72) 8 db, pc, co C 10 Short-term Retention Test; 1, 2, 3, 4, 6 C 20 and Ch affected EEG, but
C 20 Backward Digit Span Test; not C 10. No effect on any
Ch 4 Immediate Retention Test; performance tests by C or
P quantitative EEG Ch.
Simons et al. (57) 15 db, pc, co C 10 P300; subjective somnolence 2–2.5 C had no effect on P300 la-
L 10 (SSS) tency, but did ↑ subjective
A 10 somnolence compared to
Effects on CNS
A, astemizole; Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); co, crossover; d, days; D, diphenhydramine;
db, double-blind; DSS, digit-symbol substitution; EEG, electroencephalogram; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, line analog
rating scale (subjective sedation); MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled;
PHB, peripheral H 1-blockade; POMS, Profile of Mood States questionnaire; RT, reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; Tr, triprolidine;
VAS, visual analog scale; ↑, enhance/increase; ↓, impair/decrease; m, mizolastine; Pr, promethazine; qd, once daily; bid, twice daily; tid, three times daily.
357
358
Bradley and Nichol- 6 db, pc, co L 10, 20, 40 VMC; DVA; short-term mem- 0.3, 1.5, 3.5, 5.5 L 40, but not L 20 or L 10, ↓
son (86) Tr 10 ory; DSS; subjective DSS (5.5h) and DVA, sug-
P gesting sedation; Tr ↓ all
tests
Riedel et al. (111) 20 db, pc, co L 10, 20 Actual driving (weaving index); 4 Tr, but not T or L, caused weav-
T 60 self-reported sedation ing comparable to that seen
Tr 10 with blood Alc of 0.05%
⫾Alc
P
Roth et al. (64) 16 db, pc, co L 10 ⫻ 2d MSLT; SRT; CRT; auditory vig- MSLT 1, 3, 5, 7, 9; D, but not L 10 or L 40, ↓
L 40 ⫻ 2d ilance; DSS; symbol copying; performance sleep latency, affected perfor-
D 50 tid ⫻ 2d SSS (i.e., everything mance tests and ↑ sleepiness
P else) 1.5, 5.5
Gaillard et al. (120) 1) 12 db, pc 1) L 10 Reaction time; tracking; mem- 6 1) L & T no effect; Cl ↓ perfor-
2) 16 T 60 ory; subjective (VAS) mance on tracking test, ↑ sub-
Cl 1 jective drowsiness
P 2) Diaz no effect with any drug
2) ⫹ Diaz 5 or with placebo.
O’Hanlon (106) 1) 20 db, pc 1) L 10 Car driving (high-speed, open 1, 3 Tr impaired driving; T and L
2) 16 T 60 road, 10 km); highway cir- did not; T and L did not po-
Tr 10 cuit, weaving index tentiate Alc
P
2) L 10 qd ⫻ 4d
T 60 mg bid ⫻ 4d
P
Welch et al.
⫾ Alc
Adelsberg and 69 pc, co L, D, P 12 performance tests relating to 1.5, 6 L did not ↓ performance; D sig-
D’Amico-Beadon office skills nificantly impaired 8/12 tests
(44)
De Roeck (93) 16 db, pc L 20 DSS; MSLT; SSS Every 2 h ⫻ 5 D ↓ sleep latency and this ef-
C 20 fect differed significantly
D 50 ⫻ 2 from L and P but not C; simi-
P lar trends were seen in perfor-
Effects on CNS
Kay et al. (98) 98 db, pc, co L 10 qd ⫻ 5d VAS; SSS; Mood Scale; numer- 1.5 on days 1, 3, 5 L caused no deficits at anytime;
D 50 first dose, ous cognitive and psychomo- D caused deficits in measures
then 25 qid ⫻ 5d tor performance measures of sleepiness, fatigue, mood,
divided attention, speed,
working memory, and vigi-
lance on day 1; some deficits
with D present at day 3; all
deficits with D gone by day 5
Hindmarch et al. 24 db, pc, co L 10 CFF; CRT; subjective (LARS); 1.5, 3, 6, 9, 12, 24 L and F at all doses caused no
(169) F 80 actigraphy significant impairment on any
F 120 of the tests while Pr nega-
F 180 tively affected CFF, recogni-
Pr 10 tion reaction time, and acti-
graphy
Valk et al. (45) 18 db, pc, co L 10 Vig Track; MAT (objective); 1, 2, 3, 5, 6 No significant difference in alert-
Tr 5 SSS (subjective); in a hypo- ness and performance results
P baric chamber simulating an between L and P. Tr caused
altitude of 8,000 ft. significant detrimental effects
on subjective and objective
measures
A, astemizole; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; CRT, choice reaction time; d, days; D, diphenhydramine; db, double-blind; DSS,
digit–symbol substitution; DVA, dynamic visual acuity; F, fexofenadine; h, hours; K, ketotifen; L, loratadine; LARS, line analog rating scale; MAT, Multi-
Attribute Task Battery; MSLT, multiple sleep latency test; P, placebo; P300, P300 event-related potential; pa, parallel group; pc, placebo-controlled; PHB,
peripheral H 1-blockade; qd, once daily; SRT, simple reaction time; SSS, Stanford Sleepiness Scale; T, terfenadine; tid, 3 times daily; Tr, triprolidine; VAS,
visual analog scale; Vig Track, Vigilance and Tracking test; VMC, visuomotor coordination; ↑, enhance/increase; ↓, impair/decrease; Pr, promethazine;
Alc, ethanol; EEG, electroencephalogram; qid, four times daily; co, crossover.
Welch et al.
Table 6 Objective CNS Studies of Fexofenadine
No. of
Reference volunteers Design Drug/dose (mg) Tests Time postdose (h) Results
Vermeeren and 24 db, pc, co F 120 qd ⫻ 5d Critical tracking; 1.5–2.5 except driv- F at any dosage did
O’Hanlon (115) F 240 qd ⫻ 5d CRT; sustained at- ing (3–4), on days not impair driving
Effects on CNS
Vincent et al. (116) 9 sb E 10, 50 CFF; CRT; VAS 1, 2, 4, 6, 8, 24 E 10 and 50 did not ↓
P CFF performance but
Effects on CNS
CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; DSS, digit–symbol substitution; d, days; db, double-blind; E, ebastine;
EEG, electroencephalogram; h, hours; P, placebo; pc, placebo-controlled; qd, once daily; sb, single-blind; SR, sustained-released; Tr, triprolidine; VAS,
visual analog scale; ↑, enhance/increase; ↓, impair/decrease.
363
364
Kerr et al. (99) 18 db, pc, co M5 CFF, CRT, tracking, mem- 1, 3, 5, 8, 24 M 5, 15 did not affect per-
M 15 ory tests (Stroop, Stern- formance tests or subjec-
M 45 berg), subjective tive ratings whereas M
T 60 (LARS) 45 and Tr did ↓ perfor-
Tr 10 mance in various psy-
P chomotor measures. T
negatively affected CFF
only
Vuurman et al. 24 db, pc, co M5 CFF, tracking, divided at- 2–3, 3.45–4.45 (driving M 5, M 10 had no effect
(117) M 10 tention, memory search, only), 5.30–6.30 (other on psychomotor tests,
M 20 CRT, vigilance studies; tests) driving and subjective
M 40 actual driving; subjec- ratings. M 40 ↓ driving
Cl 2 tive (VAS) and performance tests
and ↑ subjective drowsi-
ness similar to Cl; M 20
had effects intermediate
Welch et al.
to M 5, 10 and M 40
Patat et al. (107) 15 (elderly females, db, pc, co M 10 CFF, CRT, DSS, free re- 4, 8 M produced no effects on
ages 66–77) Cl 2 call memory (immediate performance, memory,
P and delayed), VAS or subjective ratings of
drowsiness whereas Cl
significantly ↓ perfor-
mance (CFF, CRT)
Patat et al. (174) 16 db, pc, co M 10 qd ⫻ 8d 1) CFF, CRT, tapping, 1) 2, 4, 6, 8 M 10 at steady state de-
Effects on CNS
Alc, alcohol; C, cetirizine; CFF, critical flicker fusion; Cl, clemastine; co, crossover; CRT, choice reaction time; db, double-blind; DSS, digit–symbol
substitution; LARS, linear analog rating scale; Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; VAS, visual analog
scale; d, days; ↑, enhance/increase; ↓, impair/decrease; h, hours.
365
Table 9 Objective CNS Studies of Acrivastine, Ketotifen, and Levocabastine (Topical Ophthalmic)
Acrivastine
Cohen et al. (91) 12 db, pc, co Ac 4, 8, 16 Adaptive tracking per- 1.5, 3 Ac did not ↓ adaptive
Tr 2, 5 formance; reaction tracking or reaction
P time; VAS time; both doses of
Tr ↓ adaptive
tracking and ↑ reac-
tion time, and also
caused subjective
effects
Ramaekers and 18 db, pc, co Ac 8 Driving tests 1.5–2.75 Ac ↓ driving perfor-
O’Hanlon (110) Ac 16 3.25–4.50 mance in a dose-
Ac 24 related fashion. D
Ac/Ps 8/60 also significantly ↓.
T 60 T at all doses and
T 120 Ac/Ps did not
T 180 cause any effect on
D 50 driving
P
Ketotifen
Hindmarch and Par- 50 db, pc K 1 bid CRT; CFF; sleep eva- K did not ↓ psycho-
rott (70) Ch 4 tid luation motor behavior but
Meb 50 tid did ↑ ease of get-
Cl 1 bid ting to sleep; Ch ↓
Pr 25 od CFF; Ch and Pr af-
fected sleep and
produced early
Welch et al.
morning ‘‘hang-
over’’
Vollmer et al. (68) 7 sb, pc K 1 bid ⫻ 3 wks EEG ⫻ 15 min pre- 3, 6 Peak sedation effect
P dose, 3 and 6 h on day 3 gradually
postdose on 8 study ↓ thereafter; no pos-
days itive control
Simons et al. (57) 15 db, pc, co K2 P300; subjective som- 2–2.5 No effect on P300 la-
T 60 nolence (SSS) tency, like D did,
Effects on CNS
A, astemizole; Ac, acrivastine; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine; co,
crossover; CRT, choice reaction time; d, days; db, double-blind; EEG, electroencephalogram; h, hours; K, ketotifen (oral); L, loratadine; Le, levocabastine;
Meb, mebhydrolin; P, placebo; P300, P300 event-related potential; pc, placebo-controlled; Pr, promethazine; Ps, pseudoephedrine; qid, four times daily;
sb, single-blind; SSS, Stanford Sleepiness Scale; tid, three times daily; Tr, triprolidine; VAS, visual analog scale; wks, weeks; ↑, enhance/increase; ↓,
impair/decrease; T, terfenadine; D, diphenhydramine; LARS, linear analog rating scale.
367
368 Welch et al.
more likely a function of the individual variation from patient to patient in their
sensitivity to have, perceive, or report these adverse effects. Traditional clinical
practice advised that if sedation was occurring from an H 1-antagonist in one of
the six classes of first-generation H 1-antagonists, the patient should be given a
trial of an agent from another class because of the possibility that the sedation
would be less; however, no scientific basis for this recommendation can be found
in the literature. The availability of the second-generation H 1-antagonists with
an absent or much reduced tendency to cause sedation has made this kind of
practice both inappropriate and unnecessary.
There is also only limited comparative information among the second-
generation H 1-antagonists regarding objective CNS effects. Most studies of these
agents have been designed using the single second-generation H 1-antagonist of
interest, a positive control (a first-generation H 1-antagonist known to cause CNS
impairment) and negative (placebo) control, with no additional second-generation
H 1-antagonist comparator. Because the battery of objective tests used to study
these medications varies greatly from one study to another, it is difficult to draw
conclusions about relative CNS effects by comparing the results from these vari-
ous single-agent studies. Studies of many of the second-generation H 1-antagonists
reveal limited or no sedative effects, so one would not expect comparison studies
to be very informative. Indeed, most of the comparative studies that have been
reported, usually just studying two of the second-generation H 1-antagonists at a
time, have not revealed significant differences between agents (47, 78, 99, 104,
105, 175). Most of the rare exceptions were studies that found either a small
difference, or a difference with only one of the many objective tests done (53,
54, 65), or used a second-generation H 1-antagonist comparator (e.g., ketotifen,
acrivastine, cetirizine) known to be more sedating than the others in this class
(e.g., terfenadine, astemizole, loratadine) (110, 156, 164). Simons et al. evaluated
six different H 1-antagonists (five second-generation agents, with diphenhydra-
mine as the positive control) at one time in a single-dose, placebo-controlled,
crossover study using an objective EEG test for somnolence and a visual analog
scale (VAS) for subjective rating in 15 healthy subjects. No significant differ-
ences were found in the change in the P300 event-related potential and in the
VAS score among the five second-generation H 1-antagonists studied (loratadine,
cetirizine, astemizole, terfenadine, and ketotifen) (Fig. 5) although patients taking
cetirizine and ketotifen, similarly to patients taking diphenhydramine, had a sig-
nificant change in VAS relative to placebo (178). Hindmarch and Shamsi (41)
reviewed the extensive literature on sedating effects of H 1-antagonists and catego-
rized the tests for CNS impairment in the various studies of first- and second-
generation H 1-antagonists as ones that demonstrated impairment vs. no impair-
ment. They calculated a ratio of the number of tests in which significant impair-
ment was found over the number of tests in which no impairment was detected,
370 Welch et al.
Figure 5 Percentage change from baseline in the P300 event-related potential 2.5 h
after terfenadine 60 mg, cetirizine 10 mg, loratadine 10 mg, astemizole 10 mg, ketotifen
2 mg, diphenhydramine 50 mg, and placebo. Note that no significant differences were
found among the second-generation H 1-antihistamines, while diphenhydramine demon-
strated significant changes suggestive of sedation. *p ⬍ 0.05 compared to baseline and
placebo. (From Ref. 57.)
representing the likelihood that a given antihistamine would cause sedative ef-
fects. Fexofenadine and ebastine had the best ratio in favor of not inducing CNS
effects; triprolidine and diphenhydramine had the worst.
prehension, and tremor in certain sensitive patients. It has been theorized that
the use of a decongestant in combination with a first-generation H 1-antagonist
could potentially cancel out the sedative effects of the H 1-antagonist, an expecta-
tion commonly held by physicians using combination preparations in the pre-
second-generation H 1-antagonists era. However, when this was tested with tri-
prolidine-d (triprolidine 2.5 mg plus pseudoephedrine 60 mg three times daily)
using EEG monitoring, it could not be documented; the combination product
caused significantly more patient-reported daytime sedation and drowsiness than
either placebo or astemizole-d (193). The finding that sedation usually predomi-
nates has been reported for years by patients using either an over-the-counter or
a prescription agent that contains both an H 1-antagonist of the first-generation
type and a decongestant. With the advent of second-generation H 1-antagonists
with reduced sedating properties, the fixed-dose combination of a second-genera-
tion H 1-antagonist with a decongestant, not surprisingly, is associated with a high
incidence of patient reports of CNS stimulation (1,194–196). The impact of these
combination agents on objective measures of CNS function has not been studied
optimally, but a limited number of investigations have shown either no effect or
actual improvement of objective performance (193, 195). Given the above, the
convenience of having a single tablet or capsule of a fixed H 1-antagonist/decon-
gestant combination has to be weighed against the increased potential of adverse
subjective CNS stimulation effects due to the decongestant component.
Objective psychomotor testing and tests of actual driving performance have con-
firmed that alcohol (0.50–0.75 g/kg) or diazepam 10 mg, administered concur-
rently with a first-generation H 1-antagonist such as clemastine, chlorpheniramine,
cyproheptadine, or diphenhydramine, potentiates the CNS dysfunction produced
by the H 1-antagonist (79, 87, 92, 102, 120, 197, 198). It is presumed that other
CNS-active medications, including antidepressants and hypnotics, also potentiate
CNS dysfunction produced by older H 1-antagonists, although this has not been
well documented objectively.
In contrast, in most studies, second-generation H 1-antagonists have not po-
tentiated the adverse CNS effects of alcohol or the benzodiazepines (diazepam,
lorazepam) (63, 79, 80, 102, 106, 111, 115, 120, 161, 162, 166, 172–175) (Table
10) (Fig.6). The degree of somnolence and impairment of CNS function associ-
ated with recommended daily doses of most second-generation H 1-antagonists
in combination with alcohol or benzodiazepines is similar to that produced by
alcohol or benzodiazepines alone.
Table 10 Objective CNS Studies of H 1-Antihistamines Administered with Alcohol or Diazepam/Lorazepam 372
No. of Time
Reference volunteers Design Drug/dose (mg) Tests postdose (h) Results
Moser et al. (102) 20 db, pc, co T 60, 120, 240 Psychomotor skills, includ- 4 D ↓ subjective, not objec-
D 100 ing reaction time; CFF; tive, scores. T did not at
P subjective any dose. D potentiated
Diaz 10 adverse effects of Diaz
Alc 0.75 g/kg and D. T 120 did not
Bateman et al. (162) 7 db, pc, co A 10 qd ⫻ 7 d Psychomotor reaction 6 Alc ↓ performance; no ↑
P⫻7d time; pursuit rotor; vi- effect with A; A did not
Vodka 100ml on 7th d sual discrimination; alter Alc kinetics
VAS
Cohen et al. (92) 1) 12 db, pc, co 1) Ac 8 ⫾ Alc Adaptive tracking; reac- 1, 2.5, 5.5, 7.5 1) Ac 8 alone did not ↓
2) 12 D 50 ⫾ Alc tion time; eye move- CNS performance; Ac
P⫹P ment; body sway; VAS ⫹ Alc ↓ performance
2) Ac 4 ⫹ Alc but less than D ⫹ Alc
Ac 8 ⫹ Alc 2) Effects of Ac (4 and
T 60 ⫹ Alc 8) ⫹ Alc and T ⫹
T 120 ⫹ Alc Alc did not differ
P suggesting Ac effect
in combination with
Alc is small
Hindmarch and Bhatti (79) 18 db, pc, co A 30 CFF; CRT; car tracking 6 Ch, but not A, affected
Ch 12 (simulated); VAS; sub- tests; Alc potentiated
P jective Ch but not A
Alc 0.5 g/kg
Riedel et al. (111) 20 db, pc, co T 60 Actual driving (weaving in- 4 Tr, but not T or L, caused
L 10, 20 dex); self-reported seda- weaving comparable to
Tr 10 tion that seen with blood
⫾Alc Alc of 0.05%
P
Doms et al. (166) 36 db, pc, co C 10 Psychomotor; learning; Not stated C ⫽ P, no ↓ of perfor-
P memory; attention; mance; no interaction
⫾Alc 0.6 g/kg conc.; coordination; with Alc; C did not
VAS; subjective health; change Alc kinetics or
Welch et al.
Patat et al. (174) 16 db, pc, co M 10 qd ⫻ 8 d 1) CFF; CRT; tapping; 1) 2, 4, 6, 8 M 10 devoid of any ef-
P arithmetic calcula- 2) 3 fects on performance,
Loraz 2 or P on d 6 or 8 tion; body sway; memory, subjective rat-
with M VAS ings. Loraz caused
2) short-term, long-term marked ↓ of almost all
memory tests. M did not potenti-
ate effects of Loraz.
Patat et al. (175) 18 db, pc, co M 10 qd ⫻ 7 d 1) Driving (actual and sim- 1) 4, 7.3 (actual), 3.2, M and C had no effect on
C10 qd ⫻ 7 d ulated) 6.5 (simulated) driving or CFF. Alc
P 2) CFF; adaptive tracking; 2) 1.5, 2.6, 4.5, 6, 7.8 caused significant ↓ of
Alc or P, d 5 or d 7 divided attention all psychomotor and
2 h post dose of M, C, driving tests. M and C
or P did not potentiate ad-
verse effects of Alc.
Vermeeren and O’Hanlon 24 db, pc, co F 120 qd ⫻ 5 d Critical tracking; CRT; sus- 1.5–2.5 except driv- F did not impair driving
(115) F 240 qd ⫻ 5 d tained attention; actual ing (3–4) on days performance or most
F 60 bid ⫻ 5 d driving test 1, 4, and 5 psychomotor tests at
F 120 bid ⫻ 5 d any dose, nor did it po-
Cl 2 bid ⫻ 5 d tentiate the effects of
P Alc; F actually attenu-
Alc on day 5 ated alcohol’s adverse
effect on driving.
A, astemizole; Ac, acrivastine; Alc, alcohol; bid, twice daily; C, cetirizine; CFF, critical flicker fusion; Ch, chlorpheniramine (chlorphenamine); Cl, clemastine;
co, crossover; CRT, choice reaction time; CTT, critical tracking test; d, days; D, diphenhydramine; db, double-blind; Diaz, diazepam; DSS, digit-symbol
substitution; E, ebastine; EEG, electroencephalogram; F, fexofenadine; h, hours; H, hydroxyzine; K, ketotifen; L, loratadine; LARS, linear analog rating
scale (subjective sedation); Loraz, lorazepam; M, mizolastine; P, placebo; pc, placebo-controlled; qd, once daily; T, terfenadine; Tr, triprolidine; VAS, visual
analog scale; ↑, enhance/increase; ↓, impair/decrease.
Welch et al.
Effects on CNS 375
Figure 6 Mean degree of weaving in a standardized actual driving test undertaken 1.5–
4 h after administration of a morning dose of drug on days 1, 4, and 5. On day 5, subjects
were given a moderate alcohol dose along with study drug. Drugs used: clemastine 4 mg
bid, placebo, fexofenadine 120 mg qd, fexofenadine 60 mg bid, fexofenadine 240 mg qd,
fexofenadine 120 mg bid. Asterisks over bars indicate level of significance for drug–
placebo differences. *p ⬍ 0.05; **p ⬍ 0.01. Note that clemastine significantly impaired
driving performance on days 1 and 4; fexofenadine did not affect driving on day 1, and
appeared actually to improve driving (i.e., less weaving compared to placebo) on day 4.
Alcohol given on day 5 impaired driving but it was not potentiated by clemastine or by
fexofenadine. Fexofenadine 120 mg bid appeared to attenuate the effect of alcohol on
driving. (From Ref. 115.)
XIV. SUMMARY
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12
Potential Cardiac Toxicity
of H 1-Antihistamines
I. INTRODUCTION
Antihistamines are among the most frequently prescribed drugs worldwide for
the treatment of allergic disorders, particularly in developed countries (1). The
use of first-generation antihistamines, such as diphenhydramine, hydroxyzine,
chlorpheniramine, brompheniramine, and cyproheptadine, is limited by their sed-
ative and anticholinergic properties. The second-generation, nonsedating antihis-
tamines (e.g., terfenadine, astemizole, loratadine, cetirizine, acrivastine, mizolas-
tine) are relatively free of these side effects; however, since the 1990s there have
been some reports of syncope, torsade de pointes (TdP), and sudden death in
patients taking the nonsedating antihistamines terfenadine and astemizole. As a
result of these reports, regulatory approval for terfenadine and astemizole has
since been suspended in many countries. The cardiac safety profile of the H 1-
antihistamines is now being monitored by regulatory agencies in many countries.
Although the occurrence of cardiotoxic effects in some patients taking terfenadine
and astemizole (1–12) has led to the speculation that other nonsedating antihista-
mines may induce similar cardiotoxic effects, these potential adverse effects are
not a class property of antihistamines, as will be discussed below.
389
390 Yap and Camm
In a few cases, proarrhythmia from terfenadine and astemizole was due to over-
dose: the drugs were taken at doses considerably in excess of that recommended
by the manufacturer (1–6). In many cases, the cardiotoxicity of terfenadine or
astemizole was noted at usual doses of the drugs, but involved concurrent use of
other drugs that inhibit cytochrome P-450 CYP 3A4 drug metabolism (imidazole
antifungals and macrolide antibiotics) or patients with impaired liver function or
congenital long QT syndrome (7, 9, 10, 12). The reports are exemplified by that
of Simons et al., who described a case of ventricular tachyarrhythmia after a 10
mg dose of astemizole (8). Monahan et al. reported an episode of TdP with the
recommended therapeutic dose of terfenadine in association with ketoconazole
and cefaclor (10). Broadhurst et al. described QT prolongation and TdP with
astemizole in a patient with Romano-Ward congenital long QT syndrome (9).
Others reported a case of Mobitz-type 2 heart block with TdP after astemizole
overdose and QT prolongation and ventricular ectopics with a therapeutic dose
of terfenadine in a patient with liver cirrhosis (7). Furthermore, coadministration
of these nonsedating antihistamines with drugs that prolong the QT interval by
the same or other mechanisms (e.g., antiarrhythmics, antipsychotics, tricyclic an-
tidepressants) also increases their adverse effect on cardiac repolarization (11,
12).
Figure 1 Cardiac ionic currents and their relationship with the action potential. (Modi-
fied from Ref. 12.)
Figure 2 Alteration in the action potential with individual blockade of some potassium
channels.
the human ventricular myocardium under normal conditions are the delayed recti-
fier K ⫹ current (I Kr and I Ks) (17), the inward rectifier I Ki (18), and the transient
outward K ⫹ current I TO (19). I Kr seems to play the most important role in determin-
ing the duration of action potential.
The drug-induced proarrhythmias are mostly mediated by drugs that sup-
press the I Ki and I Kr channels that govern the rapid repolarization phase (17). I Ki
is a time-independent but voltage-dependent outward current. I Ki determines and
stabilizes the resting membrane potential near the equilibrium potential for potas-
sium and also contributes to the final phase of repolarization of the action poten-
tial. I Ki is also termed the inward rectifying current, as it allows current to flow
more easily in the inward direction (18).
Initial evidence suggested that the blockade of I Ki might be responsible for
antihistamine-induced TdP (20). The inhibition of I Ki prolongs the rapid repolar-
ization phase of the action potential, and an increase in the vulnerable period,
enhancing the chances of aberrant excitation and arrhythmia in the presence of
these drugs (20). Suppression of I Ki by nonsedating antihistamines is particularly
Potential Cardiac Toxicity 393
When measuring the QT interval, the ECG is best recorded at a paper speed of
50 mm/s and an amplitude of 0.5 mV/cm using a multichannel recorder capable
of simultaneous recording of all 12 leads. A tangent line to the steepest part of
the descending portion of the T wave is then drawn. The intercept between the
tangent line and the isoelectric line is defined as the end of T wave. The QT
interval is measured from the beginning of the QRS complex to the end of the
T wave on a standard ECG. Traditionally, lead II has been used for QT interval
measurement because the vectors of repolarization in this lead usually result in
a long single wave rather than discrete T and U waves.
The QT interval is influenced by heart rate. At least three or four RR in-
tervals preceding the QT interval should be measured for rate correction. Sev-
eral formulas may be used to correct the QT interval for the biophysical effect
of heart rate (QTc). The most commonly used are Fridericia’s cube-root for-
Potential Cardiac Toxicity 395
mula (QTc ⫽ QT/RR 1/3) and Bazett’s square-root formula (QTc ⫽ QT/RR 1/2).
Between the two, Bazett’s formula is more popular, but Fridericia’s correction
is preferred because it is more accurate at the extremes of physiological heart
rate.
Newer repolarization parameters such as QT dispersion (maximum ⫺ mini-
mum QT intervals) on the 12-lead surface ECG, which is considered to be an
indirect measure of spatial heterogeneity of repolarization, may be useful in as-
sessing drug efficacy and safety. In one important study, patients who received
a class 1A antiarrhythmic drug who developed QT prolongation and suffered
TdP had significantly increased precordial QT interval dispersion (27). In con-
trast, patients receiving amiodarone or class 1A antiarrhythmics without devel-
oping TdP did not have increased QT dispersion, although the QT interval was
similarly prolonged (27). Thus, spatial heterogeneity/dispersion of the ventricular
repolarization process may be required in addition to QT prolongation for the
genesis of TdP. Although the use of QT dispersion in the assessment of drugs
that prolong the QT interval needs further confirmation, it may provide informa-
tion about the clinical significance of QT prolongation.
Figure 4 ECG from a 24-year-old woman who presented with TdP while taking an
H 1-antihistamine. After discontinuation of the drug, the QT interval remained prolonged
(QTc ⫽ 573 ms), due to congenital long-QT syndrome.
Potential Cardiac Toxicity 397
(a)
(b)
Figure 6 Rhythm strip in a patient with drug-induced TdP. Note the typical short–
long–short initiating ventricular cycle before the onset of TdP and the classical ‘‘twisting
of a point’’ of the cardiac axis during TdP.
known to prolong QT interval showed that among the 332 patients with proar-
rhythmia, only 25% had baseline QTc ⱖ470 ms, while 90% had QTc ⱖ500 ms
when they developed arrhythmias (30). Thus, a maximal QTc value over 500 ms
(Fig. 5) should cause concern about the potential for drug-induced TdP (Table 1).
There is a characteristic initiating sequence prior to the onset of TdP, partic-
ularly in acquired TdP. The first ventricular complex of the sequence is usually
a ventricular ectopic beat or the last beat of a salvo of ventricular premature beats
(Fig. 6). This is then followed by a pause terminated by a sinus beat. The sinus
beat frequently has a very prolonged QT interval and an exaggerated U wave.
A premature ventricular beat then falls on, or is generated by, the exaggerated
U wave of the sinus beat and precipitates TdP. It has been suggested that, in
some patients, postpause accentuation of the U wave, if present, may be a better
predictor of TdP than the duration of the QTc interval (31), particularly with
drug-associated TdP. When an ectopic beat or brief tachycardia is followed by
a pause, it is therefore important to examine the QT interval and morphology of
T/U waves in the postextrasystolic sinus beat (31).
The association of nonsedating antihistamines and TdP has been reported mainly
with terfenadine and astemizole. These H 1-antihistamines potentially exhibit their
Potential Cardiac Toxicity 399
B. Physicochemical Properties
Other drug-related factors such as the physicochemical properties of the antihista-
mines (e.g., diarylalkylamine moiety, quaternization of diphenhydramine, lipo-
philicity of the side chain) and their metabolic profile (e.g., tissue distribution)
may also contribute to the cardiac toxicity of antihistamines. Like class III antiar-
400 Yap and Camm
C. Hepatic Metabolism
Cytochrome P-450 enzymes, a superfamily of heme-containing proteins present
within the endoplasmic reticulum, have low substrate specificity and are responsi-
ble for the oxidation of a wide variety of lipophilic substrates. Cytochrome P-
450 families 1, 2, and 3 (CYP1, CYP2, and CYP3) are involved in drug metabo-
lism, with isoenzymes of CYP2B, CYP2C, CYP2D, and CYP3A being responsi-
ble for most drug oxidation. Most, but not all, of the nonsedating antihistamines
are metabolized via the hepatic cytochrome P-450 CYP3A4 system (Table 3a);
therefore, administration of these antihistamines to patients with compromised
liver function or concomitant administration of drugs (e.g., imidazole antifungals,
macrolide antibiotics) (Table 3b) or food (e.g., grapefruit juice) that inhibit the
hepatic cytochrome P-450 CYP3A4 may result in the accumulation of the parent
drug and the development of cardiotoxicity (11). For instance, terfenadine under-
goes rapid first-pass metabolism by cytochrome P-450 hepatic enzymes (CYP
3A4) and is transformed into its active metabolite terfenadine carboxylate. Ter-
fenadine carboxylate had no effect on the I Kr potassium channel, even at high
concentrations (12); however, inhibition of the hepatic oxidative metabolism of
terfenadine by imidazole antifungals (e.g., ketoconazole, itraconazole) or macro-
lide antibiotics (erythromycin, clarithromycin) will result in an accumulation and
increased bioavailability of the cardiotoxic prodrug (13, 54). In addition, drugs
such as erythromycin and ketoconazole can themselves prolong the QT interval as
well as inhibit the metabolic activity of hepatic cytochrome P-450. Concomitant
administration of terfenadine and any of these antimicrobial therapies will pro-
duce marked QT prolongation that correlates with plasma concentration of unme-
tabolized terfenadine and increases the risk of arrhythmia (55). Concomitant ad-
ministration of terfenadine with drugs that can inhibit metabolic activity of
hepatic cytochrome P-450 or those that prolong the QT interval must be avoided.
With regard to astemizole, the P-450 isoenzyme CYP3A4 metabolizes the
drug into two active metabolites, desmethylastemizole and norastemizole. The
QT prolongation is caused by astemizole and desmethylastemizole (13). Ebastine,
a highly lipophilic compound, is a prodrug, which is metabolized to a large extent
through the cytochrome P-450 CYP3A4 and its effect on QT prolongation is
enhanced after oral dosage by pretreatment with ketoconazole (56). Mizolastine
is less dependent on cytochrome P-450 hepatic metabolism than astemizole, ter-
fenadine, and ebastine. It has relatively little (1.5–50%) pharmacokinetic interac-
tion with ketoconazole and erythromycin compared with the drugs mentioned
above; the increase in mizolastine plasma concentrations observed with systemic
ketoconazole led to plasma concentrations equivalent to those obtained with a
15–20 mg dose of mizolastine alone. The QT interval prolongation observed did
not seem greater than that anticipated for ketoconazole alone.
Cetirizine and fexofenadine differ from the other currently used nonsedat-
Table 3 Metabolism of Nonsedating H 1-Antihistamines
Nonsedating antihistamines and their major metabolic pathways
Terfenadine Hepatic P-450 CYP3A4
Astemizole Hepatic P-450 CYP3A4
Ebastine Hepatic P-450 CYP3A4 and CYP2D6
Loratadine Hepatic P-450 CYP3A4 and CYP2D6
Mizolastine Mainly via glucuronidation (65%), less
via hydroxylation (hepatic P-450 CYP
3A4 and 2A6)
Fexofenadine 80% via the fecal route and 10% via the
renal route
Cetirizine 60% renal, 40% hepatic
Drugs and foods that can inhibit hepatic cytochrome P-450 CYP3A4 enzymatic ac-
tivity
Imidazole antifungals Ketoconazole
Itraconazole
Fluconazole
Metronidazole
Macrolide antibiotics Erythromycin
Clarithromycin
Troleandomycin
Josamycin
Flurythromycin
Ponsinomycin
Antidepressants Fluvoxamine
Fluoxetine
Paroxetine
Sertraline
Nefazodone
HIV protease inhibitors or non-nucleoside Amprenavir
reverse transcriptase inhibitors Indinavir
(NNRTI) Nelfinavir
Ritonavir
Saquinavir
Delavirdine (NNRTI)
Anti-ulcer drugs Ranitidine
Cimetidine
Omeprazole
Ethinyl estradiol Estrogen
Oral contraceptives
Calcium antagonists Diltiazem
Verapamil
Nifedipine
Tetracyclines Tetracycline
Doxycycline
Anti-tuberculosis drug Isoniazid
Antimalarial Primaquine
Antibiotic Quinupristin/dalfopristin
Antiarrhythmic drug Amiodarone
Antihypertensive drug Hydralazine
Food Grapefruit juice
Potential Cardiac Toxicity 403
ing antihistamines because they are not metabolized to the same extent (57). In
adults, cetirizine is eliminated 60% unchanged via the renal route and 40% via
the hepatic route. Patients with renal and hepatic impairment are advised to de-
crease the dosage. Fexofenadine is eliminated primarily by the fecal route (80%)
and only 10% by the renal route (58). Consequently, the potential drug interac-
tions are less relevant. Although renal disease rather than liver disease could
result in elevated plasma concentrations, both cetirizine and fexofenadine are
devoid of QT-prolonging effect.
Grapefruit juice contains furanocoumarins (e.g., 6′, 7′-dihydroxybergamot-
tin and its dimers), which are potent inhibitors of CYP3A4, and cause a rapid
loss of enzyme activity of intestinal but not hepatic cytochrome CYP3A4 (57).
In one study of six healthy subjects, when 60 mg terfenadine was given simulta-
neously with double-strength grapefruit juice for 7 days, all subjects had in-
creased and quantifiable levels of unmetabolized terfenadine, accompanied by an
increase in the QTc interval from 420 to 434 ms ( p ⬍ 0.05) (59). Although in
most studies of drug–grapefruit interactions, double-strength grapefruit juice was
given twice daily for a week, significant interaction between terfenadine and regu-
lar-strength grapefruit juice (60) or freshly squeezed juice (61) was also demon-
strated. Thus, grapefruit juice can inhibit the metabolism of some nonsedating
antihistamines by enzymes of the cytochrome P-450 CYP3A4 located in the gut
wall and should therefore be avoided by patients taking these drugs.
and ⬍10%) that is not clinically meaningful, although it was statistically signifi-
cant compared with placebo (65). A detailed study, however, showed that the
minor QT prolongation with ebastine (and possibly with other drugs) is critically
dependent on the precision of the rate correction formulas and influenced by the
natural variability of the QTc interval. For instance, while all generalized heart
rate correction formulas showed consistent QT prolongation with terfenadine,
results were inconsistent with ebastine. Correction using Bazett’s formula sug-
gested significant QT interval increase with ebastine, but correction using the
Lecocq formula suggested a significant QT interval decrease. Even with an opti-
mized heart rate correction formula (QTc ⫽ QT/RR 0.314) from pooled QT/RR
regression during the drug-free state, the minor QT prolongation with ebastine
was not consistent. The QTc changes in a four-way crossover study after a 7 day
course of placebo, 60 mg ebastine, 100 mg ebastine, and 100 mg terfenadine
were ⫺1.95 ⫾ 6.87 ms, p ⫽ N.S.; ⫺3.91 ⫾ 9.38 ms, p ⫽ 0.053; 0.75 ⫾ 8.23
ms, p ⫽ N.S.; 12.95 ⫾ 14.64 ms, p ⫽ 0.0003, respectively (M. Malik, personal
communication). Thus, measurement imprecision and natural diurnal variability
of the QTc interval can lead to a QTc variation of at least 4–5 ms, which can
be critical when assessing minor drug-induced QT prolongation.
In contrast, loratadine does not cause a significant QT prolongation even
at supratherapeutic doses (66, 67). In one study, no patient had a QTc interval
of more than 440 ms when given loratadine 40 mg (four times the recommended
dosage) for 3 months (66). The clinical experience with mizolastine, particularly
in potentially high-risk patients, is still limited. An overview of the QT interval
monitoring performed during the clinical development of mizolastine showed
that this second-generation H 1-antihistamine has no significant effect on cardiac
repolarization in humans (68). Mizolastine was administered orally to healthy
volunteers in single doses of up to 75 mg and in a repeated dosage of 40 mg
daily (i.e., 7.5 and 4 times the recommended daily dosage, respectively) and at
a dose of 10 or 15 mg in patients. In healthy volunteers, there was no increased
incidence of QTc value ⬎440 ms or ∆QTc ⱖ40 ms compared with placebo. No
dose-related increase in QTc interval was observed. In patients, the mean QTc
interval changes from baseline were not significantly different between mizolas-
tine and placebo. In volunteers or patients receiving mizolastine, there was little
or no idiosyncratic QT interval prolongation and it did not induce changes in the
T/U wave morphology.
Cetirizine is the metabolite of hydroxyzine, a first-generation antihista-
mine, which at high dosages has been reported to be associated with T-wave
changes (55). In studies conducted in healthy subjects, however, and even in
supratherapeutic dosages of 20 or 60 mg daily, cetirizine was devoid of an effect
on QT interval (69). There was likewise no dose-related increase in QT interval
or significant increase in mean QT interval with fexofenadine, the carboxylate
Potential Cardiac Toxicity 405
The World Health Organization’s (WHO) adverse drug reaction database pro-
vides a source of data on spontaneous adverse drug reactions from 17 countries
where nonsedating antihistamines are available. Data reported include total rate
and rhythm disorders, selected reactions (QT prolongation, TdP, ventricular
tachyarrhythmias, cardiac arrest, and supraventricular tachycardia), cardiac and
sudden deaths. From 1986 to 1996 the following data were reported: 106 cases
of selected reactions, 13 cardiac and sudden deaths for loratadine; 19 cases of
selected reactions, 2 cardiac and sudden deaths for cetirizine; and 1 case of se-
Potential Cardiac Toxicity 407
lected reaction and no incidence of cardiac and sudden death for acrivastine (79).
When calculated as reports per million defined daily doses (DDD) sold, all three
antihistamines have a very low reporting rate. Specifically, the reporting rates
for cardiac and sudden deaths were approximately 0.005 for loratadine and
0.0008 for cetirizine and none for acrivastine compared with 0.038 for terfena-
dine. Although the reported incidences of deaths were themselves very low com-
pared with terfenadine, the type of report and its analysis have attracted some
criticism because of potential flaws and biases (80, 81). For instance, the report
does not take into account the spontaneous rate of background cardiac events
in the untreated population or the inclusion of a wide variety of undefined and
unsubstantiated cardiac events in a composite numerator, rather than specific ven-
tricular events of relevance to nonsedating antihistamines. This makes the analy-
sis questionable (81). The Food and Drug Administration (FDA), which monitors,
analyzes, and reviews individual reports and follow-up of cases of adverse drug
reactions with antihistamines, did not find any definitive causal association be-
tween loratadine, cetirizine, or acrivastine and ventricular tachyarrhythmia up
to 1997. It should be emphasized that apart from the specific contraindications
described, the incidence of cardiotoxicity with antihistamines is extremely low
in view of the widespread use of the drugs. Nevertheless, as antihistamines are
prescribed for non-fatal disorders such as allergic rhinitis and chronic urticaria,
the attributable risk must be assessed very critically. It will be very difficult to
conduct a large controlled clinical study to examine the causal association be-
tween nonsedating antihistamines and ventricular arrhythmias. Any crude adverse
event report must be put in perspective and used to detect trends and generate
hypotheses that may guide surveillance and help plan future studies. The Euro-
pean Association of Allergology and Clinical Immunology (EAACI) published
a guideline on the use of nonsedating antihistamines to avoid any unwanted ar-
rhythmogenic effect associated with their use (82). It includes: avoidance of ex-
cessive dosage of antihistamines beyond that recommended by the manufacturer;
avoidance of coadministration of drugs known to interfere with the hepatic metab-
olism of antihistamines; careful use of antihistamines in patients with liver im-
pairment or at risk of cardiac arrhythmias (e.g., congenital long QT syndrome
or atrioventricular block); selection of antihistamines that do not have quinidine-
like actions and are not metabolized by hepatic cytochrome P-450 in patients at
risk of cardiac arrhythmia.
Nonsedating antihistamines are widely prescribed for the treatment of aller-
gic disorders; however, the nonsedating antihistamines such as terfenadine and
astemizole that block I Kr channels are now known to cause QT prolongation and
TdP, particularly when given in overdosage, with concomitant ingestion of imid-
azole antifungals or macrolide antibiotics, or to at-risk patients including those
with congenital long QT syndrome, cardiac disease, liver disease, or electrolyte
408 Yap and Camm
disturbance. Many questions still need to be answered, such as the roles of other
potassium channels (I Ks , I To , and I Ped ) and the relative expression of various potas-
sium channels in different individuals, which may be important in the pathogene-
sis of TdP.
There are many causes of QT interval prolongation; however, by far the most
common cause of QT prolongation is a drug. The drugs that can cause QT prolon-
gation and TdP are listed in Table 4. Apart from drugs, other conditions likely
to cause QT prolongation, some of which have already been discussed above,
include:
Table 4 Drugs That Can Prolong QT Interval and Lead to TdP (not a comprehensive list)
Table 4 Continued
bance should be avoided. The serum potassium level should be checked regularly
when the patient is taking potassium-depleting diuretics. Drugs that can prolong
the QT interval should ideally be listed and regularly updated in a national drug
formulary. Any adverse event suggestive of cardiac arrhythmias should be re-
ported urgently to drug regulatory authorities and/or drug manufacturers. In our
institution, we routinely give out an advice leaflet regarding the risk of QT prolon-
gation and TdP to at-risk groups such as patients who are prescribed QT-pro-
longing drugs and those with congenital long QT syndrome (Fig. 7). Several
websites provide information about the risk of QT prolongation with a particular
drug, although none is comprehensive (Fig. 7).
TdP is often self-limiting and associated with recurrent dizziness and syn-
cope; however, it may progress to ventricular fibrillation and sudden death. The
management of patients with drug-induced TdP includes identifying and with-
drawing the offending drug(s), and identifying and correcting any electrolyte ab-
Potential Cardiac Toxicity 411
Figure 7 Contents in St. George’s Hospital advice leaflet on long-QT syndrome and
websites for checking QT-prolonging drugs.
Apart from antiarrhythmics, many drugs capable of inducing TdP are prescribed
for noncardiac indications and are used for the treatment of relatively benign
conditions. Regulatory authorities in the European Union (EU) are now con-
cerned that the risk of cardiotoxicity should be identified and if possible quantified
during the preclinical and clinical development of a drug. There are currently no
contemporary guidelines from other regulatory authorities to address this issue;
however, in 1997, the Committee for Proprietary Medicinal Products (CPMP)
adopted a document entitled ‘‘Points to Consider: The Assessment of the Poten-
tial for QT Interval Prolongation by Non-Cardiovascular Medicinal Products’’
(96). This document should be viewed as a strong signal from the public health
Figure 8 The preclinical and clinical stages for testing the safety of new active substances (NAS) proposed in the CPMP document. (Summary
from Ref. 98.)
Potential Cardiac Toxicity 413
XII. SUMMARY
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418 Yap and Camm
Michael Schatz
Kaiser-Permanente Medical Center, San Diego, California
I. INTRODUCTION
H 1-receptor antagonists are frequently used during pregnancy and lactation (1).
A major reason for this is that two of the diseases for which these antihistamines
are often used, allergic rhinitis and upper respiratory infections, are common in
women of child-bearing age. In addition, urticaria and atopic dermatitis, two other
indications for H 1-antihistamines, are not uncommon in this age group. Less
commonly, antihistamines may be necessary as part of adjunctive therapy for
life-threatening anaphylaxis during pregnancy. Therefore, the selection of antihis-
tamines during pregnancy and lactation is an important clinical issue. In this
chapter, we will first review general information and concepts regarding the use
of medications during pregnancy. Next, the data available regarding the safety
of specific antihistamines during pregnancy and lactation will be reviewed. Fi-
nally, based on this information, recommendations will be presented regarding
the choice and clinical use of H 1-receptor antagonists in the pregnant or lactating
patient.
421
422 Schatz
B. Sources of Information
Information regarding the effects of drugs administered during pregnancy comes
from several sources. Appropriately performed animal studies that do not reveal
teratogenicity of an agent are reassuring, although animal studies showing ad-
verse effects are harder to interpret due to species variability and dose consider-
ations (4). Human case reports of malformations must be considered, although
the coincidental occurrence of a sporadic birth defect or a birth defect caused by
another environmental teratogen cannot be excluded. Most prospective cohort
studies of asthma medications during pregnancy suffer from low statistical power,
and case–control studies may be biased by retrospective design.
Several large prospective studies have addressed the relationship between
medications (including antihistamines) prescribed during early pregnancy and
Pregnancy and Lactation 423
Benefit may
Category Animal studies Human data outweigh risk
D. Lactation
Almost all drugs pass into breast milk, usually in amounts less than 2% of the
maternal dose (15). The amount of drug passing into milk varies with its dose,
Pregnancy and Lactation 425
sure and adverse perinatal outcomes, including pre-eclampsia, preterm birth, low-
birth weight infants, small-for-gestational age infants, or congenital malforma-
tions.
Seto et al. (20) recently reported a meta-analysis of pregnancy outcome
following first-trimester exposure to H 1-antihistamines. Twenty-four controlled
studies published between 1960 and 1991 involving more than 200,000 women
were included. The summary odds ratio of major malformations associated with
H 1-antihistamines taken during pregnancy was 0.76, suggesting that the maternal
use of antihistamines during pregnancy does not increase the teratogenic risk.
There is a report in the literature (21) that associates H 1-antihistamine use
within 2 weeks of delivery with a twofold increased risk of retrolental fibroplasia
in very-low-birthweight (⬍1750 g) premature infants. The mechanism of this
association is unclear, but the authors suggest that histamine antagonism in the
immature retinal vasculature could initiate or promote the physiological process
leading to retrolental fibroplasia.
None of the available information suggests that the maternal use of H 1-
antihistamines during lactation is associated with serious adverse reactions in the
nursing infant (17). Moreover, no data show that the use of antihistamines by
the lactating mother interferes with lactation (3). There are a few reports associat-
ing the use of first-generation antihistamines during nursing with infant drowsi-
ness or irritability (22, 23).
B. Specific Drugs
1. First-Generation Antihistamines
Information regarding the duration of availability and the results of animal terato-
genicity studies for currently available oral first-generation antihistamines is sum-
marized in Table 2. However, only first-generation drugs for which human data
are available (Table 3) will be discussed below.
Brompheniramine. Brompheniramine is an old antihistamine for which
animal reproduction data have not demonstrated adverse effects; however, a sta-
tistically significant relationship between brompheniramine use and total congen-
ital malformations was reported in 65 exposed women in the CPP (5). The data
in 206 exposed women in two other studies were more reassuring (Table 3).
Chlorpheniramine. Chlorpheniramine is one of the oldest available anti-
histamines, and animal data have been reassuring. Gestational exposure to chlor-
pheniramine has not been associated with a significantly increased risk of congen-
ital malformations in a relatively large number of women (Table 3). No adverse
effects were reported in five nursing infants whose mothers were receiving chlor-
pheniramine (22).
Pregnancy and Lactation 427
Year introduced
Drug (USA) Animal studies a FDA class b
First-Generation
Azatadine 1977 Positive C
Brompheniramine 1957 Negative —c
Clemastine 1977 Negative B
Chlorpheniramine 1949 Negative —
Dexchlorpheniramine 1982 Negative B
Diphenhydramine 1946 Negative B
Hydroxyzine 1956 Positive —
Pheniramine 1948 None —
Tripelennamine 1946 Negative —
Triprolidine 1958 Negative —
Second-Generation
Astemizole d 1988 Positive C
Cetirizine 1995 Negative B
Fexofenadine 1996 Positive C
Loratadine 1993 Negative B
Terfenadine d 1985 Positive C
Topical
Azelastine 1996 Positive C
Levocabastine 1993 Positive C
Olopatadine 1996 Positive C
Pheniramine 1948 None —
a
Positive, adverse effects demonstrated; negative, adverse effects not demonstrated; none, no animal
studies reported (33).
b
See Table 1 (33).
c
Drugs for which no FDA class is listed were introduced and labeled before classification was man-
dated (1979).
d
These drugs are no longer marketed in most countries.
599 children with oral clefts and 599 controls found a 3.3-fold increased fre-
quency of exposure to diphenhydramine in the mothers of cases vs. controls
(p ⬍ 0.01) (24).
Diphenhydramine has been associated with several other adverse events
during pregnancy or lactation. Withdrawal manifestations (generalized tremu-
lousness and diarrhea) have been reported in the newborn of a woman receiving
150 mg diphenhydramine daily during pregnancy (25). A case of diphenhydra-
mine overdose during pregnancy has also been reported, associated with disorien-
tation and painful uterine contractions (26). The latter was attributed to the oxyto-
cin-like effects of diphenhydramine, which had been previously reported (27).
Finally, 1 of 12 nursing infants whose lactating mothers were receiving diphenhy-
dramine manifested drowsiness (22).
Hydroxyzine. Hydroxyzine, which has been available since 1956, appears
to cause adverse effects in animal studies. No statistically significant increases
in congenital malformations have been reported in nearly 1000 exposed human
pregnancies (Table 3), although somewhat increased odds ratios (1.6 and 3.4 for
any malformations) have been reported in two studies (5, 28). There is a report
of a neonatal withdrawal syndrome (jitteriness, clonic movements of the upper
extremities, and poor feeding) in the infant of a mother who ingested 600 mg
hydrozyzine daily throughout pregnancy (29).
Pheniramine. Pheniramine has been available orally and topically since
1948. No animal reproduction studies have been reported. Data from the CPP
were reassuring in 831 subjects (5).
Tripelennamine. Along with diphenhydramine, tripelennamine is the old-
est available antihistamine. Animal and human studies during pregnancy have
been reassuring, but only 100 exposed human subjects have been reported (5).
Triprolidine. Animal studies have been reassuring for triprolidine. Hu-
man data have also not suggested an increased risk of selected malformations,
although fewer exposed patients have been reported than for older antihistamines
such as chlorpheniramine or diphenhydramine (Table 3).
2. Second-Generation Antihistamines
Information regarding the duration of availability and results of animal reproduc-
tion studies for second-generation antihistamines is summarized in Table 2, and
published human studies are summarized in Table 3.
Astemizole. Animal studies with astemizole have produced adverse fetal
effects. A small human study has been reassuring, but this study does not exclude
as much as a sevenfold increased risk of congenital malformations with 95%
certainty (30). A report describing apparent reactions in nursing infants to mater-
430 Schatz
3. Topical Antihistamines
Animal studies for azelastine, levocabastine, and olopatadine have reported ad-
verse fetal effects, but no human gestational data have been published. Phenira-
Pregnancy and Lactation 431
mine, which is available in both oral and topical preparations, has been discussed
above.
2. Lactation
As described above, there are no data suggesting that the maternal use of antihis-
tamines causes serious adverse reactions in the nursing infant. Drowsiness has
been occasionally reported with first-generation antihistamines. Although lacta-
tion pharmacokinetic data have been reassuring with terfenadine and loratadine,
irritability has been reported in some nursing infants whose mothers were taking
terfenadine or astemizole. My recommendation would be to use whatever antihis-
tamine seems best for the lactating mother, watching for drowsiness in the infant
if first-generation antihistamines are being utilized and for irritability with sec-
ond-generation antihistamines. As mentioned above, in patients with rhinitis, top-
ical (cromolyn or intranasal corticosteroid) therapy may be preferred to minimize
further infant drug exposure through breast milk.
Pregnancy and Lactation 433
B. Informed Consent
Although the patient’s informed consent to the therapeutic approach recommended
during pregnancy should be obtained as part of good medical care and in order to
optimize compliance, it also has important medical–legal implications. The thalido-
mide tragedy raised public awareness of the adverse effects of drugs on the fetus.
Moreover, in today’s litigious environment, the lay public and legal profession have
often related the occurrence of an adverse pregnancy outcome to malpractice.
The following approach to obtaining a woman’s informed consent during
pregnancy has been recommended (36, 37). First, state what is known and not
known regarding the effect of the particular drug(s) on pregnancy and the devel-
oping infant. These risks should be presented in relationship to the background
risk in the general population discussed in Section II.A of this chapter. It should
be emphasized that, although relatively few medications have been proved to be
harmful during pregnancy, no asthma or allergy medication can be considered
to be proven absolutely safe. Second, discuss with the patient the potential conse-
quences for the mother and for the baby of the inadequately controlled allergic
disorders. Third, discuss the medication options available for the patient’s partic-
ular situation and the rationale for the specific treatment plan recommended. Em-
phasize that this recommended treatment program is considered to entail less risk
than the uncontrolled illness that could result if it was not used. Fourth, continu-
ally address any questions the parents may have. Fifth, obtain the patient’s con-
currence with the therapeutic decisions. Finally, document the informed consent
discussion(s) on the patient’s chart. I suggest including a statement such as the
following: ‘‘The benefits, risks, and alternatives of (the specific pharmacological
approach) have been discussed with the patient and her informed consent to that
approach has been obtained.’’ A formal written consent form is not considered
to be necessary (36).
V. SUMMARY
Antihistamines may be used for the treatment of allergic rhinitis, upper respira-
tory infections, urticaria/angioedema, atopic dermatitis, and, rarely, as adjunctive
treatment for anaphylaxis, during pregnancy. Because these illnesses may affect
maternal comfort and safety as well as threaten the fetus directly (anaphylaxis) or
indirectly, they often require therapy during pregnancy. Based on the information
available to date, in this chapter we have attempted to provide rational guidelines
for the gestational use of H 1-receptor antagonists in a manner that will lead to
the optimal well-being of both the mother and her infant. As more information
becomes available, the recommendations herein may require modification.
434 Schatz
REFERENCES
F. Estelle R. Simons
University of Manitoba, Winnipeg, Manitoba, Canada
I. INTRODUCTION
437
438 Simons
Evidence Level
Allergic rhinoconjunctivitis 1A
Urticaria 1A
Atopic dermatitis 1B
Upper respiratory tract infections (colds) 3D
Otitis media 3D
Asthma 1C
Other (mosquito bites, eosinophilic cellulitis, etc.) 1B
A. Pharmacokinetic Studies
H 1-antagonists are well-absorbed after oral administration as liquid or solid for-
mulations, with peak plasma concentrations usually being reached within 2 hours
(4–15). The old H 1-antagonists and the new H 1-antagonists loratadine and ebas-
tine are metabolized by the hepatic microsomal mixed-function oxygenase sys-
tems; plasma concentrations of these H 1-antagonists are low after single oral
doses, indicating considerable first-pass hepatic extraction.
Cetirizine, the active carboxylic acid metabolite of hydroxyzine, is elimi-
nated 40% unchanged in the urine within the first 24 hours of a single dose in
children (9, 10), compared to being eliminated 60% unchanged in the urine in
adults (3). Fexofenadine elimination (3), in contrast to fexofenadine pharmacoki-
netics (13) (Fig. 1), has not been studied directly in children; in adults, the drug
is eliminated largely unchanged in the feces.
Concomitant administration of H 1-antagonists with cytochrome P-450 in-
hibitors and other potential pharmacokinetic medication interactions has not been
studied directly in young subjects, with the exception of a novel study of the
effect of chlorpheniramine on the pharmacokinetics of chloroquine in children
with chloroquine-resistant falciparum malaria (16).
Table 2 Pharmacokinetics and Pharmacodynamics of H 1-Antihistamines in Children
Dosage
Drug (active (mg) or No. of Cp max ↓ Wheal/
metabolite) (mg/kg)* pts. (么) Age (yr) Weight (kg) (ng/mL) t max (h) t1/2β(h) flare (h) Reference
First-Generation
Use in Children
Brompheniramine 4 14 (8) 9.5 ⫾ 0.4 31.9 ⫾ 1.7 7.7 ⫾ 0.7 3.2 ⫾ 0.3 12.4 ⫾ 1.1 0.5–36 (30) 4
Chlorpheniramine 0.12* 11 (7) 11 ⫾ 3.0 39.6 ⫾ 9.2 13.5 ⫾ 3.5 2.5 ⫾ 1.5 13.1 ⫾ 6.3 1–24 a 5
Diphenhydramine 1.25* 7 8.9 ⫾ 1.7 31.6 ⫾ 6.8 81.8 ⫾ 30.2 1.3 ⫾ 0.5 5.4 ⫾ 1.8 1–8/1–12 6
Hydroxyzine 0.7* 12 (6) 6.1 ⫾ 4.6 22.0 ⫾ 12.0 47.4 ⫾ 17.3 2.0 ⫾ 0.9 7.1 ⫾ 2.3 n/a 7
Ketotifen b 1 bid 6 2–4 3.25 1.33 n/a n/a 8
Second-Generation
Cetirizine 5 10 (7) 8.0 ⫾ 0.6 30.5 ⫾ 2.7 427.6 ⫾ 144.2 1.4 ⫾ 1.1 7.1 ⫾ 1.6 c 1–24 9
10 9 (8) 8.0 ⫾ 0.6 25.4 ⫾ 1.9 978.4 ⫾ 340.6 0.8 ⫾ 0.4 6.9 ⫾ 1.6 0.5–24
5 8 (5) 2.7⫾ 15.0⫾ 560 ⫾ 200 1.44 ⫾ 1.1 4.9 ⫾ 0.6 c n/a 10
0.25 15/10 12.3 ⫾ 5.5 9.0 ⫾ 1.1 (est.) 2 3.1 ⫾ 1.8 90%/87% 11
months 390 ⫾ 135 2.0 ⫾ 1.3 at 12 hr
Ebastine (carebastine) 5 10 (6) 7.3 ⫾ 0.4 26.4 ⫾ 1.7 (108.6 ⫾ 11.8) (2.8 ⫾ 0.3) (11.4 ⫾ 0.7) 0.5–28 12
10 10 (6) 7.8 ⫾ 0.4 26.1 ⫾ 1.0 (209.6 ⫾ 24.2) (3.4 ⫾ 0.4) (10.1 ⫾ 1.1) 0.5–28
Fexofenadine 30/60 14 (13) 9.8 ⫾ 1.8 32.1 ⫾ 9.3 178 ⫾ 22/286 ⫾ 34 2.4 ⫾ 0.2 18.3 ⫾ 1.2/17.6 ⫾ 1.0 1–24 13
Loratadine (descarbo- 10 13 10.6 4.38 (3.79) 1.0 (1.69) n/a (13.79) 1–12 e 14
ethoxy-loratadine) 5 18 (11) 3.8 ⫾ 1.1 17.4 ⫾ 4.4 7.8 (5.1) 1.2 (2.3) n/a n/a 15
There are no published studies in children to date of acrivastine, azelastine, desloratadine, levocabastine, levocetirizine, mizolastine, or tecastemizole
pharmacokinetics/pharmacodynamics. Medications were administered as liquid formulations, except for fexofenadine and cetirizine (8-year-olds).
n/a, data not available; Cp max (ng/ml), maximum plasma concentration; t max (h), time of maximum plasma concentration; t1/2β, plasma elimination half-
life; ↓ wheal/flare (h), suppression of wheal and flare vs. baseline and vs. placebo treatment (p ⬍ 0.05).
a
Also clinical score for allergic rhinitis.
b
Sometimes classified as a second-generation H 1-receptor antagonist but is, in fact, sedating.
c
Urinary excretion of unchanged cetirizine ⫽ 40 ⫾ 15% and 33 ⫾ 14%.
d
37.8 ⫾ 5.2%.
e
Duration of study limited to 12 h.
439
440 Simons
B. Pharmacodynamic Studies
In children, as in adults, suppression of the histamine-induced wheal and flare
in the skin is used as an objective test of the magnitude, onset, time to peak, and
duration of peripheral H 1-blockade (3). The amount of wheal and flare suppres-
sion varies from one H 1-antagonist to another and with the H 1-antagonist dose
administered. In studies in the pediatric population, a single oral dose of the old
H 1-antagonists brompheniramine, chlorpheniramine, diphenhydramine, hydrox-
yzine, or ketotifen and the new H 1-antagonists cetirizine, ebastine, fexofenadine,
or loratadine has a prompt onset of action (3–6, 9, 11–13, 17) (Fig. 1). During
regular daily administration over weeks or months, no tachyphylaxis or resistance
to their effects occurs (9).
The residual action of H 1-antagonists (the length of time required for their
effect to wear off after the last dose of a short course of treatment) has not been
studied directly in children; however, in young patients, as in adults, it is recom-
Use in Children 441
mended that H 1-antagonists be discontinued for at least 3–4 days before allergen
skin testing.
Although the clinical pharmacology of H 1-antagonists, as objectively mea-
sured in pharmacokinetic and pharmacodynamic studies, differs to some extent
in children and adults, once- or twice-daily dosing is still possible for most H 1-
antagonists in children age 6–11 years (Table 3).
The challenges involved in performing clinical trials for development of the evi-
dence base for the efficacy and safety of each H 1-antagonist in children should not
be underestimated (18) (Table 4). Here, we review the evidence for H 1-antagonist
efficacy in allergic rhinoconjunctivitis, upper respiratory tract infections, otitis
media, asthma, urticaria, atopic dermatitis, and other disorders.
A. Allergic Rhinoconjunctivitis
Allergic rhinitis affects up to 42% of children worldwide (19, 20) and is an impor-
tant cause of morbidity and impaired quality-of-life in the pediatric population
(21). The indoor and outdoor airborne allergens and other provoking factors for
allergic rhinitis are similar in children and adults, as is the pathophysiology of
the disorder. Diagnosis is based on symptoms and physical signs. Children are
more likely than adults to present with non-nasal symptoms and signs that are
indirectly related to the allergic inflammation in the nasal mucosa. For example,
they may develop tics or facial grimacing secondary to itching of the nose and
eyes, or behavioral or learning problems due to nocturnal sleep disturbance and
subsequent daytime fatigue, sometimes exacerbated by treatment with old sedat-
ing H 1-antagonists (22). Diagnosis is supported by the presence of eosinophils
in nasal secretions, and by one or more positive epicutaneous tests to airborne
allergens. Although other objective measurements such as documentation of ele-
vated histamine concentrations in nasal secretions, and of nasal blockage, can be
made, these tests are better suited to research than to office use (23, 24).
In children with allergic rhinitis challenged intranasally with allergens to
which they have been naturally sensitized, H 1-antagonists prevent sneezing, itch-
ing, and rhinorrhea during the early response, but are less effective in preventing
or relieving the nasal blockage characteristic of the late response. In children
with allergic conjunctivitis who receive an ocular challenge with allergen, H 1-
antagonists effectively prevent itching, tearing, and conjunctival erythema during
the early response, and decrease the nonspecific conjunctival hyperreactivity re-
lated to allergic inflammation.
442 Simons
C. Otitis Media
Histamine concentrations are elevated in the middle ear effusions in otitis media
(52, 53). The eustachian tube response to intranasal histamine and other chemical
mediators of inflammation is increased in subjects with allergic rhinitis compared
to healthy subjects. Allergic inflammation may be a contributing factor in the
development of otitis media with effusion.
Acute otitis media and otitis media with effusion have high spontaneous
remission rates. H 1-antagonists, often in combination with an α-adrenergic ago-
nist decongestant, are frequently prescribed for infants and young children with
otitis media; however, placebo-controlled, double-blind studies incorporating re-
peated objective assessment of tympanic membrane compliance do not support
beneficial effects of H 1-antagonists on eustachian tube function in these disorders
(54).
Additional insight into the relationship between allergic inflammation and
otitis media may eventually be obtained from clinical trials of H 1-antagonists in
the prevention or treatment of otitis media in atopic children.
D. Asthma
Histamine is one of many chemical mediators of inflammation contributing to
the pathophysiology of asthma. The early and late bronchoconstrictor responses
produced by inhalation of allergen are associated with increased plasma concen-
trations of histamine. Increased circulating histamine has also been reported dur-
ing naturally occurring acute asthma episodes. Relatively high doses of H 1-antag-
onists seem to be required for H 1-blockade in the lower airways, in comparison
to those required for H 1-blockade in the nasal mucosa or skin (55–58). In addition
to production of H 1-blockade, the antiallergic and anti-inflammatory effects of
cetirizine, fexofenadine, ketotifen, loratadine, and other H 1-antagonists may be
relevant in asthma. These effects include prevention of mediator release from
mast cells and decreased retention and activation of inflammatory cells in the
airways (59, 60).
H 1-antagonists such as cetirizine, loratadine, and ketotifen have been found
to prevent histamine- and exercise-induced asthma, and to relieve allergic cough
and other mild persistent asthma symptoms in children (59, 60). Previous con-
cerns about their adverse effects in asthma, including specific concerns about
Use in Children 447
potential drying of the secretions and bronchoconstriction, have not been substan-
tiated.
Allergic rhinitis and asthma are linked epidemiologically. They are also
linked histologically by the respiratory epithelium lining the upper and lower
airways, physiologically by the nasobronchial reflex, and pathologically by simi-
lar early- and late-phase allergic responses throughout the airways and by the
systemic immunological response to airborne allergens (61). In adults, H 1-antago-
nists in doses ordinarily used for seasonal allergic rhinitis have been reported to
improve coexisting mild seasonal asthma symptoms and to improve pulmonary
function (62).
As a potential strategy in combatting the global epidemic of asthma, there
is currently considerable interest in preventing or delaying the onset of asthma
in high-risk children by using H 1-antagonists. Ketotifen, widely used as an oral
antiasthmatic medication in some countries, was reported to prevent or delay
asthma development in infants who, at study onset, were asthma-free but had
atopic dermatitis and elevated total serum IgE concentrations (63, 64).
In the Early Treatment of the Atopic Child (ETAC) study, cetirizine 0.25
mg/kg twice daily (total daily dose, 5–11 mg) prevented asthma development
in children sensitized to house dust mite or grass pollen at study entry (65)
(Fig. 4). This randomized, double-blind, placebo-controlled, parallel-group, 18-
month study was conducted in 800 children who, at enrollment, were age 12–
24 months and asthma-free, but had atopic dermatitis and a family history of
atopic disease. After treatment with cetirizine was discontinued, its ability to
prevent asthma was still evident during 18 months of double-blind follow-up
evaluation.
In the Preventia Study described previously, loratadine 2.5 or 5 mg reduced
the average number of wheezing episodes significantly, from 1.2 per child to 0.8
per child during 12 months of treatment (46).
have been performed in pediatric patients with urticaria. One of the most interest-
ing and important outcomes of the ETAC study was that acute urticarial epi-
sodes were significantly reduced in the infants and toddlers treated with cetirizine
5–11 mg/day, compared to those receiving placebo (68) (Fig. 5). The protective
effect occurred only during the 18-month active treatment period, and disap-
peared during double-blind follow-up after the cetirizine was discontinued.
In most children with pediatric mastocytosis syndrome, plasma histamine
concentrations are elevated. H 1-antagonists are effective in the treatment of this
disorder (69,70).
In anaphylaxis (71), H 1-antagonists are a helpful adjunctive treatment for
controlling pruritus and urticaria (Table 3A), however, they are not a substitute
for epinephrine injected intramuscularly, and reliance on H 1-antagonists alone
may contribute to a fatal outcome.
Use in Children 449
Figure 5 In the ETAC study, the children treated with cetirizine 5–11 mg daily had
fewer episodes of urticaria than those treated with placebo (p ⬍ 0.001). The protection
provided by cetirizine occurred throughout the 18-month double-blind treatment period,
but did not persist after the medication was discontinued. (From Ref. 68.)
F. Atopic Dermatitis
Children with atopic dermatitis have increased numbers of mast cells in the papil-
lary and reticular dermis of affected areas of skin. A report that H 1-antagonist
treatment reduces the number of these cells (72) remains to be confirmed. Hista-
mine is an important pruritogen in atopic dermatitis and H 1-antagonists are often
given to infants and children with this disorder, primarily to decrease itching and
scratching (73–75). Some physicians are convinced that there is a role for first-
generation H 1-antagonists such as hydroxyzine in the treatment of severe atopic
dermatitis, when the itching is so intense that the nocturnal sleep of the infant
or child (and of the parents!) is disturbed. The sedation produced by the old H 1-
antagonist is perceived as being a beneficial effect rather than an adverse effect
in this situation (Table 3A).
A recent meta-analysis of the efficacy of H 1-antagonists in atopic dermatitis
did not provide strong support for their use in this disorder (76); however, no
large, randomized, double-blind, placebo-controlled clinical trial was available
for inclusion in the analysis. In the subsequently published 18-month ETAC
study, the young children with the most severe atopic dermatitis (SCORAD index
ⱖ 25 on a scale of 0–50) at enrollment who were treated with cetirizine were
reported to have significantly reduced requirements for application of high-po-
tency (class II, III, and IV) topical glucocorticoids to the skin (77).
G. Other Disorders
H 1-antagonists have been reported to be effective in a variety of other disorders
in children, including itching during varicella (78), mosquito bite reactions (79),
450 Simons
eosinophilic cellulitis (80), and ulcerative colitis (81). They are used as antiemet-
ics and sedatives (82–84) and in the treatment of cluster headache (85). They are
also given as an adjunctive treatment to chloroquine in uncomplicated falciparum
malaria (86).
When an H 1-antagonist is recommended for an off-label (nonapproved)
use, the evidence base for such use should be examined critically, since the rec-
ommendation may not be substantiated in a prospective, randomized, double-
blind, placebo-controlled clinical trial (87).
Figure 6 Fifteen children (8.9 ⫾ SD 1.3 yrs) with allergic rhinitis were tested before
and 2–2.5 hours after administration of diphenhydramine 37.5 mg or hydroxyzine 10 mg,
or placebo, in a randomized, double-blind, single-dose, three-way crossover study. Impair-
ment of cognitive processing was assessed objectively by using the latency of the P300
event-related potential (P300). Somnolence was assessed subjectively using a visual ana-
log scale (shown). Peripheral H 1-blockade was assessed by suppression of the histamine-
induced wheals and flares (not shown). At the central (Cz) and frontal (Fz) electrodes,
diphenhydramine and hydroxyzine increased the P300 latency ( p ⬍ 0.05) compared to
baseline. Both H 1-antihistamines increased subjective somnolence and decreased the
wheals and flares (not shown). (From Ref. 90.)
Figure 7 Seasonal allergic rhinitis adversely affected learning in children age 10–12
years who were given computer-assisted instruction in the form of a didactic simulation.
Factual knowledge, conceptual knowledge, and knowledge application were tested. Aller-
gic children treated with diphenhydramine retained significantly less factual knowledge
than healthy controls did ( p ⫽ 0.012). The adverse effect of the allergic rhinitis on learning
was partially ameliorated by loratadine 10 mg, but exacerbated by diphenhydramine 25
mg. (From Ref. 22.)
of severe toxic reactions and fatalities following overdose of these old medica-
tions in infants and children continue to appear in the medical literature (104–
107). Most overdoses are accidental, but suicide attempts and deliberate poison-
ing of very young children using these agents have also been reported (106). All
old H 1-antagonists, including cyproheptadine, diphenhydramine, dimenhydrinate,
doxylamine, hydroxyzine, pheniramines, promethazine, and tripelennamine, are
potentially lethal after overdose. Infants and young children do not necessarily
manifest lethargy, drowsiness, or coma, but may develop excitation, irritability,
hyperactivity, visual hallucinations, and seizures, as well as anticholinergic ef-
fects such as dryness of the mucous membranes, fever, flushed facies, pupillary
dilation, urinary retention, and decreased gastrointestinal motility. Hypotension
secondary to α-adrenergic blockade and sinus tachycardia secondary to the anti-
cholinergic effects of the first-generation medications have been reported.
Treatment of infants and children who have had an overdose of a first-
generation H 1-antagonist should include supportive measures such as use of anti-
convulsants or hemodialysis, if indicated. Centrally-acting emetics such as ipecac
are no longer recommended in poisonings and, in any case, are likely to be inef-
Use in Children 453
antagonist Dose (mg) days treated children (yr) Comparator(s) Results Reference
P, placebo; CH, chlorpheniramine; od, once daily; bid, twice daily; Rx, treatment; ECG, electrocardiogram.
455
456 Simons
lastine, and tecastemizole also appear to have a negligible potential for cardiac
toxicity. Desloratadine, levocetirizine, mizolastine, and tecastemizole have not
yet been studied optimally in children.
V. SUMMARY
REFERENCES
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drugs. N Engl J Med 1994; 330:1663–1670.
2. Simons FER. H 1-receptor antagonists in children. In: Simons FER, ed. Histamine
and H 1-Receptor Antagonists in Allergic Disease. New York, N.Y.: Marcel Dekker,
Inc., 1996:329–356.
3. Simons FER, Simons KJ. Clinical pharmacology of new histamine H 1-receptor an-
tagonists. Clin Pharmacokinet 1999; 36:329–352.
4. Simons FER, Roberts JR, Gu X, Kapur S, Simons KJ. The clinical pharmacology
of brompheniramine in children. J Allergy Clin Immunol 1999; 103:223–226.
5. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorphe-
niramine in children. J Allergy Clin Immunol 1982; 69:376–381.
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464 Simons
Michael A. Kaliner
Institute for Allergy and Asthma, Wheaton and Chevy Chase, Maryland
I. INTRODUCTION
465
466 Kaliner
diate-phase allergic reactions (3, 4). Histamine can elicit many, if not most, of
the pathological processes involved in allergic rhinitis, conjunctivitis, urticaria,
and anaphylaxis, as well as three of the four cardinal signs of asthma. Acting
through H 1-receptors in peripheral tissues, histamine initiates increased vascular
permeability, pruritus, contraction of smooth muscles of the respiratory and gas-
trointestinal tracts, and mucus secretion, and stimulates the biosynthesis and se-
cretion of additional inflammatory mediators and the recruitment of pro-inflam-
matory cells (2). Through the H 1-receptor, histamine acts as a neurotransmitter
in the central nervous system (CNS).
B. Histamine Receptors
H 1-receptors have been identified in brain, retina, adrenal medulla, liver, endothe-
lial cells, cerebral microvasculature, lymphocytes, and smooth muscle in the air-
way, intestinal, genitourinary, and vascular tissue (2, 7). H 2-receptors are found
in the gastrointestinal tract and within the heart (8), but identifying them in pe-
ripheral tissues has been difficult since no H 2-radioligand of sufficient specificity
that exclusively differentiates the presence of H 2-receptors in those tissues has
as yet been developed. H 3-receptors are found in brain (cortical) tissue and in
some peripheral tissues, including human bronchial smooth muscles, where the
receptors mediate inhibition of cholinergic transmission.
The H 1-receptor is a G-protein-coupled receptor and as such induces inter-
nal mobilization of Ca 2⫹ and mobilization of Ca 2⫹ associated with hydrolysis of
membrane inositide phospholipids by phospholipase C (8, 9). Histamine acting
through H 1-receptors and inositol phospholipid hydrolysis causes smooth muscle
contraction in the respiratory and gastrointestinal tracts and, through sensory-
nerve stimulation, can cause pruritus. Histamine H 1-receptors acting alone at or
in combination with H 2-receptors induce the following reactions (2):
III. H 1-ANTIHISTAMINES
Antihistamines are among the top four categories of pharmaceutical products sold
(combining sales of both prescription and over-the-counter brands). Billions of
dollars are spent annually on these medications (11).
A. First-Generation H 1-Antihistamines
First-generation H 1-receptor antagonists contain aromatic rings and alkyl substi-
tutions that create lipophilic characteristics, explaining their ability to cross the
blood–brain barrier readily (2, 8, 12). These products bind to the H 1-receptor
and prevent histamine interactions with the receptor, thereby reducing histamine-
mediated allergic symptoms; however, the ability to cross the blood–brain barrier
gives rise to myriad CNS side effects (12–14) (Table 2). Of concern in providing
antihistamine therapy for the elderly are the classic antihistamine CNS side ef-
fects of dyskinesia, activation of epileptogenic foci, tachycardia, anxiety, confu-
sion, sedation, dilation of the pupils, blurred or diplopic vision, dizziness, sleepi-
ness, and reduced mental alertness. Moreover, first-generation H 1-receptor
antagonists lack specificity for H 1-receptors and, as a result, interact with a variety
of dopaminergic, serotoninergic, muscarinic, and cholinergic receptors, produc-
ing additional side effects (Table 2). Of concern, also, with the use of first-genera-
tion agents for the elderly are the muscarinic/cholinergic side effects of urinary
hesitancy, urinary retention, constipation, sedation, impaired coordination, and
memory dysfunction. Additionally, the α-adrenergic blockade side effects of su-
praventricular arrhythmias, peripheral vasodilation, postural hypotension, reflex
tachycardia, and dizziness are important since cardiac/cardiovascular disease is
common in the elderly, and prevention of falls is of paramount importance. In
addition to the direct and indirect cardiac effects, postural hypotension, dizziness,
and sedation can contribute to falls and put the elderly patient’s safety in jeopardy.
Concomitant diseases may be aggravated or enhanced by the lack of receptor
specificity of first-generation antihistamines, which, for example, can cause my-
driasis and worsen glaucoma.
Elderly persons medicated with first-generation H 1-antagonists may have
a heightened risk of the side effects mentioned above and in Table 2, especially
if they are taking MAO inhibitors, antidepressants, or other psychotropic medica-
tions concomitantly. All first-generation H 1-antagonists have a warning on the
470 Kaliner
B. Second-Generation H 1-Antihistamines
The principal characteristics that differentiate second-generation H 1-antagonists
from their first-generation counterparts are their decreased ability to cross the
blood–brain barrier and their increased selectivity/specificity for the H 1-receptor.
Use in the Elderly 471
First-Generation
Chlorpheniramine Not listed Not listed 27.9 ⫾ 8.7 h Many carry warnings against use in patients with uri-
Hydroxyzine 15–30 min Not listed 29 h (⬍65 yr) nary retention, renal obstruction, narrow angle glau-
Triprolidine Not listed 1.8 ⫾ 0.7 h 4 ⫾ 2.2 h coma, and in conjunction with MAO inhibitor ther-
Diphenhydramine Not listed 1 h* 14 h (⬎65 yr) apy. Caution is urged in patients with severe
Brompheniramine Not listed 5 h* hypertension and/or severe coronary artery disease.
Clemastine Not listed 5–7 h 12 ⫹ h
Azatadine Not listed Not listed 12 h
Second-Generation
Loratadine 60–180 min 1–1.5 h 18.2 h (⬎65 yr) 10 mg/d; renal or liver failure: 10 mg every other day
Cetirizine 30–90 min 30–90 min 8.3 ⫾ 1.8 h Usual dose 10 mg/day; decrease by 50% in renal and
(⫹50% ⬎65 yr) hepatic failure
Fexofenadine 60 min 120–180 min 14.4 h Dose is 60 mg bid or 180 mg qd. 60 mg/day in renal
failure
Topical Spray
Azelastine 60–180 min 5.3 h ⫾ 1.6 h 22 ⫾ 2 h
C. Pruritus
Pruritus has many different triggers but results primarily from stimulation of
H 1-receptors in the skin, although prostaglandins may also contribute. Current
opinion is that there are only a few types of pruritus: itching provoked by immu-
nological or nonimmunological stimuli, with subsequent release of inflammatory
mediators (primarily histamine); intrinsically itchy skin, often a result of dry skin
associated with the aging process; and itching secondary to deposition of salts
in the skin, such as occurs in obstructive jaundice and renal failure. Occasionally,
patients with Hodgkin’s disease or other lymphomas may present with pruritus
unaccompanied by a rash.
Topically applied local anesthetics or antihistamines are moderately effec-
tive in relieving localized pruritus, and are useful for short-term treatment. Topi-
cal doxepin (Zonolon cream), a first-generation antihistamine, may be useful,
although systemic absorption and sedation do occur and skin sensitization has
been reported. Systemic antihistamine therapy is helpful for some patients with
pruritus. Cetirizine is often the agent of choice (15, 21, 27, 28), although both
loratadine and fexofenadine are effective alternatives. Emollients and other non-
pharmacological measures should be used to improve skin hydration in patients
with skin dryness and itchiness.
V. DRUG–DRUG INTERACTIONS
VI. SUMMARY
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Index
483
484 Index
[Diphenhydramine] [Ebastine]
pharmacokinetic/pharmacodynamic assay for, 146
map, 143 CNS effects, lack of, 363, 373
pharmacokinetics and pharmacody- chemical structure, 142
namics in children, 439 pediatric dose, 442
pregnancy and, 427, 428 pharmacodynamics, 152, 155, 163
Doxepin pharmacokinetic/pharmacodynamic
CNS adverse effects of, 261 map, 143, 144
in chronic urticaria, 260, 261, 275 pharmacokinetics, 148, 162, 163
Drowsiness tests (assessment of H1- pharmacokinetics in special popula-
antihistamine effects on CNS), tions, 150, 439
342–347 QT interval, 403, 404
CNS arousal, 342, 343 specific properties of, 78
digit-symbol substitution, 343–344 Economic evaluations in health care,
electroencephalogram (EEG), 342– 319–322
343, 345 Elderly
Leed’s Sleep Evaluation Score, 342, 343 adverse effects of first-generation H1-
memory, 342, 343 antihistamines in, 469, 470, 472
performance tests, 342, 343 allergic rhinitis and allergic rhinocon-
reaction time, 342, 343 junctivitis in, 473, 476
sensory, 343 anaphylactoid reactions in, 478
sleep latency, 342, 343, 345, 349 atopic dermatitis in, 477, 478
Stanford Sleepiness Scale, 342, 343 drug-drug interactions in, 150, 474,
subjective tests/self-rating, 342, 343 475, 478, 479
Drug-drug interactions, 150, 474–475, pharmacokinetic profiles of H1-antihis-
478, 479 tamines in, 150, 472
Drugs polypharmacy in, 465
anaphylaxis and, 288, 290, 291, 305– prophylaxis of anaphylactoid reac-
307 tions in, 478
associated with torsade de pointes, pruritus in, 477
409, 410 safety of second-generation H1-antihis-
Duration of action of H1-antihistamines, tamines in, 470–473
155 urticaria in, 476–477
Dyskinesias, from first-generation H1- Emedastine, 77, 196
antihistamines, 470 Emesis, first-generation H1-antihista-
mines in treatment of, 72
Endothelial cells, histamine effect on,
Early allergic response to allergen, 102, 10
111–113, 117–119, 121 Eosinophilic chemotactic protein (ECP),
Early Treatment of the Atopic Child 104, 114, 115, 117, 118, 121, 123,
(ETAC) Study, 447–449, 453 126–128
Ebastine, 78 Epinastine, 77, 152, 196
adult dose, 156 Erythromycin, interactions of H1-antihis-
allergic rhinoconjunctivitis, 195, 196, tamines and, 149, 401, 402
199 Ethanolamine H1-antihistamines, 74, 75,
antiallergic effects, 116, 117 338
490 Index
[H1-antihistamines] [H2-receptor]
gastrointestinal disturbances, 74 mRNA in nasal mucosa, 7
mechanism of action, 228, 229 selective ligands for, 29, 30
onset of action in allergic rhinocon- signal transduction of, 45–47
junctivitis, 185, 186 H3-receptor
tumor-promoting effects, 74 biochemistry, 36, 37
H1-receptor chemical structure of agonists and an-
biochemistry, 32, 33 tagonists, 31
calcium signaling and, 40, 41 cloning of gene for, 37
chemical structure of agonist and an- heterologous expression of, 36, 37
tagonists, 29 molecular biology, 37
chromosomal localization of gene for, selective ligands for, 30–32
33 signal transduction of, 47
cloning of gene for, 33, 34 H4-receptor
constitutive signaling of, 43–44 cloning of gene for, 37, 38
cyclic AMP and, 43 protein, 37, 38
knockout mice, 35 selective ligands for, 32
molecular biology, 33–35 signal transduction of, 48
molecular model, 34 Half-life of H1-antihistamines (see Phar-
mRNA in nasal mucosa, 7 macokinetics)
nitric oxide synthase, 41, 42 Hay fever (see Allergic rhinoconjunctiv-
phospholipase A2 activation and, itis)
42 Heart
phospholipase C signaling, 38, 39 anaphylaxis-related action of hista-
phospholipase D stimulation and, mine on, 297, 298
42, 43 Heparin, as a mediator of anaphylaxis,
selective ligands for, 28, 29 292
signal transduction of, 38–45 Hepatic dysfunction, H1-elimination,
H2-antihistamines 149–151
allergic rhinitis and, 184, 185 Hepatic metabolism of drugs, 401–403
anaphylaxis and, 307, 308 HERG K⫹ channel, 454
chronic urticaria and, 266–271 Histamine
effect on elimination of H1-antihista- allergic rhinoconjunctivitis and, 13–
mines and, 270 15, 181–185
prevention of anaphylactic and ana- anaphylaxis and anaphylactoid
phylactoid reactions, 301–307 reactions, 16, 19, 292, 294–
H2-receptor 299
adenylcyclase stimulation, 45 asthma and, 12, 13, 224–228
biochemistry, 35, 36 atrioventricular node conduction
chemical structure of agonists and an- and, 7
tagonists, 30 bacteria and, 8, 9
chromosomal localization of gene for, bronchial smooth muscle and, 7
35, 36 cell recruitment and, 10, 11
cloning of gene for, 36 cellular localization of, 1, 2, 9
constitutive signaling, 47 chemical structure of, 67
molecular biology, 36 common cold and, 17, 18
492 Index
Trimeprazine [Urticaria]
urticaria, 273 guidelines for use of H1-antihista-
Tripelennamine mines in treatment of, 258–280
pregnancy and, 427, 428, 429 H1-antihistamines in children with,
Triprolidine 447–449
CNS adverse effects of, 347, 348, H2-antihistamines in, 266–271
354, 355, 358, 360, 362, 363, 364, histamine and urticaria, 251, 252
366, 367 hydroxyzine in, 260, 264, 265, 268,
elimination half-life in adults, 141 273, 274
pregnancy and, 429 in the elderly, 476–477
Tryptase in allergic response, 112, 119, ketotifen in, 261
121, 127, 128, 185 loratadine in, 255, 262–265
Tumor-promoting effects of H1-antihista- mizolastine in, 263, 265
mines, lack of, 74 pathophysiology of, 251, 252, 256,
257
Uncontrolled allergic disease during physical urticarias, 272–279
pregnancy, risks of, 424 prognosis, 252
Upper airway, links with lower airway, second-generation H1-antihistamines
237–240 in, 261–266
Upper respiratory tract infection (see solar, 275, 278
Common cold), treatment of chronic idiopathic, 258–
H1-antihistamines in, 205 271
in children with, 445, 446 urticarial vasculitis, 252, 279
Urine, histamine in, 2 Urticaria and angioedema (see Urticaria)
Urticaria Urticarial vasculitis, 252, 279 (see also
acute, 255, 447, 448, 449 Urticaria)
cetirizine in, 262, 264, 274, 275
chlorpheniramine in, 260, 268, 269, Vancomycin, anaphylactoid reactions to,
273 306
cholinergic, 276, 277 Vasculature
chronic idiopathic, 255–257 anaphylaxis-related actions of hista-
cinnarizine, 275 mine on, 296, 297
classification of, 250 histamine effect on permeability of,
cold, 275, 277, 278 6, 7, 10, 14, 17, 251, 294, 296,
cost-effectiveness of H1-antihista- 297, 467, 468
mines in, 331–332 Vasodilation, histamine effect on, 7, 13,
cyproheptadine in, 268, 273, 275 14, 17, 251, 294, 296, 297, 467,
delayed pressure, 252, 278, 279 468
dermographism, 272–274, 276, 278, Vasomotor rhinitis, 473
279 Volume expanders
diagnosis of, 257 anaphylaxis from, 304
doxepin in, 260, 261, 275 Volume of distribution of H1-antihista-
fexofenadine in, 264–267 mines (see Pharmacokinetics)
first-generation H1-antihistamines in,
259–261 Wheal and flare, 151–155, 157–158,
general management of, 252–254 160–161, 163, 164, 166–168
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