Mehu525 U4 T3 INTOXICACIONES2-4

92
Histamine and Antihistamines

Thomas Eiwegger, F. Estelle R. Simons, Cezmi A. Akdis
CONTENTS
Introduction, 1487 Allergic Conjunctivitis, 1502
Molecular Basis of Histamine Action, 1487 Urticaria, 1502
Histamine Receptors, 1489 Other Diseases and Uses, 1503
Histamine in Immune Response Regulation, 1491 Adverse Effects, 1506
Clinical Pharmacology of H1 Antihistamines, 1495 Summary and Future Directions, 1511
Allergic Rhinitis, 1499
SUMMARY OF IMPORTANT CONCEPTS INTRODUCTION

• Histamine plays an important role in immune modulation and allergic inflam- Histamine was isolated and characterized more than 100 years ago, and
mation through at least four histamine receptors (HRs), with HR1 and HR3 medications targeting its receptors have been in clinical use for 70
playing a pivotal role in neurotransmission. years1–5 (Fig. 92.1). Histamine plays a major role in human health and
• All four known HRs exist in active and inactive forms and have constitutive disease, exerting diverse biologic effects through four types of receptors.
activity in the absence of histamine, the agonist. Knowledge about histamine metabolism, receptors, signal transduction,
• Through HR1, histamine increases antigen-presenting capacity and Th1 physiologic and pathologic effects, and complex interrelationships and
priming, enhances Th1 cell proliferation and interferon-γ production, and crosstalk continues to increase. Histamine can influence many functions
blocks humoral immunity. of the cells in relationship with regulation of immune response and
• HR2 is expressed on the same cells as HR1 and plays a suppressor role in hematopoiesis, including macrophages, dendritic cells, T lymphocytes,
excess doses of histamine because of approximately 10 times less affinity B lymphocytes, and endothelial cells.1,6–9 These cells express histamine
to histamine. It has important immunoregulatory roles that involve many receptors (HRs), and some also secrete histamine, which can induce
immune system cells. chemotaxis of mast cells and eosinophils into tissue sites and affect
• The old concept of mast cells and basophils being the sole major source their maturation, activation, polarization, and effector functions, leading
of histamine has been expanded in the recent years. In addition to these to chronic inflammation.10 Importantly, mast cells and basophils are
two major sources of histamine, many immune cells can make histamine, not the only cellular sources of histamine. In addition to gastric
but more importantly commensal and pathogenic microbes in the body enterochromaffin-like cells, platelets, and histaminergic neurons, some
express histidine decarboxylase and can produce high amounts of cells in the immune system that do not store histamine have high his-
histamine. tamine decarboxylase activity and are capable of producing large amounts
• H1 antihistamines are functionally classified as first (old) generation and of histamine, which is secreted immediately after synthesis. These cells
second (new) generation. PET documentation of H1 antihistamine penetration include platelets, monocytes/macrophages, dendritic cells, neutrophils,
into the human brain provides a new standard by which central nervous and T and B cells. In addition, it was recently shown that commensal
system H1-receptor occupancy can be related directly to effects on central and pathogenic bacteria express histamine decarboxylase enzyme and
nervous system (CNS) function. can actively produce histamine.11–13
• First (old)-generation H1 antihistamines in standard doses may cross the In conclusion the major sources of histamine are basophils and
blood-brain barrier; interfere with neurotransmission in the CNS; and impair mast cells, but a number of other cell types and bacteria are capable
alertness, learning, memory, and multitasking, with or without sedation or of producing histamine.
other adverse effects. Overdose can cause toxicity and death, and these
are no longer medications of choice for allergic diseases in community MOLECULAR BASIS OF HISTAMINE ACTION
settings.
• Second (new)-generation H1 antihistamines are used in allergic rhinitis, Histamine (2-[4-imodazole]-ethylamine) was first identified as an auto-
allergic conjunctivitis, and urticaria. In standard doses, these cross the coid having potent vasoactive properties. Its smooth muscle–stimulating
blood-brain barrier minimally; do not impair alertness, learning, memory, and vasodepressor action was demonstrated in the first experiments
or multitasking; and are associated with minimal sedation. Overdose does by Dale and Laidlaw, who also found that the effects of histamine
not cause toxicity or death. mimicked those occurring during anaphylaxis. In 1927, histamine was
isolated from liver and lung tissue, followed by several other tissues,
1487
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1488 SECTION H Therapeutics
1943
Adverse CNS effects of first generation
1910–1911 H1 antihistamines reported
Physiologic and 1986
pathologic effects 1942 Cardiac toxicity of
of histamine H1 antihistamines some H1 antihistamines
described introduced for clinical use reported
1907 1955 1981
Histamine synthesis 1937 Anti-allergic effects of Second generation
by decarboxylation H1 antihistamines H1 antihistamines non-sedating H1 antihistamines
of histidine described synthesized described introduced for clinical use
1900 1950 1990 2000

NH2 H1-RECEPTOR LIGANDS: MILESTONES
HN R1
N OH N X
R2
O
NH2
HN
N HISTAMINE RECEPTORS: MILESTONES
1900 1950 1990 2000
1991 1999
Human H2 receptor Human
cloned H3 receptor
cloned
1993 2000
Human H1 receptor Human
cloned H4 receptor
cloned
Fig. 92.1 Timeline featuring historical highlights related to histamine, histamine receptors, and H1 antihista-
mines. The physiologic and pathologic effects of histamine were described in 1910 to 1911. H1 antihistamines
were introduced for clinical use in the 1940s; for example, antergan (1942), diphenhydramine (1946), and
chlorpheniramine (1949). In the 1980s, relatively nonsedating second (new)-generation H1 antihistamines
were introduced for clinical use, and histamine-containing neurons were identified in the central nervous
system (CNS). Cloning and characterization of human histamine receptors were reported for the H2 receptor
in 1991, H1 receptor in 1993, H3 receptor in 1999, and H4 receptor in 2000. (From Simons FER, Simons KJ.
Histamine and H1-antihistamines: celebrating a century of progress; J Allergy Clin Immunol 2011;128:1139-50.)
demonstrating that it is a natural constituent of the body; thus the 15 in humans, and expression is controlled by lineage-specific transcrip-
name “histamine” was given after the Greek word for tissue, histos. tion factors. These factors interact with a promoter region consisting
Histamine is a low-molecular-weight amine synthesized from l-histidine of a GC box, four GATA consensus sequences, a c-Myb–binding motif,
exclusively by histidine decarboxylase. Histamine is produced by various and four CACC boxes.19 Several studies have shown that the HDC
cells throughout the body, including gastric mucosa parietal cells, mast transcription is regulated by various factors in gastric cancer cells (e.g.,
cells, basophils, lymphocytes, and central nervous system neurons3,5,14–16 gastrin, oxidative stress, PMA) through a RAS-independent, RAF-
(Fig. 92.2). dependent mechanism, mitogen-activated protein kinase (MAPK/ERK)
Histamine is involved in the regulation of many physiologic func- and protein kinase C (PKC) pathways functioning on three overlapping
tions, including cell proliferation and differentiation, hematopoiesis, cisacting gastrin response elements (GASRE 1, 2, and 3). In hemato-
embryonic development, regeneration, and wound healing.14,17,18 Within poietic cells the regulation of the HDC gene is unknown, and nuclear
the central nervous system, histamine affects cognition and memory, factor E2 (NF-E2) appears to be involved indirectly in this mechanism.
regulation of the sleep-wake cycle, energy, and endocrine homeostasis. It is well known that the expression of HDC in basophils and mast cells
In human pathology, histamine triggers acute symptoms because of its results from the state of CpG methylation in the promoter region.20
rapid activity on vascular endothelium and bronchial and smooth muscle Mast cells and basophils are the major source of granule-stored hista-
cells, leading to the development of such symptoms as acute rhinitis, mine, where it is closely associated with the anionic proteoglycans and
bronchospasm, cramping, diarrhea, and cutaneous wheal and flare chondroitin-4-sulfate. Histamine is released when these cells degranulate
responses. In addition to these effects on the immediate-type response, in response to various immunologic and nonimmunologic stimuli. In
histamine also significantly modulates chronic-phase inflammatory addition, several myeloid and lymphoid cell types (e.g., dendritic, T
events.14–16,18 This chapter highlights the findings leading to a change cells) that do not store histamine show high HDC activity and are
of perspective in histamine immunobiology. capable of production of high amounts of histamine. HDC activity is
Histamine is synthesized by decarboxylation of histidine by l-histidine modulated by cytokines, such as interleukin-1 (IL-1), IL-3, IL-12, IL-18,
decarboxylase (HDC), which depends on the cofactor pyridoxal-5′- granulocyte macrophage–colony stimulating factor (GM-CSF, M-CSF,
phosphate. Histamine regulation is dependent on the gene of HDC tumor necrosis factor α [TNF-α]), and calcium ionophore, in vitro.21
enzyme, which is expressed in the cells throughout the body. The loca- HDC activity has been demonstrated in vivo in conditions such as
tion of HDC gene is found on chromosome 2 in mice and chromosome lipopolysaccharide (LPS) stimulation, infection, inflammation, and graft
CHAPTER 92 Histamine and Antihistamines 1489
NH2 O HISTAMINE RECEPTORS

CH2 CH C OH The pleiotropic effects of histamine are triggered by activating one or
several of histamine membrane receptors on different cells. Four sub-
HN N types of HR have been described: HR1, HR2, HR3, and HR4, or H1R
L-histidine to H4R (H1 to H4; Table 92.1).2–4 In 1966, HRs were first differentiated
into HR1 and HR2.25 In 1999 a third HR subtype was cloned and called
L-histidine decarboxylase HR3.26 In 2000 the fourth HR subtype was named HR4.27 All these
receptors belong to the G protein–coupled receptor (GPCR) family.
CH2 CH2 NH2 These heptahelical transmembrane molecules transduce extracellular
signal by using G proteins and intracellular second-messenger systems.27–29
HN N The active and inactive states of HRs exist in equilibrium. However, it
Histamine has been shown in recombinant systems that HRs can trigger down-
stream events in the absence of receptor occupancy by an agonist, which
N-methyltransferase Diamine oxidase accounts for constitutive, spontaneous receptor activity.
HR agonists stimulate the active state in the receptor, and inverse
agonists stimulate the inactive state. An agonist, with a preferential
CH2 CH2 NH2 O affinity for the receptor’s active state, stabilizes the receptor in its active
conformation, leading to continuous activation signal. An inverse agonist,
N N CH2C OH
CH3 N-methyl- with a preferential affinity for the receptor’s inactive state, stabilizes the
histamine HN N Imidazole receptor in this conformation and consequently induces an inactive
Monoamine oxidase acetic acid state, which is characterized by blocked signal transduction via the
HR.25 In reporter gene assays, constitutive HR1-mediated nuclear factor-
O
Conjugated with ribose κB (NF-κB) activation has been shown to be inhibited by many clinically
CH2C OH N-methyl- to form used H1 antihistamines, indicating that these agents are inverse HR1
imidazole
N N imidazole agonists. Constitutive activity has now been shown for all four HRs.25
acetic acid acetic acid
CH3 In addition to four membrane receptors, histamine binds to some intra-
riboside
cellular receptors such as cytochrome P-450 (CYP) and cytochrome c,
Fig. 92.2 Synthesis and catabolism of histamine in humans. Histamine
is a low-molecular-weight amine synthesized from L-histidine exclusively as well as high-affinity lipocalins isolated from saliva of ticks. Specific
by histidine decarboxylase. Based on recovery of histamine and its activation or blockade of HRs showed that they differ in expression,
metabolites in the urine during 12 hours after intradermal tests with 14C signal transduction, or function and improved understanding of the
histamine, 2% to 3% of histamine is excreted unchanged. Through the role of histamine in physiology and disease mechanisms.
N-methyltransferase pathway in the central nervous system, small intes- Histamine-releasing factor (HRF; also known as translationally
tine mucosa, liver, and kidneys, 4% to 8% is eliminated as N-methyl- controlled tumor protein [TCTP] and fortilin) has been implicated in
histamine and 42% to 47% as N-methyl–imidazole acetic acid. Through late-phase allergic reactions (LPRs) and chronic allergic inflammation.30,31
the diamine oxidase (histaminase) pathway in the small intestine mucosa, Its overexpression in an inducible transgenic mouse model with HRF
liver, kidneys, placenta, skin, and such cells as eosinophils and neutro-
targeted to lung epithelial cells, via the Clara cells in antigen-naïve mice,
phils (but not in CNS), 9% to 11% is eliminated as imidazole acetic acid
yielded increases in bronchoalveolar lavage (BAL) macrophages and
and 16% to 23% as imidazole acetic acid riboside.
mRNA levels for MCP-1 in the HRF-transgenic mice compared with
littermate controls. In the ovalbumin (OVA)–challenged model, HRF
exacerbates the allergic, asthmatic response with increases in serum
rejection. The generation of HDC-deficient mice provided histamine- and BAL IgE, IL-4 protein, and eosinophils in transgenic mice compared
free systems to study the role of endogenous histamine in a broad range with controls. Intranasally administered HRF recruits inflammatory
of normal and disease processes. These mice show decreased numbers immune cells to the lung in naïve mice in a mast cell– and Fc receptor–
of mast cells and significantly reduced granule content, which suggests dependent manner.30,31 The HRF dimer activates mast cells in an HRF-
that histamine might affect the synthesis of mast cell granule proteins.22 reactive IgE-dependent manner. Prophylactic and therapeutic
IgE binding to FcεRI on IL-3–dependent mouse bone marrow–derived administration of HRF inhibitors that block HRF-IgE interactions
mast cells induces the expression of HDC through a signaling pathway reduces the incidence of diarrhea and mastocytosis in a murine model
distinct from that during antigen-stimulated FcεRI activation.23 of food allergy. Patients with egg allergy had higher blood levels of
More than 97% of histamine is metabolized in two major pathways HRF-reactive IgE compared with individuals who were not hypersensi-
before excretion. Histamine N-methyltransferase metabolizes most of tive. Successful oral immunotherapy in egg-allergy patients and food-
the histamine to N-methylhistamine, which is further metabolized to allergic mice reduced HRF-reactive IgE levels, thereby suggesting a
the primary urinary metabolite N-methyl-imidazole acetic acid by pathologic role for HRF in food allergy.32 These results indicate that
monoamine oxidase. Diamine oxidase metabolizes 15% to 30% of his- HRF has a proinflammatory role in asthma and skin immediate hyper-
tamine to imidazole acetic acid. HDC is highly expressed in myeloid sensitivity that may be a therapeutic target.30–32
cells, but its function in these cells is poorly understood. Yang and
associates24 recently demonstrated that HDC-knockout mice show a Histamine Receptor 1
high rate of colon and skin carcinogenesis, indicating key roles for HDC The human Gq/11-coupled HR1 is encoded by a single exon gene located
and histamine in myeloid cell differentiation and immature myeloid on the distal short arm of chromosome 3p25b and contains 487 amino
cells in early cancer development. The recent demonstration of histamine acids. The HR1 is expressed in several cells, including airway and vas-
production by intestinal bacteria opens a new window for its patho- cular smooth muscle cells, hepatocytes, chondrocytes, nerve cells, endo-
genesis in many diseases.11,12 thelial cells, dendritic cells, monocytes, neutrophils, T cells, and B cells.33
TABLE 92.1 Histamine Receptor Subtypes

G Protein–Coupled Representative
Subtype Receptor Signalinga Expression Antihistamines Clinical/Potential Usec
H1 (HR1) Gq/G11 family to PLC CNS neurons, smooth muscle cells Diphenhydramine, hydroxyzine, Allergic rhinitis, allergic
stimulation (vascular, respiratory, GI), CVS, cetirizine, desloratadine, conjunctivitis, urticaria, and
neutrophils, eosinophils, monocytes, fexofenadine, levocetirizine, many other allergic and
macrophages, DCs, T and B cells, loratadine, bilastine, rupatadine nonallergic diseases, including
endothelial cells, epithelial cells and 40 others CNS diseases
H2 (HR2) Gs family to adenylate Gastric parietal cells, smooth muscle, Cimetidine, ranitidine, famotidine, Peptic ulcer disease,
cyclase stimulation and CNS, CVS, neutrophils, eosinophils, nizatidine gastroesophageal reflux disease
increase in cAMP monocytes, macrophages, DCs, T and B
cells, endothelial cells, epithelial cells
H3 (HR3) Gi/o family to adenylate CNS and peripheral neurons,b CVS, lungs, No agents approved for use to Potentially useful in allergic
cyclase inhibition and monocytes, eosinophils, endothelial date; those in clinical trials have rhinitis and neurologic disorders,
decrease in cAMP cells included JNJ 39220675 and including Alzheimer disease,
PF-03654746 for allergic rhinitis attention-deficit hyperactivity
disorder, schizophrenia,
epilepsy, narcolepsy, and
neuropathic pain; also in obesity
H4 (HR4) Gi/o family to adenylate Neutrophils, eosinophils, monocytes, No agents approved for use to Potentially useful in allergic
cyclase inhibition and DCs, Langerhans cells, T cells, date; those in clinical trials have rhinitis, atopic dermatitis,
decrease in cAMP basophils, mast cells, fibroblasts, bone included JNJ 39758979, JNJ asthma, and in other chronic
marrow, endocrine cells, CNS 7777120, UR-63325, PF-3893787, inflammatory and autoimmune
and toreforant (JNJ 38518168) disorders.
cAMP, Cyclic adenosine monophosphate; CNS, central nervous system; CREB, cAMP response element–binding; CVS, cardiovascular system;
DAG, 1,2-diacylglycerol; DCs, dendritic cells; EPAC, exchange protein directly activated by cAMP; GI, gastrointestinal; GPCR, G protein–coupled
receptor; IP3, inositol-1,4,5-triphosphate; PIP2, phosphatidylinositol-4,5-biphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC,
phospholipase C.
a
The primary signaling mechanism is shown. Additional intracellular signals at the H1 receptor include PLC, DAG, IP3, PIP2, PKC, and intracellular
calcium. Additional intracellular signals at the H2 receptor include PKA, CREB, and EPAC. At the H3 and H4 receptors, stimulation of calcium
mobilization from intracellular stores constitutes an important signal.
b
The H3 receptor is a presynaptic autoreceptor on histaminergic neurons in the CNS and on non-histamine-containing neurons in the CNS and
peripheral nervous system. H3 regulates levels of a variety of neurotransmitters, including norepinephrine, acetylcholine, serotonin, and
dopamine.
c
Issues in the development of H3 and H4 antihistamines include nondisclosure of ligand structure, instability of some synthesized ligands,
different outcomes in different species, and adverse events in some clinical trials. Nevertheless, H3 and H4 antihistamines should eventually
prove effective and safe in the treatment of allergic disorders, not only in patients with allergic rhinitis, but also in those with atopic dermatitis/
and asthma.
Histamine binds to transmembrane domains 3 and 5. Activation of the vascular permeability in the lung.33 Targeted disruption of the HR1
HR1-coupled Gq/11 stimulates the inositol phospholipid signaling path- gene in mice impairs neurologic functions such as memory, learning,
ways, resulting in formation of inositol-1,4,5-triphosphate (IP3) and locomotion, and nociception and in aggressive behavior. Immunologic
diacylglycerol, and an increase in intracellular calcium,34 which accounts abnormalities have also been described in HR1-deleted mice, with
for nitric oxide (NO) production and liberation of arachidonic acid impairment of both T and B cell responses.7 Potential mechanisms of
from phospholipids. The H1R also activates phospholipase D and phos- HR1 antagonists for a general immune suppressive effect were tested
pholipase A2. HR1 has also been reported to activate the transcription in mice infected with Listeria monocytogenes and in a human trial.37
factor NF-κB35 through Gq/11 and Gβγ on agonist binding. Constitutive Clemastine and desloratadine strongly reduced innate responses to L.
activation of NF-κB occurs only through Gβγ.34 H1-receptor polymor- monocytogenes in mice comparable to dexamethasone. The immune
phisms have been described, although it is not yet clear how they influ- suppression, characterized by inhibition of the MAPK-extracellular
ence the clinical response to H1 antihistamines. Activation of HR1 results signal–regulated signaling pathway, led to an overall impaired innate
in airway and vascular smooth muscle contraction. The contractile immunity with reduced TNF-α and IL-6 production. In addition, one
responses to HR1 stimulation initially involve mobilization of calcium intravenous dose of clemastine reduced the TNF-α secretion poten-
(Ca2+) from intracellular stores such as inositol phospholipids hydrolysis. tial of peripheral blood macrophages and monocytes in a double-
HR1 stimulation causes various cellular responses in vascular endothelial blind placebo-controlled (DBPC) clinical trial.37 This inhibition could
cells, including changes in vascular permeability as a result of cell con- be exploited to find applications in the treatment of inflammatory
traction, synthesis of prostacyclin and platelet-activating factor, release diseases.
of von Willebrand factor, and in NO release.14
Thus HR1 mediates many pathologic processes, including allergic Histamine Receptor 2
rhinitis, atopic dermatitis, conjunctivitis, urticaria, asthma, and anaphy- In humans the intronless gene encoding HR2 is located on chromo-
laxis.2,36 The receptors also mediate bronchoconstriction and enhanced some 5. The human HR2 is a protein of 359 amino acids coupled to
both adenylate cyclase and phosphoinositide second-messenger systems

by separate guanosine triphosphate (GTP)–dependent mechanisms, Histamine Receptor 4
including Gαs. Similar to that demonstrated for HR1, histamine binds Human HR4 is encoded by a gene containing three exons and separated
to transmembrane (TM) domains 3 (aspartate) and TM 5 (threonine by two large introns located in chromosome 18q11.2. HR4 has 37% to
and aspartate). The short third intracellular loop and the long C-terminal 43% homology to HR3 (58% in TM region). HR4 is functionally coupled
tail are features of the HR2 subtype.38 Similar to HR1, HR2 is expressed to Gi/o, which inhibits cAMP formation, as does HR3.29 H4 activation
in various cell types. Studies in different species and several human leads to an inhibition of adenylyl cyclase and downstream of cAMP-
cells demonstrated that inhibition of characteristic features of the responsive elements (CREs) as well as activation of MAPK and phos-
cells by primarily cyclic adenosine monophosphate (cAMP) formation pholipase C with Ca2+ mobilization. HR4 shows high expression in
dominates in HR2-dependent effects of histamine. Receptor binding bone marrow and peripheral blood hematopoietic cells (neutrophils,
stimulates activation of FOS (formerly c-Fos), JUN (c-Jun), protein eosinophils, T cells) and moderate expression in spleen, thymus, lung,
kinase C (PKC), and p70S6 kinase.14,39 These cAMP-independent effects small intestine, colon, and heart.29 Both basophils and mast cells express
might depend on the level of receptor expression or subtle differences H4 messenger RNA. Related to high homology between the two recep-
between clonal cell lines. Effects of H2 receptors can inhibit a variety of tors, presently available HR3 agonists and antagonists are also recognized
functions within the immune system. H2 receptors negatively regulate by HR4. However, clobenpropit, an H3 antagonist, exerts agonistic activity
the release of histamine on basophils and mast cells. The inhibition on H4. Relatively little is known about the biologic function of HR4.
of antibody synthesis, T cell proliferation, cell-mediated cytolysis, and It seems to be involved in immune regulatory functions, including
cytokine production are evidence of H2 receptors on lymphocytes.18 chemotaxis and cytokine secretion. Presumably, HR4 plays an important
Rapid upregulation of HR2 has been reported within the first 6 hours role in autoimmune disorders, allergic conditions, and nociceptive
of the buildup phase of venom immunotherapy (VIT).40 HR2 strongly responses. Early results in animal models suggest that H4 antagonists
suppressed FcεRI-induced activation and mediator release of baso- may be helpful in treating conditions in which H1 antagonists are not
phils, including histamine and sulfidoleukotrienes, as well as cytokine clinically effective.45 Selective H4 antagonists (e.g., JNJ7777120) show
production in vitro. Data suggest that HR2-mediated basophil sup- a potential role in treatment of inflammation in humans.45
pression might contribute to early protective mechanisms during the The H1 antagonists doxepin, cinnarizine, and promethazine are
buildup phase of VIT.40 This receptor also controls excessive dendritic reported to exhibit high affinity binding to the H4 receptor. HRs form
cell responses to microbial ligands.41 Histamine suppresses LPS-induced dimers, and even oligomers, which allow cooperation between HRs
myeloid dendritic cell TNF-α secretion and CpG-induced plasmacy- and other GPCRs. The affinity of histamine binding to different hista-
toid dendritic cell interferon α (IFN-α) gene expression. Lactobacillus mine receptors varies significantly, with Ki values ranging from 5 to
rhamnosus, which secretes histamine, significantly suppressed Peyer’s 10 nM for the H3 and H4 receptors to 2 to 10 µM for the H1 and H2
patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild- receptors. Thus the effects of histamine on receptor stimulation can
type but not H2R-deficient animals. In addition, HR2 modifies invariant be complex.
natural killer T (iNKT) cell activity within the inflamed lung.42 Lipid
antigen (αGalCer) administration to the lung resulted in enhanced Nonconventional Binding Sites of Histamine
mucus secretion, inflammatory cell recruitment, and cytokine produc- Histamine can affect cell function by binding to nonclassic binding
tion in H2R-deficient or famotidine-treated animals, whereas dimaprit sites that include cytochrome P-450 (CYP) and histamine transporters.
dampened the lung iNKT cell response to αGalCer. Removal of iNKT Histamine’s binding to CYP suggested a second messenger role for
cells in H2R-deficient (CD1d-/- H2R-/-) animals normalized the lung intracellular histamine via this binding site. This hypothesis was based
response to house dust mites. These data demonstrate a role for H2R mainly on a finding that N, N diethyl-2-(4-(phenylmethyl) phenoxy-
in diseases in which CD1d-mediated Ag-presentation of lipid antigens ethanamine (DPPE), an arylalkylamine analog of tamoxifen, inhibits
to iNKT cells is contributing to the pathogenesis. binding of histamine to CYP.46 The effect of DPPE on histamine binding
depends on activity of the CYP enzymes; CYP2E1 and CYP3A are
Histamine Receptor 3 upregulated in HDC-deficient mice.47 Vesicular monoamine histamine
Human HR3 is encoded by a gene that consists of four exons on chro- transporter 2 (VMAT2) had been cloned from rat and human brain.
mosome 20 and has been cloned.26 More than one HR3 subtype has The gene expression of VMAT2 can be modulated via cytokines, either
been suggested. HR3 has initially been identified in the central and positively (transforming growth factor β [TGF-β]) or negatively (IL-1
peripheral nervous system as presynaptic receptors controlling the release and TNF-α).48 The bone marrow–derived mast cells from HDC-deleted
of histamine and other neurotransmitters (dopamine, serotonin, nor- mice are completely devoid of endogenous histamine but can take it
adrenaline, gamma-aminobutyric acid [GABA], and acetylcholine). HR3 up from histamine-supplemented medium and store it in their secre-
signal transduction involves Gi/o of G proteins leading to inhibition of tory granules.
cAMP and accumulation of Ca2+ and activation of the MAPK pathway.
R-α-methylhistamine and imetit are agonists, and thioperamide and HISTAMINE IN IMMUNE RESPONSE REGULATION
clobenpropit are HR3 antagonists. HR3 is mainly involved in brain
functions and mast cells, via H3 receptors. HR3 is involved in cognition, Antigen-Presenting Cells
sleep-wake cycle, homeostatic regulation, and inflammation and is The first step in allergen-specific immune response development is
presynaptically located as an autoreceptor controlling the synthesis and sensitization with stimulation and clonal expansion of specific T and
release of histamine.43 H3-autoreceptor activation stimulates a negative B cells by allergens/antigens, autoantigens, superantigens, and infectious
feedback mechanism to reduce central histaminergic activity.44 The agents and production of specific antibodies49,50 (Fig. 92.3).
control of mast cells by histamine acting on HR3 involves neuropeptide- Dendritic cells (DCs) are often located near various histamine sources,
containing nerves that might be related to a local neuron–mast cell such as connective tissue mast cells, and are potent antigen-presenting
feedback loop controlling neurogenic inflammation. Dysregulation of cells (APCs) and cytokine-producing cells. Therefore histamine may
this feedback loop may lead to excessive inflammatory responses, sug- effectively influence the immune response through DCs. These profes-
gesting a novel therapeutic approach by using H3 agonists. sional APCs mature from monocytic and lymphoid precursors and
IgE+ memory B cell

expansion
Allergen
T cell epitopes (linear) IgE
Memory
IgM B cell
B cell epitopes (surface)
Naive Memory
MHC-II B cell IgE class
B cell
Memory T cell switching
DC Naïve
B cell IL-4
Th2 IL-13
TCR
IL-4 Th2 switch IgE

and Th2 Th2
expansion
Allergens
B cell
epitopes
Vasoactive amines
(histamine) Mast IgE
Lipid mediators cell FcεRI
Histamine (PGD2, PAF,
Suppression and HR2 LTC4, LTD4, LTE4)
of Th2 cells and DC Cytokines
(IL-3, IL-4, IL-5, IL-13) Degranulation Basophil
Chemokines
Fig. 92.3 Immunologic events during the sensitization phase against allergens. After antigen presentation
by dendritic cells (DC) in the presence of low-dose innate immune response–stimulating substances, Th2
cells develop from naïve T cells and show clonal expansion (TCR, T cell receptor). Th2 cell interaction with
naïve B cells leads to immunoglobulin class switch to IgE and expansion of allergen-specific memory B cells.
IgE produced by plasma cells sensitizes mast cells and basophils by binding to surface FcεRI. The cross-
linking of mast cell and basophil surface FcεRI-bound IgE by B cell epitopes of allergens leads to the release
of vasoactive amines (e.g., histamine), lipid mediators such as prostaglandin D2 (PGD2), platelet-activating
factor (PAF), and leukotrienes LTC4, LTD4, and LTE4, as well as cytokines and chemokines, and to immediate
symptoms of allergic disease (type 1 hypersensitivity), including pruritus, wheal and flare, nasal conjunctival
discharge, angioedema, systemic anaphylaxis, and bronchoconstriction. (From Jutel M, Watanabe T, Adkis
M, Blaser K, Adkis CA. Immune regulation by histamine. Curr Opin Immunol 2002;14:735-40.)
acquire DC1 and DC2 phenotypes, which in turn facilitate development subtypes. Maturation of DCs results in loss of these responses. In matur-
of helper T type 1 (Th1) and type 2 (Th2) cells, respectively. Endogenous ing DCs, however, histamine, in a dose-dependent fashion, enhances
histamine is actively synthesized during cytokine-induced DC differ- intracellular cAMP levels and stimulates IL-10 secretion while inhibiting
entiation, which acts in autocrine and paracrine fashion and modifies production of IL-12 via HR2.52 Interestingly, although human monocyte-
DC markers. Histamine actively participates in the function and activity derived DCs have both histamine H1 and H2 receptors and can induce
of DC precursors as well as their immature and mature forms (Fig. CD86 expression by histamine, human epidermal Langerhans cells
92.3). Immature and mature DCs express all four HRs; however, their express neither H1 nor H2 receptors.53 Inflammatory DCs express a
levels of expression have not yet been compared. In the differentiation functionally active HR4, which on stimulation leads to downregulation
process of DC1 from monocytes, HR1 and HR3 act as positive stimu- of CCL2 and IL-12. This might have implications for the treatment of
lants to increase antigen presentation capacity and proinflammatory atopic dermatitis.54
cytokine production and Th1 priming activity. In contrast, HR2 acts
as a suppressive molecule for antigen presentation capacity by enhanc- T Cells and Antibody Isotypes
ing IL-10 production and inducing IL-10–producing T cells or Th2 Histamine has been shown to intervene in the Th1, Th2, regulatory T
cells. It also suppresses many proinflammatory factors released by myeloid (Treg) cell balance and consequently antibody formation. Differential
DCs and anti-viral IFN release from plasmacytoid DCs.41 patterns of histamine receptor expression on Th1 and Th2 cells deter-
In monocytes stimulated with Toll-like receptor (TLR)–triggering mine reciprocal T cell responses after histamine stimulation9 (Fig. 92.4).
bacterial products, histamine inhibits the production of proinflamma- Th1 cells show predominant, but not exclusive, expression of HR1,
tory IL-1-like activity, TNF-α, IL-12, and IL-18, but enhances IL-10 whereas Th2 cells show increased expression of HR2. Histamine enhances
secretion through HR2 stimulation.51 Histamine also downregulates Th1-type responses by triggering the HR1, whereas both Th1- and
CD14 expression via H2 receptors on human monocytes. The inhibitory Th2-type responses are negatively regulated by HR2 from activation
effect of histamine via H2 receptor appears through the regulation of of different biochemical intracellular signals.9 In mice, deletion of HR1
intercellular adhesion molecule 1 (ICAM-1) and B7.1 expression, leading results in suppression of IFN-γ and dominant secretion of Th2 cytokines
to the reduction of innate immune response stimulated by LPS.51 (IL-4, IL-13). HR2-deleted mice show upregulation of both Th1 and
Histamine induces intracellular Ca2+ flux, actin polymerization, and Th2 cytokines. Bphs, a non–major histocompatibility complex–linked
chemotaxis in immature DCs because of stimulation of HR1 and HR3 gene involved in the susceptibility to many autoimmune diseases, has
HR1 blocks humoral immunity, induces cellular immunity

HR2 blocks cellular immunity
HR1-deficient mice show increased specific IgE
HR2-deficient mice show suppressed specific IgE
B cells
HR2 suppresses IL-4 and
B cell Th2 IL-13 production and Th2
cell proliferation
Th1 cells
HR1 enhances T cells
IFN-γ production Histamine enhances
and Th1 cell the production of IL-10
Th1 Histamine TReg
proliferation, and the suppressive
HR2 antagonizes effect of TGF-β is
this effect potentiated via HR2
IL-10 IL-10
DC
Dendritic cells
HR1 increases antigen-presenting capacity and Th1 priming.
HR2 induces IL-10 production, suppresses antigen
presentation and aids development of IL-10-secreting Y cells
Fig. 92.4 Regulation of the immune system through histamine receptors (HRs). In lymphatic organs and
subepithelial tissues of allergic inflammation, histamine regulates monocytes, dendritic cells (DCs), T cells,
and B cells. Monocytes and DCs express all known HRs. HR1 and HR3 induce proinflammatory activity and
increased antigen-presenting cell (APC) capacity, whereas HR2 plays a suppressive role on monocytes and
monocyte-derived DCs. Helper T type 1 (Th1) cells show predominant, but not exclusive, expression of HR1,
whereas Th2 cells show upregulation of HR2. Histamine induces increased proliferation and interferon-γ
(IFN-γ) production in Th1 cells. Th2 cells express predominant HR2, which acts as the negative regulator of
proliferation and IL-4 and IL-13 production. Histamine enhances Th1-type responses by triggering the HR1,
whereas both Th1- and Th2-type responses are negatively regulated by HR2, showing an essential role for
immune regulation for this receptor. These distinct effects may suggest roles of HR1 and HR2 on T cells
for autoimmunity and peripheral tolerance, respectively. Histamine also modulates antibody production.
Histamine directly effects B cell antibody production as a costimulatory receptor on B cells. HR1 predomi-
nantly expressed on Th1 cells may block humoral immune responses by enhancing Th1-type cytokine IFN-γ.
In contrast, HR2 enhances humoral immune responses. Allergen-specific IgE production is differentially
regulated in HR1- and HR2-deficient mice. HR1-deleted mice show increased allergen-specific IgE production,
whereas HR2-deleted mice show suppressed IgE production. TGF, Transforming growth factor. (From Jutel
M, Watanabe T, Adkis M, Blaser K, Adkis CA. Immune regulation by histamine. Curr Opin Immunol
2002;14:735-40.)
been identified as HR1 gene in mice. HR1-deleted mice show delayed In contrast, HR2-deleted mice showed decreased serum levels of OVA-
disease onset and decreased disease severity when immunized to develop specific IgE compared with wild-type mice and HR1-deficient mice.
experimental allergic encephalomyelitis. Also, histamine stimulation Although T cells of H2R-deficient mice secreted increased IL-4 and
induces IL-10 secretion through HR2. Increased IL-10 production in IL-13, OVA-specific IgE was suppressed in the presence of highly increased
both DCs and T cells may account for an important regulatory mecha- IFN-γ. Thus HR1 and the related Th1 response may play a dominant
nism in the control of inflammatory functions through histamine. role in the suppression of humoral immune response.
Various cytokines regulate the production of histamine and its receptor Peripheral T cell tolerance characterized by immune deviation to
expression. IL-3 and GM-CSF enhance histamine release from basophils, regulatory/suppressor T cells represents a key event in the control of
whereas stem cell factor (SCF) accomplishes this action for mast cells.14 specific immune responses during allergen-specific immunotherapy
In addition, IL-3 stimulation significantly increases HR1 expression on (Fig. 92.5). Although multiple suppressor factors, including contact-
Th1, but not on Th2 cells.9 dependent or contact-independent mechanisms, might be involved,
In mice, histamine enhances anti-IgM–induced proliferation of B IL-10 and TGF-β predominantly produced by allergen-specific T cells
cells, which is abolished in HR1-deleted mice. In HR1-deleted mice, play an essential role.55 High-dose bee venom exposure in beekeepers
antibody production against a T cell–independent antigen, TNP-Ficoll, by natural bee stings represents a model to understand mechanisms of
is decreased, suggesting an important role of HR1 signaling in responses T cell tolerance to allergens in healthy individuals. Continuous exposure
triggered from B cell receptors. Antibody responses to T cell–dependent of nonallergic beekeepers to high doses of bee venom antigens induces
antigens (e.g., OVA) show a different pattern. HR1-deleted mice pro- diminished T cell–related cutaneous late phase swelling to bee stings
duced high OVA-specific IgG1 and IgE compared with wild-type mice. in parallel with suppressed allergen-specific T cell proliferation and
HN
N NH2 H4R
Chemotactic receptor which also
inhibits IL-12 and CCL2 secretion
HN
HN
N NH2
HN H1R N NH2
NH2
H2R
N
H3R
IL-12 IL-10
H3R neuronal activation alters

neurotransmitter release with TH1 TREG TH2
downstream effects on T cell
chemokine secretion
H1R enhances IFN-γ H1R promotes H2R suppresses

production and TH1 cell IL-10 production IL-4 and IL-13
proliferation, H2R and enhances the secretion and TH2
antagonizes this effect suppressive proliferation
effect of TGF-β
H4R mediates chemotaxis of multiple T cell subsets to histamine
Fig. 92.5 Induction and regulation of immune tolerance to allergens by histamine. Histamine released during
allergen-specific immunotherapy plays a suppressive role on monocytes and monocyte-derived dendritic cells
(DCs) through H2R (HR2). Th2 cells express predominantly HR2, which acts as the negative regulator of
proliferation, and suppression of IL-4 and IL-13 production, suggesting a role for HR2 on T cells for peripheral
tolerance. Histamine also modulates antibody production by directly effecting B cell antibody production as
a costimulatory receptor on B cells and enhances humoral immune responses through HR2. (From O’Mahony
L, Akdis M, Akdis CA. Regulation of the immune response and inflammation by histamine and histamine
receptors. J Allergy Clin Immunol 2011;128:1153-62.)
Th1 and Th2 cytokine secretion.56 After multiple bee stings, venom HR1 antihistamine premedication had a systemic allergic reaction to
antigen-specific Th1 and Th2 cells show a clonal switch toward IL-10– the reexposure by either a field sting or a sting challenge, whereas 6 of
secreting type 1 Treg (Tr1) cells. T cell regulation continues as long 21 given placebo did. This highly significant difference suggests that
as antigen exposure persists and returns to initial levels within 2 to 3 H1 antihistamine premedication during the initial dose-increase phase
months after bee stings stop. HR2, upregulated on specific Th2 cells, may have enhanced the long-term efficacy of immunotherapy. Expres-
displays a dual effect by directly suppressing allergen-stimulated T sion of HR1 on T lymphocytes is strongly reduced during ultrarush
cells and increasing IL-10 production. Thus rapid clonal switch to and immunotherapy, which may lead to a dominant expression and function
expansion of IL-10–producing Tr1 cells and the HR2-related effects of tolerance-inducing HR2. This indicates a positive role of histamine
represent essential mechanisms in immune tolerance to high dose of in immune regulation during SIT.60 In a recent DBPC prospective study,
allergens in nonallergic individuals.56 Apparently, histamine interferes the effect of treatment with l-cetirizine during ultrarush venom immu-
with the peripheral tolerance induced during specific immunotherapy notherapy was investigated. Patients treated with l-cetirizine produced
(SIT) in several pathways. Histamine induces the production of IL-10 significantly more IFN-γ. IL-10 production was induced in both groups
by DCs.52 In addition, histamine induces IL-10 production by Th2 but only significantly in l-cetirizine group. Decreased HR1/HR2 expres-
cells.56,57 Furthermore, histamine enhances the suppressive activity sion ratio, indicating H2 signal dominance after 21 days, was observed
of TGF-β on T cells. All three of these effects are mediated through in the placebo group.61
HR2, which is relatively highly expressed on Th2 cells and suppresses Selective H2 antagonists have attracted interest because of their
IL-4 and IL-13 production and T cell proliferation. Apparently, these potential immune response–modifying activity. Most data suggest that
recent findings suggest that HR2 may represent an essential recep- cimetidine has a stimulatory effect on the immune system, possibly by
tor that participates in peripheral tolerance or active suppression of blocking the receptors on subsets of T lymphocytes and inhibiting
inflammatory/immune responses. In the murine model, HR4 stimula- HR2-induced immune suppression. Cimetidine has also been used suc-
tion enriches for a Foxp3+ Treg cell with potent suppressive activity for cessfully to restore immune functions in patients with malignant dis-
proliferation.58 orders, hypogammaglobulinemia, and AIDS-related complexes. On the
A DBPC trial analyzed the long-term protection from honeybee other hand, H2 agonists such as dimaprit significantly reduce disease
stings by terfenadine premedication during rush immunotherapy with severity in mice with experimental allergic encephalomyelitis. HR2 with
honeybee venom.59 After an average 3 years of treatment, 41 patients dimaprit suppresses many inflammatory cell responses in different
were stung by a honeybee. Surprisingly, none of the 20 patients given models including DC, basophils, T cells, and natural killer T cells.
Immune Regulation by Histamine-Secreting Bacteria. In addition Inactive

Extracellular
Active
to mammalian cells, bacteria can also secrete histamine, and the influ- H1-receptor H1-receptor
space
ence of microbiota-derived histamine on host immunologic processes conformation conformation
has been described. Histamine-secreting microbes are present within
the human gut microbiota, and their levels are increased in asthma
patients. The isolation from asthma patients and characterization of Cytoplasm
bacterial strains with the ability to secrete high amounts of histamine Gγβ Gγβ
in vitro opened a new window in the pathogenesis of the disease. The Gα GTP Gαq GTP
strains were classified as Escherichia coli (E. coli), Morganella morganii, GDP GDP
or Lactobacillus vaginalis. The functionality of histamine secreted from A Inactive state Active state
bacteria was investigated by using CHO cells with an H1R chemilumi-
nescent reporter. Histamine in the bacterial culture supernatants activated Agonist
the HR1 on these cells, and activity was blocked using the HR1 antago- (histamine)
nist, diphenhydramine.11,12 These findings seem to have strong in vivo
relevance. Patients with inflammatory bowel disease display dysregulated
expression of histamine receptors, with diminished antiinflammatory
effects associated with H2R signaling. Triggering of H2R signaling sup-
presses excessive TLR responses to bacteria within the gut, and famotidine Gγβ Gγβ
usage or HR2-deficient mice show extreme tissue injury in a colitis Gα GTP Gαq GTP
model.62,63 GDP GDP
B Inactive state Active state
CLINICAL PHARMACOLOGY OF
H1 ANTIHISTAMINES Inverse agonist
(antihistamine)
More than 45 H1 antihistamines are available worldwide, representing
the largest class of medications used in the treatment of allergic diseases.
Most recent additions of H1 antihistamines include bilastine and rupa-
tadine for oral administration64–67 and bepotastine, alcaftadine, and
olopatadine for ophthalmic application.68–70
Gγβ Gγβ
Histamine receptors are heptahelical transmembrane molecules that Gα GTP Gαq GTP
transduce extracellular signals by way of G proteins to intracellular GDP GDP
second-messenger systems. These receptors have constitutive activity, C Inactive state Active state
defined as the ability to trigger downstream events, even in the absence
of ligand binding. Their active and inactive states exist in equilibrium. Fig. 92.6 Molecular basis of action of histamine and antihistamines.
(A) The inactive state of histamine H1 receptor is in equilibrium with
At rest, the inactive state isomerizes with the active state, and vice
the active state (B) The agonist, histamine, has preferential affinity
versa3,4,10,71 (Fig. 92.6).
for the active state, stabilizes the receptor in this conformation, and
The low H1-receptor selectivity of first (old)-generation H1 antihis- shifts the equilibrium toward the active state. (C) An H1 antihistamine
tamines has been attributed to direct interaction with tryptophan 428,6,72 (inverse agonist) has preferential affinity for the inactive state, stabilizes
a highly conserved key residue in GPCR activation. In contrast, second the receptor in this conformation, and shifts the equilibrium toward the
(new)-generation H1 antihistamines interact with lysine 1911,30 and/or inactive state. GDP, Guanosine diphosphate; GTP, guanosine triphosphate.
lysine 179,ECL2 a residue in GPCR activation that confers high selectiv- (From Simons FER, Simons KJ. Histamine and H1 antihistamines: celebrat-
ity.8 H1-deleted mice have neurologic abnormalities, including aggressive ing a century of progress; J Allergy Clin Immunol 2011;128:1139-50.)
behavior and impaired vigilance, learning, memory, and locomotion,
in addition to immunologic and metabolic abnormalities.
receptors, and 5-hydroxytryptamine (5-HT, serotonin) receptors. In
Structure and Classification high concentrations, diphenhydramine and dimethindene also have
The chemical structures of representative H1 antihistamines are shown local anesthetic activity. In contrast, second (new)-generation H1 anti-
in Fig. 92.7. The presence of multiple aromatic or heterocyclic rings histamines are highly specific for the H1 receptor and have little or no
and alkyl substituents in first (old)-generation H1 antihistamines results affinity for muscarinic cholinergic, α-adrenergic, or serotonin receptors.3–5
in lipophilicity. Along with other properties, such as relatively low
molecular weight, positive electrostatic charge, and for many of these Pharmacokinetics: Concentration Versus Time
H1 antihistamines, lack of recognition by the P-glycoprotein efflux trans- Using gas-liquid chromatography (GLC), high-performance liquid
porter enhances brain penetration.5,73–75 chromatography (HPLC), and HPLC with tandem mass spectrometry
Historically, H1 antihistamines have been categorized into six groups: (MS/MS) assays and immunoassays, after usual doses, H1 antihistamine
ethanolamines, ethylene diamines, alkylamines, piperazines, piperidines, concentrations can be detected in picogram to nanogram amounts in
and phenothiazines (Table 92.2).2,4,5 This traditional classification system plasma, urine, and tissue, facilitating pharmacokinetic studies. After
now has limited clinical relevance, because H1 antihistamines within overdose, H1 antihistamine concentrations can be detected in milligram
each group (e.g., the large piperazine group) differ considerably in H1 amounts, facilitating forensic studies.5,76–83
activity and adverse effects.5
First (old)-generation H1 antihistamines have poor specificity for Pharmacokinetic Studies. Pharmacokinetic studies provide clini-
the H1 receptor, as noted previously. To varying degrees, they inhibit cally relevant information on bioavailability (rate and extent of H1
transmission at muscarinic cholinergic receptors, α-adrenergic antihistamine absorption), volume of distribution, protein binding,
Histamine
CH2 CH2 NH2
HN N
First-generation H1 antihistamines
N
CH3 CH3
CH CH2 CH2 N CH O CH2 CH2 N CH N N CH2 CH2 O CH2 CH2 OH
CH3 CH3
Chlorpheniramine Diphenhydramine Hydroxyzine
Cl Cl
Second-generation H1 antihistamines
O O
CH N N CH2 CH2 O CH2 C OH H C N N CH2 CH2 O CH2 C OH
Cetirizine Levocetirizine
Cl
Cl
Cl Cl
N C O CH2 CH3 N H
N N
Loratadine Desloratadine
OH OH CH3 O
C N CH2 CH2 CH2 CH C C OH
CH3
Fexofenadine
Fig. 92.7 Chemical structures of representative H1 antihistamines: first (old)-generation and second (new)-
generation. Many H1 antihistamines are structurally similar to each other; for example, cetirizine is a metabolite
of hydroxyzine; levocetirizine is an enantiomer of cetirizine; desloratadine is a metabolite of loratadine; and
fexofenadine is a metabolite of terfenadine (not shown; no longer approved for use or used in the United
States and most other countries). Also, the availability of different H1 antihistamines and different formula-
tions of the same H1 antihistamine varies from country to country; for example, azelastine, ketotifen, and
olopatadine, available in topical, intranasal, and ophthalmic formulations in the United States, are also available
in oral formulations in some countries.
elimination half-life, clearance, and interactions with other drugs, foods, protein (OATP) and P-glycoprotein expression on the luminal surfaces
or herbal products. The pharmacokinetics of the first (old)-generation of intestinal endothelial cells. It is also impacted by the type of meals.
H1 antihistamines have not been optimally investigated in healthy adults Loratadine (area under the curve [AUC] increased by more than 50%84).
or in vulnerable patients, such as children, elderly persons, patients with Rupatidine (AUC increased by 26%85) and bilastine (30% AUC reduc-
hepatic or renal dysfunction, or in drug interaction studies (Table 92.3).4,5 tion86) resorption is impacted by co-administration with food (reviewed
In contrast, the pharmacokinetics of all the second (new)-generation by reference 87). Fexofenadine is a well-studied example of an H1 anti-
H1 antihistamines have been studied in healthy young adults, with most histamine that is dependent on transport proteins for absorption and
also studied in children, elderly persons, patients with hepatic or renal elimination. P-glycoprotein inducers such as grapefruit juice, rifampin,
impairment, and those concomitantly ingesting drugs, foods, or herbal and St. John’s wort have the potential to decrease fexofenadine absorp-
products that potentially interfere with H1 antihistamine elimination.5,76–83 tion. To a lesser extent this is also the case for bilastine (33% reduction
After oral administration, H1 antihistamines are typically well Cmax and 24% lower AUC values87). P-glycoprotein inhibitors such as
absorbed. Peak plasma concentrations are reached within 0.7 to 2.6 erythromycin and ketoconazole have the potential to increase fexofena-
hours after administration to fasting individuals (Table 92.3). Bioavail- dine absorption.76,82 However, fexofenadine and bilastine are a substrate
ability is influenced by several types of drug transporters, including of the P-glycoprotein efflux transporter in the blood-brain barrier (BBB),
ATP-binding cassette (ABC transporters) such as organic anion transport which prevents its penetration into the central nervous system and
TABLE 92.2 H1 Antihistamines: Chemical and Functional Classification

Functional Class
Chemical Class First (Old) Generation Second (New) Generation
Alkylamines Brompheniramine, chlorpheniramine, dexchlorpheniramine, Acrivastineb
dimethindene,a pheniramine, triprolidineb
Piperazines Buclizine, cyclizine, hydroxyzine,b meclizine, oxatomidea Cetirizine,b levocetirizineb
Piperidines Azatadine, cyproheptadine, diphenylpyraline, ketotifen Astemizole,a bepotastine, bilastine, desloratadine,b ebastine,a
fexofenadine,b levocabastine, loratadine,b mizolastine,a rupatadine,b
terfenadine,a,b alcaftadine
Ethanolamines Carbinoxamine, clemastine, dimenhydrinate, —–
diphenhydramine, doxylamine, phenyltoloxaminea
Ethylenediamines Antazoline, pyrilamine, tripelennamine —–
Phenothiazines Methdilazine, promethazine —–
c
Other Doxepin Azelastine, emedastine, epinastine, olopatadine
a
In the United States, these H1 antihistamines either are not yet approved or have never been approved. Regulatory approval was withdrawn for
astemizole and terfenadine in the 1990s.
b
Some of the H1 antihistamines listed are related to each other; for example, acrivastine is a derivative of triprolidine; cetirizine is a metabolite of
hydroxyzine; levocetirizine is an enantiomer of cetirizine; and desloratadine is a metabolite both of loratadine and rupatadine. Of the H1
antihistamines currently approved for use in the United States, cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine are the most
thoroughly investigated in randomized controlled trials and other prospective studies.
c
Doxepin is classified as both an H1 antihistamine and a tricyclic antidepressant. It has potent H1- and H2-antihistaminic properties and inhibits
reuptake of serotonin and norepinephrine.
contributes to its favorable therapeutic index. Fexofenadine is also an increases in serum concentrations and potential toxicity. In vitro screening
organic acid that binds to aluminum- and magnesium-containing ant- systems are now used to predict in vivo metabolic drug–drug interac-
acids; therefore administration within 15 minutes of ingestion of these tions, and to prescreen H1 antihistamine candidate drugs for future
agents should be avoided to prevent a clinically relevant decrease in development.82,83
absorption.76–80,82,83
Pharmacokinetic values for H1 antihistamine volume of distribution Population Pharmacokinetics. Population pharmacokinetic data
are proportionality factors between plasma concentrations and the dose can be obtained during Phase-2 and Phase-3 clinical trials of H1 anti-
administered, rather than actual volumes. These values vary from 0.33 L/ histamines involving large numbers of patients with allergic rhinitis or
kg for levocetirizine and 0.5 L/kg for cetirizine to more than 100 L/kg urticaria. In such studies, plasma antihistamine concentrations are
for loratadine. H1 antihistamine plasma protein binding also varies con- measured in the intermittent blood samples taken for hematology and
siderably, from 60% for fexofenadine to more than 95% for cetirizine, chemistry tests,79 and the intervals between H1 antihistamine dosing
levocetirizine, and desloratadine. Elimination half-life values range from and blood samples are precisely documented. In these studies the influ-
2 hours for acrivastine to 27 hours for desloratadine76–80,82,83 (Table 92.3). ence on H1 antihistamine pharmacokinetics from clinical and biologic
Some second (new)-generation H1 antihistamines are excreted largely covariates such as H1 antihistamine dosage form, allergic disease, age,
unchanged in the urine and feces. For example, more than 50% of a gender, ethnicity, and body mass can be examined. Theoretically, the
cetirizine dose is eliminated unchanged in the urine, more than 85% influence of hepatic and renal function on pharmacokinetics and assess-
of a levocetirizine dose is eliminated unchanged in the urine, and more ment of drug–drug interactions can also be investigated. However,
than 80% of a fexofenadine dose is eliminated unchanged in the feces patients with impaired hepatic or renal function and those taking other
after biliary excretion76–80,82,83 (Table 92.3). systemic medications with the potential for drug–drug interactions are
Phenotypic polymorphism has been observed in the metabolism of typically excluded from Phase-2 and Phase-3 clinical trials.3–5
some H1 antihistamines. Some individuals, for example, have decreased
ability to form 3-hydroxy-desloratadine, the major metabolite of des- Pharmacodynamics: Concentration Versus Effect
loratadine, although the increased exposure to desloratadine in these The pharmacodynamics of H1 antihistamines can be studied objectively
poor metabolizers does not affect the safety and tolerability profiles of using the allergic rhinoconjunctivitis model and the cutaneous wheal
desloratadine.78 and flare model in humans.
Drug–drug interaction studies are of practical clinical relevance for
all of the first (old)-generation H1 antihistamines as well as for second Allergic Rhinoconjunctivitis Model. H1 antihistamines prevent and
(new)-generation H1 antihistamines such as desloratadine and lorata- suppress the response to histamine, allergen, and other agents in the
dine, which are extensively metabolized in the hepatic CYP450 system. nasal and conjunctival mucosa and can be tested in patients with allergic
Metabolism of the first (old)-generation H1 antihistamines is poten- rhinitis or allergic conjunctivitis who are challenged intranasally or
tially decreased by CYP inhibitors such as erythromycin, azithromycin, conjunctivally, respectively, with these agents. Experimental models
and other macrolide antibiotics or ketoconazole and other imidazole involve pretreatment of a patient with an H1 antihistamine followed
antifungals. Plasma and tissue concentrations of unmetabolized H1 by allergen challenge in that patient, pretreatment of a group of patients
antihistamines may increase and potentially lead to toxicity. Lorata- followed by natural allergen challenge of the group in an outdoor setting
dine (as well as desloratadine and rupatadine) are also metabolized such as a park, or group challenge with high doses of allergen in an
through the alternative CYP2D6 pathway, which greatly reduces potential indoor environmental exposure unit. These experimental models can
TABLE 92.3 H1 Antihistamines: Pharmacokinetics and Pharmacodynamics in Healthy Adults

Time to Maximum Terminal Clinically
Plasma Concentration Elimination Relevant
(tmax, hr) after Single Half-Life Drug−Drug Onset of Duration of
Medication Dose ( t 12 , hr) Interactionsa Action (hr)b Action (hr)
Orally Administered H1 Antihistamines
First (Old) Generation
Chlorpheniraminec 2.8 ± 0.8 27.9 ±8.7 Possible 3 24
Diphenhydraminec 1.7 ± 1.0 9.2 ±2.5 Possible 2 12
c
Doxepin 2 13–17 Possible n/a n/a
Hydroxyzinec 2.1 ± 0.4 20.0 ±4.1 Possible 2 24
Second (New) Generation

Bilastinea 1.2 14.5 Unlikely 2 24
Cetirizine 1.0 ± 0.5 6.5–10 Unlikely 0.7 ≥24
Desloratadine 1–3 27 Unlikely 2–2.6 ≥24
Fexofenadinea 1–3 11–15 Unlikely 1–3 24
Levocetirizine 0.8 ± 0.5 7 ± 1.5 Unlikely 0.7 >24
Loratadine (metabolite: 1.2 ± 0.3 7.8 ± 4.2 Unlikely 2 24
descarboethoxyloratadine) (1.5 ± 0.7) (24 ± 9.8)
Rupatadine 0.75–1.0 6 Unlikely 2 24
(4.3–14.3)
Nasal/Ophthalmic H1 Antihistamine Formulationsd

Alcaftadine (ophthalmic) 0.25 8–12 No 0.05 24
Azelastine (metabolite: desmethylazelastine, 5.3 ± 1.6 22–27.6 No 0.5 12
nasal and ophthalmic) (20.5) (54 ± 15)
Bepotastine (ophthalmic) 1.3 2.5 No 0.25 12–24
Emedastine (ophthalmic) 1.4 ± 0.5 7 No 0.25 12
Epinastine (ophthalmic) 2 6.5 No 0.1 12
Ketotifen (ophthalmic) 2–4 20–22 No 0.25 12
Levocabastine (ophthalmic) 1–2 35–40 No 0.25 12
Olopatadine (nasal and ophthalmic) 0.5–2 8–12 No 0.25 12–24
Results are expressed as mean ± standard deviation, unless otherwise indicated. n/a, Information not available or incomplete.
a
Clinically relevant drug–drug interactions are unlikely with most of the second (new)-generation H1 antihistamines. Clinically relevant drug–food
interactions have been well studied for fexofenadine. Naringin, a flavonoid in grapefruit juice, and hesperidin, a flavonoid in orange juice, reduce
the oral bioavailability of fexofenadine through inhibition of OATP-1A2. Apple juice decreases it to the same extent. This interaction can be
avoided by waiting 4 hours between juice consumption and fexofenadine dosing. Bilastine Cmax is reduced by 33% by grapefruit juice.
b
For oral H1 antihistamines, onset and duration of action are based on wheal and flare studies. For nasal and ophthalmic H1 antihistamine
formulations, onset and duration of action are based on standard adult doses, such as 1 or 2 sprays in each nostril or 1 drop in each eye, as
determined in nasal and conjunctival challenge studies, respectively.
c
Six or seven decades ago, when many of the first (old)-generation H1 antihistamines were introduced, regulatory agencies did not require
pharmacokinetic and pharmacodynamic studies for any medication. Although subsequently these studies were performed for some H1
antihistamines, empiric dosage regimens persist. For example, manufacturers’ recommended diphenhydramine dose for allergic rhinitis is 25 to
50 mg every 4 to 6 hours, yet the diphenhydramine dose for insomnia is 25 to 50 mg at bedtime. Despite the long terminal elimination half-life
values identified for some of the medications, traditionally they are still dosed several times daily. For example, doxepin, which has an
elimination half-life of 13 to 17 hours, is given in doses of up to 25 to 50 mg three times daily for chronic spontaneous urticaria, yet a
considerably lower dose of doxepin, 3 mg or 6 mg once daily at bedtime, is FDA-approved for insomnia. Chlorpheniramine has an elimination
half-life longer than 24 hours; yet traditionally it is either given several times daily or in an extended-release formulation.
d
For nasal and ophthalmic H1 antihistamines, tmax, t1/2, and drug–drug interaction information are based on serum levels obtained after oral
administration. After topical applications, serum levels are too low to permit calculation of pharmacokinetic parameters; most of these
medications cause minimal systemic effects, including skin test suppression.
be used to investigate H1 antihistamine onset of action, peak effect, and (less often) the allergen-induced wheal and flare response (Fig. 92.8).
duration of action.66,68,69,88–94 In some studies, plasma and skin H1 antihistamine concentrations have
been measured concomitantly64,65,67,77,78,80,83,95–97 (Fig. 92.9). H1 antihis-
Cutaneous Wheal and Flare Model. Objective information about tamines decrease the size of the wheal directly by acting on endothelial
the onset, intensity, and offset of H1 antihistamine activity is often cells to decrease postcapillary venule permeability and leakage of plasma
obtained by measuring the suppression of the histamine-induced or protein. They decrease the size of the flare indirectly by blocking the
500 half-life values but still need to be administered every 12 hours because
Plasma levocetirizine concentrations (ng/mL)
100 of medication washout by continuous bathing of the nasal mucosa and

400 90 conjunctivae with secretions and tears.
Percent wheal/flare suppression

80 After discontinuing a second (new)-generation H1 antihistamine
70 taken regularly for 1 or more weeks, residual suppression of skin test
300 Wheal % suppression
60 reactivity to histamine and allergens varies with the H1 antihistamine,
Flare % suppression
50 lasting 1 day after loratadine or desloratadine, 2 days after fexofenadine,
200 Levocetirizine concentrations
40 and 3 to 4 days after cetirizine or levocetirizine.3,5
30
100 20 Peripheral H1 Activity During Regular Administration. No loss
10 of H1 antihistamine effects during regular daily administration has been
0 0 found in rigorously controlled, double-blind studies of up to 12 weeks’
duration that monitor skin wheal and flare suppression or in long-term
0 5 10 15 20 25 30 clinical studies monitoring symptom suppression in allergic rhinitis or
Time (hour) urticaria. The apparent subsensitivity to some first (old)-generation H1
Fig. 92.8 Levocetirizine plasma concentrations and effect on the wheals antihistamines described decades ago may have resulted from their
and flares (erythema) produced by skin prick tests with histamine phos- weak, inconsistent pharmacologic effects or lack of compliance because
phate 1 mg/mL. Mean plasma levocetirizine concentrations and mean of adverse effects.
wheal and flare percent suppression are plotted against time before
and after ingestion of levocetirizine 5 mg by children age 6 to 11 years. Clinical Relevance of Wheal and Flare Studies. Significant, clini-
Compared with predose values, wheals were significantly suppressed cally relevant differences among H1 antihistamines can be clearly shown
from 1 to 28 hours, inclusive, and flares were also significantly sup- in 10 to 20 participants in clinical pharmacology studies using objective
pressed from 1 to 28 hours, inclusive (data not shown). (From Simons
outcomes in the wheal and flare model.64,65,83,96,97,101 Wheal and flare
FER, Simons KJ. Levocetirizine: pharmacokinetics and pharmacodynamics
suppression has direct clinical relevance for patients with urticaria. For
in children age 6 to 11 years. J Allergy Clin Immunol 2005;116:355-61.)
some H1 antihistamines (e.g., cetirizine, fexofenadine, levocetirizine),
wheal and flare suppression also correlates with relief of allergic rhi-
histamine-induced axon reflex. Using a standardized wheal and flare nitis symptoms. For others, however, such as loratadine and deslorata-
bioassay, dose-response curves can be identified for each H1 antihista- dine, there is poor correlation with relief of rhinitis symptoms. This
mine (see Fig. 92.8), and significant differences in onset, amount, and may involve dosing issues; in the wheal and flare model, desloratadine
duration of activity among H1 antihistamines can be consistently identi- 10 mg and levocetirizine 1.25 mg provide equivalent suppression for
fied (see Fig. 92.9). For some H1 antihistamines such as cetirizine, 4 hours after dosing, although manufacturers’ recommended dose for
fexofenadine, and levocetirizine (Fig. 92.10), wheal and flare suppression allergic rhinitis treatment is desloratadine 5 mg or levocetirizine 5 mg
in humans has been shown to correlate with H1-receptor occupancy daily.95 Significant, clinically relevant differences in efficacy among H1
by free (unbound) H1 antihistamine.4,5,77,95–100 antihistamines or among different doses of the same H1 antihistamine
are difficult to demonstrate in randomized controlled trials (RCTs)
Onset of Action and Peak Action. The pharmacodynamics of H1 in allergic rhinitis, with hundreds of participants in each treatment
antihistamines are medication- and dose-dependent. For second (new)- group and the main outcomes being subjective symptom scores and
generation H1 antihistamines, peak plasma concentrations (Cmax) in quality-of-life scores.
target organs such as the skin are achieved rapidly after oral adminis-
tration (see Figs. 92.8 and 92.9). After a single oral dose, significant
suppression of the histamine-induced wheal and flare begins within 1
ALLERGIC RHINITIS
hour (bilastine, cetirizine, levocetirizine) to 2 hours (loratadine, des- H1 antihistamines (aerosolized as well as oral formulations) are medica-
loratadine, rupatadine) of H1 antihistamine ingestion, and peak sup- tions of initial choice in allergic rhinitis102 without affecting the natural
pression occurs at 5 to 8 hours.64,65,67,78,80,83,95–97 history of the disease (Fig. 92.11).
Histamine plays an important role in the pathophysiology of allergic
Duration of Action and Residual Action. The duration of action rhinitis, especially in the early allergic response. Acting at H1 receptors,
of a single dose of an H1 antihistamine, assessed objectively from sup- histamine causes sneezing and itching of the nose and potentially the
pression of the histamine- or allergen-induced wheals and flares in the palate, throat, and ears through sensory nerve stimulation. It contributes
skin, or subjectively by suppression of nasal symptoms after allergen to rhinorrhea through parasympathetic reflex stimulation of glandular
challenge, is more prolonged than might be expected from elimination secretions, and to both rhinorrhea and congestion through vasodilation
half-life values. This persistent effect is associated with high tissue/ and increased permeability of postcapillary venules. It also plays a role
plasma concentration ratios of H1 antihistamines such as cetirizine in the late allergic response; in the recruitment, adherence, and activa-
or fexofenadine97 (see Fig. 92.9). For other H1 antihistamines such as tion of epithelial cells, eosinophils, basophils, mast cells, T cells, and
desloratadine or loratadine, it is likely associated with the presence of Langerhans cells; and in the upregulation of the expression and mobi-
active metabolites, although these have not been directly measured in lization of cell adhesion molecules. H1 antihistamines downregulate
human tissue. allergic inflammation mainly through the H1 receptor4,5 (Fig. 92.12).
The duration of action of most second (new)-generation H1 anti- The ARIA classification based on symptom duration and severity
histamines is at least 24 hours, facilitating once-daily dosing (see Table has revised the former terminology “seasonal” and “perennial” disease
92.3). For some of these medications, it may be even longer in elderly to “intermittent” and “persistent.” However, the traditional classification
persons and in patients with hepatic or renal dysfunction, necessitating has defined the inclusion criteria in most RCTs of H1 antihistamines
a reduced dose or dose frequency. Some topically administered H1 anti- in allergic rhinitis. The definition of persistent allergic rhinitis (4 days
histamines such as azelastine and levocabastine have long elimination a week for 4 consecutive weeks) can be considered as a suggestion,
1000 † 7
† Wheal
Fexofenadine concentrations (ng/mL or ng/g)
†
*† Flare
500 6
*p ≤ 0.05 vs all others
†p ≤ 0.05 vs diphenhydramine
Wheal or flare area (cm2)

5
100
50 4 *
3
10 Plasma
2
5 Skin
1 *†
†p ≤ 0.05 vs diphenhydramine *†
*† *† *† *† *†
1 0
Pre-dose 1 3 6 9 24 168 Pre-dose 1 3 6 9 24 168
A Time (h) B Time (h)
1000 7 Wheal
Diphenydramine concentrations (ng/mL or ng/g)
500 Flare
6
Wheal or flare area (cm2)

5
100
50 4
3
10
2 *
5
Plasma
1
Skin * *
1 0
Pre-dose 1 3 6 9 24 168 Pre-dose 1 3 6 9 24 168
C Time (h) D Time (h)
Fig. 92.9 Correlation of skin and plasma H1 antihistamine concentrations during multidose administration. In
a randomized, double-blind, multiple-dose, parallel-group study, fexofenadine 120 mg/day or diphenhydramine
50 mg/day was administered for 1 week. At predose baseline and 1, 3, 6, 9, and 24 hours after the initial H1
antihistamine dose, skin and plasma antihistamine concentrations were monitored, and wheal and flare areas
were measured after epicutaneous tests with histamine phosphate 1 mg/mL. Subsequently, on each of 6
consecutive days, participants took their H1 antihistamine dose at 9 PM. All the tests were repeated at 168
hours (i.e., at steady-state, depicted in shaded area), exactly 12 hours after the seventh and last dose. The
values shown are mean ± standard error of the mean (SEM). Fexofenadine (A and B) achieved significantly
higher concentrations in the skin and significantly greater wheal and flare suppression than did diphenhydramine
(C and D). Predose, plasma concentrations of both H1 antihistamines were zero. (From Simons FER, Silver
NA, Gu X, et al. Skin concentrations of H1-receptor antagonists. J Allergy Clin Immunol 2001;107:526-30.)
because they do not relate from direct evidence. Additional subpheno- parallel-group clinical trials involving thousands of participants. Addi-
typing may be performed based on monosensitization, polysensitization, tional studies are still needed in children and elderly persons.104–113
or the coexistence of asthma. All these variables confer to the choice Traditional “diary card” studies in seasonal allergic rhinitis involve
of treatment. Recently an entity of rhinitis linked to allergy that is called self-report of symptoms and quality of life during the pollen season.
local allergic rhinitis has been described. It is characterized by the local Typically, regular H1 antihistamine treatment begins before peak pol-
presence of allergen-specific IgE in the nasal mucosa in the absence of lination and is continued for the duration of the season. The duration
systemic allergen-specific IgE, which is considered to respond to the of clinical trials in perennial allergic rhinitis is usually 4 to 8 weeks,
same treatment modalities as allergic rhinitis.102,103 although some studies have lasted 26 to 52 weeks. In seasonal allergic
First-generation H1-antihistamines are no longer recommended for rhinitis and perennial allergic rhinitis studies, participants demonstrate
the treatment of allergic rhinitis due to their well-established side effects. a predefined pretreatment level of self-recorded nasal symptoms (e.g.,
There is solid evidence for the use of orally administered second- itch, sneezing, rhinorrhea) and nonnasal symptoms (e.g., itchy watery
generation H1 antihistamines such as bilastine, cetirizine, desloratadine, eyes; itchy throat, palate, or ears; cough). Such studies document sen-
fexofenadine, loratadine, levocetirizine, and rupatadine, as well as for sitization to the allergens likely to be encountered. In seasonal allergic
nasal H1 antihistamine formulations such as azelastine and olopatadine rhinitis studies, daily allergen exposure (e.g., pollen counts) is monitored.
and ophthalmic formulations such as alcaftadine and bepotastine. Effi- In addition to subjective self-assessment of rhinitis symptoms used to
cacy has been well documented in hundreds of randomized DBPC evaluate efficacy, objective measurements such as measurement of nasal
120 120
6h 4h
8h 3h
2h 6h 4h
100 10h 100 8h 3h
10h 2h
Wheal suppression (%)
Wheal suppression (%)

80 24h 80 24h
26h
60 26h
60
1h 28h 1h
28h
40 40
20 20
0.5h* 0.5h*
0 0
0 10 20 30 40 50 60 70 80 90 0 20 40 60 80 100 120
A Levocetirizine unbound (free) plasma concentration (nM) B Receptor occupancy (%)
100 10h 8h 6h 4h 3h 2h 100 10h 8h 6h 4h

24h 26h 24h
28h 3h
90 90 2h
26h
80 28h 80
Flare suppression (%)
Flare suppression (%)

70 70
60 60
1h 1h
50 50
40 40
30 30
20 20
0.5h* 0.5h*
10 10
0 0
0 10 20 30 40 50 60 70 80 90 0 20 40 60 80 100 120
C Levocetirizine unbound (free) plasma concentration (nM) D Receptor occupancy (%)
* Times (h) at which skin tests were performed and blood samples collected
Fig. 92.10 H1 antihistamines and H1-receptor occupancy. (A) Percent suppression of the histamine-induced
wheal versus levocetirizine unbound (free) plasma concentrations. (B) Percent suppression of the histamine-
induced wheal versus percent levocetirizine H1-receptor occupancy. (C) Percent suppression of the histamine-
induced flare versus levocetirizine unbound (free) plasma concentrations. (D) Percent suppression of the
histamine-induced flare versus percent levocetirizine H1-receptor occupancy. Receptor occupancy kinetics
are a better representation of the time course of H1 antihistamine pharmacodynamics than plasma pharma-
cokinetics. (From Simons KJ, Benedetti MS, Simons FE, Gillard M, Baltes E. Relevance of H1-receptor
occupancy to H1 antihistamine dosing in children. J Allergy Clin Immunol 2007;119:1551-4.)
peak inspiratory flow have been incorporated into some clinical In some studies, oral H1 antihistamines have had a small, statistically
trials.105,106,112–114 significant decongestant effect that may or may not be clinically relevant.
Most studies of H1 antihistamines have involved regular daily admin- Some H1 antihistamines are therefore marketed in fixed-dose combina-
istration, which is associated with a significant decrease in symptoms tion with a decongestant such as pseudoephedrine to improve relief of
and nasal mucosal inflammation compared with “as needed,” “on nasal congestion and overall efficacy.117 Concomitant administration
demand,” or “on-again, off-again” use.115,116 of an H1 antihistamine and an H3 antihistamine might be useful in
prevention of nasal congestion and other allergic rhinitis symptoms.112
Practical Issues Although second-generation H1 antihistamines are more efficacious
The H1 antihistamines reduce symptoms in allergic rhinitis and improve than montelukast or cromolyn, all three of these classes of medication
quality of life significantly. They relieve nasal itching, sneezing, and are less efficacious than nasal glucocorticoids. Nonresponders to H1
rhinorrhea to a greater extent than placebo and are also effective for antihistamines who are adherent to treatment thus should be considered
relieving itching of the palate, throat, and ears. Overall, a 50% to 70% candidates for nasal glucocorticoid treatment.104,106,113 A step-up approach
reduction in symptoms is typically documented, versus a 30% to 40% to treat allergic rhinitis has been proposed in analogy to asthma treat-
reduction after placebo. The dose-response curve for symptom relief ment102 (Fig. 92.13).
from H1 antihistamines is relatively flat.106,113 Now that relatively inexpensive generic second (new)-generation
Small, inconsistent but statistically significant differences in efficacy H1 antihistamines such as cetirizine and loratadine are available, addi-
among oral H1 antihistamines have been demonstrated in a few allergic tional comprehensive cost-effectiveness studies of H1 antihistamines in
rhinitis studies. When all RCTs are reviewed, however, no H1 antihis- allergic rhinitis are needed. In such studies the indirect costs incurred
tamine emerges with an overall superior efficacy profile that is clinically from adverse effects of first (old)-generation H1 antihistamines need
relevant. Selection of an H1 antihistamine for allergic rhinitis treatment to be considered.118 Pharmacoeconomic evaluations of allergic rhinitis
should therefore be based first on safety and considerations such as should include comparisons of patients with severe versus mild chronic
convenience of dose regimen and patient preference. upper airway disease.105
Conditions Currently Treated with H1 Antihistamines erythema, tearing, and edema that characterize the early response to
Weak evidence base allergens.68–70,103,119–123 Standardized criteria for patient selection and
Strong evidence base for first (old)-generation quantifiable primary outcomes are not yet universally incorporated
for second (new)-generation Weak evidence base H1 antihistamine use in into randomized controlled trials of therapeutic interventions in allergic
H1 antihistamine use for H1 antihistamine use CNS and vestibular disorders
conjunctivitis.122
H1 antihistamines inhibit mast cell activation and histamine release
Atopic dermatitis Insomnia
in a concentration-dependent manner. Although the mechanisms involved
Asthma Conscious sedation
have not yet been delineated fully, downregulation of intracellular calcium
Anaphylaxis Perioperative sedation ion accumulation seems to play a role34,124 (Fig. 92.12). Most ophthalmic
Allergic rhinitis Nonallergic angioedema Analgesia H1 antihistamine formulations also function as mast cell stabilizers,
Upper respiratory tract Anxiety because H1 antihistamines in high concentrations are applied directly
infections (colds) Serotonin syndrome to the conjunctivae; these high concentrations are difficult to achieve
Otitis media Akathisia after oral dosing.68–70,124
Sinusitis Migraine Ophthalmic formulations have a rapid onset of action of 3 to 15
Allergic conjunctivitis Nasal polyps Motion sickness minutes.119–123 Some are reported to treat nasal symptoms in addition
Nonspecific cough Vertigo to conjunctival symptoms. In patients with allergic conjunctivitis,70 H1
Nonallergic, antihistamines have a more favorable benefit/risk ratio than all other
nonspecific itching classes of medications, including nonsteroidal antiinflammatory drugs
(NSAIDs), decongestants, and glucocorticoids.103 A recent metaanalysis
suggested that the ophthalmic glucocorticoid loteprednol displayed com-
Urticaria
parable efficiency compared with olopatadine or fluorometholone acetate
Fig. 92.11 Science versus reality: evidence-based use of H1 antihista-
with the limitation of a higher rate of intraocular pressure. Noninferior-
mines in allergic diseases and other disorders. On the basis of well-
ity was reported in children with seasonal allergic conjunctivitis.125,126
designed randomized controlled trials and metaanalyses of such trials,
the evidence base for the efficacy and safety of second (new)-generation
H1 antihistamines is strong in patients with allergic rhinitis, allergic con- URTICARIA
junctivitis, and urticaria (category of evidence I, strength of recommen-
dation A), but not in those with atopic dermatitis and other diseases Histamine, acting through H1-receptors, is the main mediator of pruritus
(category of evidence II to IV, strength of recommendation B, C, or D, in acute and chronic urticaria. Along with proteases, tachykinins, eico-
depending on the disease). The evidence base for the efficacy and sanoids, prostanoids, neuropeptides such as substance P, and other
safety of first (old)-generation H1 antihistamines remains weak in patients vasoactive substances, it leads to increased vascular permeability, vaso-
with allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis, dilation, and wheals and flares that blanch under pressure.95,103 In chronic
and other diseases, including central nervous system (CNS) and vestibular
urticaria, skin tissue fluid histamine concentrations are increased in
disorders (category of evidence II to IV, strength of recommendation
urticarial lesions and in uninvolved skin. The presence of urticarial
B, C, or D, depending on the disease). The potential adverse effects of
these first (old)-generation H1 antihistamines remain a concern. (From lesions correlates with increased histamine-releasing activity by auto-
Simons FER, Simons KJ. Histamine and H1-antihistamines: celebrating antibodies. Clinical tolerance to histamine is reduced in individuals
a century of progress; J Allergy Clin Immunol 2011;128:1139-50.) with chronic urticaria. In localized urticarial lesions induced by cold
challenge or other relevant stimulus, plasma histamine concentrations
are not increased; however, histamine concentrations in venous blood
Nasal H1 antihistamine formulations have a more rapid onset of draining the site increase transiently, peaking at 2 to 5 minutes, and
action than oral H1 antihistamine formulations, for example, 15 minutes declining to baseline within 30 minutes.5
for intranasal azelastine versus 150 minutes for oral desloratadine.110,111 In urticaria, H1 antihistamines provide symptomatic relief of itching
In patients with seasonal allergic rhinitis, intranasal H1 antihistamines and reduce the number, size, and duration of flares (erythema). Relief
are reported to be as efficacious as (or more efficacious than) oral H1 may be incomplete, because additional vasoactive mediators contribute
antihistamines, particularly for relief of nasal congestion. They improve to the vasodilation, vascular permeability, and extravasation.
symptoms in patients who are unresponsive to oral H1 antihistamines In acute urticaria, defined as hives lasting less than 6 weeks, the
and in those with vasomotor rhinitis.111 Patient preference should be evidence base for the use of either first (old)-generation or second
considered when recommending a nasal versus an oral H1 antihista- (new)-generation H1 antihistamines remains small. In young atopic
mine.109 Nasal azelastine combined with nasal fluticasone in a single–nasal children, a planned secondary outcome was H1 antihistamine efficacy
spray delivery device provides a significantly greater improvement of in intermittent acute urticaria in two large randomized DBPC trials,
symptoms, including congestion, than either medication alone (Fig. each 18 months in duration; cetirizine127 and levocetirizine99 were sig-
92.14). Antihistamines such as azelastine and olopatadine can cause a nificantly more effective than placebo in preventing and reducing urti-
bitter taste. The revised ARIA guidelines of 2017 thus suggest to use carial lesions.
either a combination of intranasal H1 antihistamines with intrana- In chronic urticaria, defined as hives lasting 6 weeks or more, second-
sal steroids or intranasal steroids alone and to use the combination generation H1 antihistamines initially at standard dose and as a second
of both intranasal H1-antihistamines and steroids over intranasal H1 step in up to fourfold doses represent the first-line treatment according
antihistamines. Intranasal H1 antihistamines are supported over oral to the European Academy of Allergy and Clinical Immunology/Global
H1 antihistamines.106 Allergy and the Asthma European Network/European Dermatology
Forum/World Allergy Organization (EAACI/GA2LEN/EDF/WAO)
guidelines, which are endorsed by all major societies worldwide.128
ALLERGIC CONJUNCTIVITIS Despite the almost uniform agreement of second-generation antihis-
In patients with allergic conjunctivitis, H1 antihistamines administered tamine up-dosing, additional studies comparing head-to-head efficiency
orally or applied directly to the conjunctivae relieve the itching, of high-dose second-generation H1 antihistamines and additional safety
Beneficial Effects of H1 Antihistamines
Direct effects NF-κB– and calcium ion channel–modulated anti-allergic effects

Antigen H1 antihistamine
IgE (inverse agonist)
Calcium
H1 receptor ion channel
PIP2
Mast cell PLCβ
releasing
histamine Gγβ Ca++
DAG
Gα Gαq GTP
IP3 ↓ Mediator
GDP release
H1 receptor ↑ Mast cell
↓ Sensory PKCβ Ca++ stabilization
nerve Cytoplasm
stimulation
(itch)
Calcium
Nucleus
ion channel
↓ Antigen NF – κB
↓ Vascular permeability presentation DNA
↓ Expression of pro-inflammatory cytokines,
↓ Vasodilation ER
cell adhesion molecules, chemotactic factors
Fig. 92.12 Mechanisms underlying beneficial effects of H1 antihistamines. In addition to acting directly to
interfere with histamine action at H1 receptors on sensory neurons and small blood vessels, mainly postcapil-
lary venules, H1 antihistamines also downregulate allergic inflammation indirectly through nuclear factor-κB
and through calcium ion channels. DAG, 1,2-Diacylglycerol; ER, endoplasmic reticulum; GDP, guanosine
diphosphate; GTP, guanosine triphosphate; IP3, inositol 1,4,5-triphosphate; PIP2, phosphatidylinositol-4,5-
bisphosphate; PKC, protein kinase C; PLC, phospholipase C. (From Simons FER, Simons KJ. Histamine and
H1-antihistamines: celebrating a century of progress; J Allergy Clin Immunol 2011;128:1139-50.)
data is demanded.129 Omalizumab and cyclosporine are defined as a high level of evidence for the efficacy exists only for nonsedating
second- (omalizumab) and third-line treatments. Omalizumab is pre- antihistamines (cetirizine, levocetirizine, desloratadine, fexofenadine,
ferred over cyclosporine in adults and adolescents. There is a consensus- and rupatadine) with very good response rates of 50% to 60% at a
based recommendation against the usage of different second-generation standard dose. A total of 97.5% responded at a fourfold dose. No RCT
antihistamines at the same time. This is supported by a high consensus data is available on dose increase. Although high-dose second-generation
but low evidence. The evidence for the usage of leukotriene receptor H1-antihistamines were well-tolerated, rare adverse events cannot be
antagonists is low at best. excluded because of lack of power. In contrast to the adult population,
Randomized DBPC trials constitute a strong evidence base for use data on omalizumab is restricted to case reports and/or case series
of second (new)-generation H1 antihistamines such as bilastine, ceti- (cyclosporine).134 Cyclosporine has been reported to be associated with
rizine, desloratadine, fexofenadine, levocetirizine, loratadine, and rupa- known side effects such as elevated blood pressure or increased creati-
tadine in chronic urticaria (Fig. 92.15). In these trials, they have been nine levels, which are reversible upon cessation of the treatment. More-
given on a regular basis rather than on an as-needed or on-again, off- over, agitation and sleeplessness have been reported.135
again basis, which is less effective.130 In RCTs, second (new)-generation The evidence base for the efficacy of sulfasalazine, hydroxychloro-
H1 antihistamines are as effective as first (old)-generation H1 antihis- quine, mycophenolate, and oral tacrolimus in chronic urticaria is weak.
tamines and also are less impairing and sedating.131,132 Exacerbations of hives can be treated with a brief 3- to 7-day course
Although many patients respond to usual doses of a second (new)- of a glucocorticoid, but long-term glucocorticoid treatment should be
generation H1 antihistamine, even more respond to higher daily doses avoided. Therapy with cyclosporine, dapsone, sulfasalazine, hydroxy-
of some of these medications up to fourfold. Although there is strong chloroquine, mycophenolate, or tacrolimus requires regular monitoring
agreement on the efficacy of up-dosing regarding symptom control, a and dose adjustments to avoid potentially severe adverse effects.128
recent metaanalysis suggested that there is only a positive effect on
pruritus but not wheal number.129 These findings are limited by the OTHER DISEASES AND USES
fact that there is significant heterogeneity among the different studies.
A randomized controlled trial demonstrated that the use of sedating First (Old)- and Second (New)-Generation
antihistamines (hydroxyzine 50 mg) before nighttime in combination H1 Antihistamines
with nonsedating antihistamines (levocetirizine 15 mg) increases daytime Medications of Choice. A small RCT supports H1 antihistamine use
somnolence but not efficacy compared with levocetirizine 20 mg to prevent and relieve itching and flushing in mastocytosis.136 Similarly,
monotherapy.133 small RCTs support the use of H1 antihistamines such as cetirizine,
Chronic urticaria is not well studied in children under the age of ebastine, loratadine,137,138 levocetirizine,139 and rupatadine140 for preven-
12 years. A recent metaanalysis of data from 2005 to 2016 found that tion and relief of the itching, redness, and swelling of early and late
40
IMMUNOTHERAPY
ENVIRONMENTAL CONTROL 35
CONTROL MEDICATION STEPS

4 (SPECIALIST 30
1 2 3 CARE ONLY) Switch to
Number of symptom-free patients

20 mg Deslo
One of: One of: • Combination of CONSIDER (0)
Intranasal OMALIZUMAB 25
corticosteroids IN
• Oral antihistamine • Intranasal
SEVERE RHINITIS
corticosteroid WITH
(preferred) WITH ONE OR MORE OF*:
20
• Intranasal CONCURRENT 20 mg (5)
antihistamine ASTHMA
• Oral antihistamine (NOT APPROVED Switch to
• Intranasal FOR 15 20 mg Levo
• Intranasal antihistamine RHINITIS ALONE) (7)
cromolyn/ • Intranasal 10 mg (8)
20 mg (1)
nedocromyl antihistamine
• Oral antihistamine CONSIDER 10
SURGICAL
• Leukotriene • Leukotriene • Leukotriene TREATMENT OF 10 mg (7)
receptor receptor receptor CONCURRENT 5 5 mg (9)
antagonist antagonist antagonist PATHOLOGY
Rescue medication 5 mg (4)
• Decongestants (oral/intranasal) 0
• Oral
• Anticholinergics (intranasal) Levocetirizine Desloratadine
corticosteroids
Fig. 92.15 Effectiveness of levocetirizine and desloratadine in up to
Reassess diagnosis and/or adherence and evaluate potential four times conventional doses in difficult-to-treat urticaria. The number
comorbidities and/or anatomic abnormalities prior to considering step-up of patients whose symptoms were relieved by levocetirizine (Levo) and
desloratadine (Deslo) during the 4 weeks of the study are shown. The
Fig. 92.13 Stepwise treatment algorithm for allergic rhinitis based on numbers in parentheses refer to the number of patients who were
control. Step-up is indicated if symptoms remain uncontrolled and step- symptom free on 5 mg (week 1), 10 mg (week 2), 20 mg (week 3), or
down if control is achieved with the used regimen. Although the control after switching from one drug to the other (week 4). (From Staevska
principle may be valid for other rhinitis phenotypes as well, specific M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine
medications should be adjusted accordingly. *There is little evidence and desloratadine in up to 4 times conventional doses in difficult-to-treat
of additional efficacy of the INCS/oral AH or INCS/LTRA combinations urticaria. J Allergy Clin Immunol 2010;125:676-82.)
over INCS alone, but there is stronger evidence for the INCS/intranasal
AH combination. (From Papadopoulos N G, Bernstein JA, Demoly P
et al. Phenotypes and endotypes of rhinitis and their impact on manage-
ment. a PRACTALL report. Allergy 2015;70,474-94.)
rTNSS ≤ 18.9 rTNSS > 18.9 RQLQ ≤ 3.9 RQLQ > 3.9
0
–1
rTNSS (LS mean change from baseline)
–2
–3
*
–4 * *
*
‡ ‡
–5
‡ ‡ ‡
MP29-02 ‡
–6 †
FLU
AZE
–7 PLA
Fig. 92.14 Nasal H1 antihistamine combined with nasal glucocorticoid for allergic rhinitis treatment. Effect
of azelastine and fluticasone in combination (MP29-02) versus fluticasone propionate (FLU), azelastine (AZE),
and placebo (PLA) on the reflective total nasal symptom scores (rTNSSs) (morning plus evening) by severity
in patients with seasonal allergic rhinitis (SAR). Data are presented as least squares (LS) mean change from
baseline for the metaanalysis. *P ≤ .001 versus all active treatment. Patients with moderate-to-severe SAR
(rTNSS >18.9 and Rhinitis Quality of Life Questionnaire [RQLQ] >3.9) had the best response to treatment.
(From Carr W, Bernstein J, Lieberman P, et al. A novel intranasal therapy of azelastine with fluticasone for
the treatment of allergic rhinitis. J Allergy Clin Immunol 2012;129:1282-9.)
allergic reactions to mosquito bites. Small RCTs also support pretreat- that typically accompanies their use might be relevant in emergency
ment with an H1 antihistamine to reduce adverse effects and modulate department settings from which patients are discharged within hours
allergen-specific immune responses during subcutaneous immunotherapy of treatment.
with stinging insect venoms.61 In a randomized trial in young patients with food challenge–associated
acute allergic reactions confined to the skin, cetirizine (0.25 mg/kg)
Not Medications of First Choice. Largely on the basis of tradition, had a similar onset of action compared with diphenhydramine (1 mg/
H1 antihistamines remain in widespread use for many diseases despite kg), as well as similar efficacy, longer duration of action, and reduced
a weak evidence base for drug efficacy and safety and not being sup- sedation profile. Similar numbers of children in each treatment group
ported by RCTs that meet current standards (Fig. 92.11). received epinephrine and glucocorticoid treatment.144
Atopic Dermatitis. In some patients with atopic dermatitis, histamine Prevention of Allergic Reactions. In a variety of protocols an H1
concentrations are elevated in the skin and plasma. Histamine acts as antihistamine in combination with other medications, such as an H2
a pruritogen through H4 receptors as well as H1 receptors and through antihistamine and a glucocorticoid, is recommended for prophylaxis
cytokines (e.g., IL-31), neuropeptides, proteases, and eicosanoids. Relief of anaphylaxis triggered by agents such as radiocontrast media, volume
of itching in atopic dermatitis is therefore typically incomplete after expanders, plasma exchange transfusion, fluorescein, morphine, prot-
H1 antihistamine use. Moreover, the evidence that these medications amine, and other drugs. With a few exceptions,145 the protocols in use
have significant topical glucocorticoid-sparing effects in dermatitis is are based on clinical experience rather than RCTs.3,5
not convincing.141 No high-quality randomized DBPC trials of H1 anti-
histamines confirm their overall efficacy in atopic dermatitis. Regardless, Nonallergic Angioedema. In the absence of itching or urticaria,
first (old)-generation H1 antihistamines are still widely applied for the angioedema is typically nonallergic, not mediated by histamine, and
treatment of atopic dermatitis.141 This is a concern, particularly in infants not prevented or relieved by H1 antihistamines. The recommended
and young children, in whom adverse effects are well documented not pharmacologic treatment of hereditary angioedema type 1, 2, and
only after usual doses but also when higher doses or extra doses are 3 attacks includes C1-esterase inhibitor concentrates, ecallantide,
given due to lack of efficacy.141 Recently a positive correlation between or icatibant. Treatment of nonallergic angioedema associated with
the increase of attention-deficit/hyperactivity symptoms and a history angiotensin-converting enzyme (ACE) inhibitor use involves substi-
of antihistamine use has been reported.142 tution of another medication if possible. Treatment of malignancy-
associated nonallergic angioedema focuses on definitive treatment of the
Asthma. The role of histamine and of H1 antihistamines in asthma malignancy.
has been extensively reviewed.3,5 H1 antihistamine treatment for asthma
has evolved through several phases, with initial enthusiasm for first Weak Efficacy and Off-Label Uses. H1 antihistamines are used
(old)-generation H1 antihistamines fading quickly. Later, they were to treat symptoms of upper respiratory tract infections, acute otitis
thought to be contraindicated in asthma because of their anticholinergic media, otitis media with effusion, sinusitis, nasal polyps, and acute
effects and potential drying and inspissation of secretions. Recent RCTs and chronic nonspecific cough. However, their efficacy and safety
suggest that, although they are not medications of first choice for asthma, have not been confirmed in high-quality RCTs in patients with these
second (new)-generation H1 antihistamines provide indirect benefit in conditions.146–152
patients with concomitant seasonal asthma and allergic rhinitis and First (old)-generation H1 antihistamines are also used to relieve
are safe for use. nonspecific itching and to relieve intractable itching in patients with
In an 18-month study in very young children with atopic dermatitis polycythemia vera or those with hepatic disease or renal disease in
and house dust mite or grass sensitization at risk for development of which pruritis is not histamine-mediated. Lack of H1 antihistamine
asthma, regular administration of cetirizine was reported to delay asthma efficacy, leading to updosing and potential adverse effects, is a concern
onset. However, this observation was not confirmed with levocetirizine.3,5 in these clinical situations.
In addition, H1 antihistamines are used “off label” in many other
Anaphylaxis. A Cochrane review of 2070 H1 antihistamine studies diseases, including neurofibromatosis, eosinophilic gastroenteritis,
identified no RCTs that provided satisfactory evidence for use of this eosinophilic fasciitis, interstitial cystitis, aphthous ulceration, lichen
class of medications in anaphylaxis. The onset of action of oral H1 nitidus, rheumatoid arthritis, scleroderma, myotonic congenita, and
antihistamines is slow, ranging from 0.7 to 2.6 hours. Although they chronic fatigue syndrome. In most of these diseases, claims of H1 anti-
decrease itch and hives, H1 antihistamines do not prevent or relieve histamine efficacy are anecdotal and are not supported by RCTs: either
laryngeal edema, lower respiratory tract obstruction, hypotension, or such trials have not been performed, or they have been performed with
shock and are not lifesaving. First (old)-generation H1 antihistamines negative results.
such as diphenhydramine potentially impair recognition of anaphylaxis Interestingly, in malaria, RCTs do support the concomitant use of
symptoms. Improvement in anaphylaxis attributed to H1 antihistamine the first (old)-generation H1 antihistamine chlorpheniramine with the
treatment may reflect spontaneous improvement from endogenous antimalarial chloroquine or amodiaquine. Chlorpheniramine plays a
production of epinephrine, endothelin, angiotensin II, and other agents. cost-effective role by acting as a CYP inhibitor and increasing plasma
Epinephrine (adrenaline) is the lifesaving medication of choice for initial levels of the antimalarial to reverse drug resistance.153
use. Consequently there is a strong recommendation to “Never administer
H1 and H2 antihistamines or corticosteroids as initial therapy for ana- First (Old)-Generation H1 Antihistamines
phylaxis instead of epinephrine and consider these agents optional or Insomnia and Other Central Nervous System Symptoms. First
adjunctive therapy.”143 (old)-generation H1 antihistamines have a comparable sedative effect
First (old)-generation H1 antihistamines (diphenhydramine, chlor- to that of triazolam or ethanol. These drugs decrease the time elapsed
pheniramine) are available in parenteral formulations for intravenous before falling asleep but also may distort sleep architecture and cause
injection and remain in use in hospital settings for relief of itching rebound insomnia. Diphenhydramine, doxepin, doxylamine, and pyril-
and generalized hives in patients with anaphylaxis. The sedation amine are the most frequently used medications in the world for the
Potential Adverse Effects of First (Old)-Generation H1 Antihistamines
R1
N X
R2
Q
CNS H1 receptors Muscarinic receptors Serotonin receptors α-Adrenergic receptors Cardiac ion channels
(IKr, INa, and others)
↓ Alertness, cognition, ↑ Dry mouth ↑ Appetite ↑ Dizziness
learning, memory, ↑ Urinary retention ↑ Weight gain ↑ Postural hypotension ↑ QT interval
and psychomotor ↑ Sinus tachycardia ↑ Ventricular
performance arrhythmias
↑ Impairment with or
without sedation
Fig. 92.16 Mechanisms associated with potential adverse H1 antihistamine effects. First (old)-generation H1
antihistamines cross the blood-brain barrier and occupy central nervous system (CNS) H1 receptors, as docu-
mented by means of positron emission tomography. High H1-receptor occupancy correlates directly with
impairment of CNS function, with or without accompanying sedation. These medications also may cause
adverse effects through other mechanisms, such as their antimuscarinic and antiserotonin effects. IKr, Rapid
component of the delayed outward rectifying potassium channel; INa, rapid component of the inward rectify-
ing sodium channel. (From Simons FER, Simons KJ. Histamine and H1-antihistamines: celebrating a century
of progress. J Allergy Clin Immunol 2011;128:1139-50.)
treatment of insomnia and are effective when given in low doses, such Anxiety. Hydroxyzine is still used as an inexpensive treatment for
as 25 mg of diphenhydramine or 3 or 6 mg of doxepin once daily at anxiety disorders.3,5,159
bedtime. A systematic review on the efficacy of antihistamines to treat
insomnia reported small to moderate effect with fast tolerance develop-
ment.154,155 No metaanalysis on this topic is available. The European
ADVERSE EFFECTS
guidelines do not recommend the usage of sedating antihistamines to The risk of adverse effects from an H1 antihistamine is fundamen-
treat insomnia.154 tally associated with its chemical structure and functional classifica-
tion. First (old)-generation H1 antihistamines are more likely to cause
Sedation. Although not drugs of choice, first (old)-generation H1 known H1 antihistamine adverse effects than second (new)-generation
antihistamines such as diphenhydramine, hydroxyzine, and promethazine H1 antihistamines.3,5,160 First (old)-generation H1 antihistamines have
are still prescribed, often in combination with other medications, for been marketed to the medical profession and general public as safe
patients needing conscious sedation, perioperative sedation, and medications since the 1940s and 1950s, despite extensive documenta-
analgesia.156 tion of their adverse effects and toxicity during this period (Fig. 92.16
and Table 92.4). Even in standard doses, all these medications may
Nausea, Vertigo, and Motion Sickness. First (old)-generation H1 cause adverse effects in the central nervous system and elsewhere.75
antihistamines, including cinnarizine, dimenhydrinate, diphenhydramine, After accidental or intentional overdose, all first (old)-generation
meclizine, and promethazine, are among the limited therapeutic options H1 antihistamines may cause serious toxicity and, in the absence of
available for the prevention and treatment of vertigo and motion sick- supportive treatment, death.160 Some antihistamines (e.g., diphenhy-
ness. They block the signal sent through the histaminergic nervous dramine) are documented drugs of abuse.161 First (old)-generation
system from the vestibular nucleus to the vomiting center in the medulla. H1 antihistamines are not selective for the H1 receptor (Fig. 92.16).
Their impairing and sedating effects are widely recognized, and first Their antimuscarinic anticholinergic effects include mydriasis, dry
(old)-generation H1 antihistamines are contraindicated for use by pilots eyes, dry mouth, constipation, and urinary hesitancy and retention;
and others in safety-critical jobs that require a continuous high level antiserotonin effects include increased appetite and weight gain; and
of alertness. Second (new)-generation H1 antihistamines do not prevent anti-α-adrenergic effects include dizziness and orthostatic hypoten-
motion sickness.3,5,199,200 sion.23,162,163 These first-generation H1 antihistamines have also been
Dimenhydrinate, diphenhydramine, and promethazine are used for implicated in impairing the innate immune response to bacterial infec-
prevention and treatment of nausea and vomiting during the postop- tion, although this is more likely attributable to co-administered H2
erative period and after chemotherapy.182 Doxylamine is used to decrease antihistamines.164
nausea and vomiting in pregnancy.3,5,157,158
Central Nervous System
Movement Disorders. Diphenhydramine or cyproheptadine is still Histamine plays an important role in neurotransmission in the central
used to decrease rigidity and increase voluntary movement in some nervous system (CNS).165,166 It is produced in neurons with cell bodies
patients with dystonia and akathisia, including those who develop extra- located in the tuberomammillary nucleus of the posterior hypothalamus
pyramidal reactions during treatment with antipsychotic drugs. Cypro- that send their axons throughout the histaminergic nervous system in
heptadine is still used to treat serotonin syndrome and also for relief the cerebrum, cerebellum, posterior pituitary, and spinal cord. Histamine
of sweating during treatment with selective serotonin reuptake inhibitors has natural anticonvulsant activity and contributes to regulation of
(SSRIs). vigilance (alertness), cognition and learning, memory, and the circadian
TABLE 92.4 H1 Antihistamines: Potential Adverse Effects

Mechanism First (Old) Generationa,b Second (New) Generationb,c
Central Nervous System (CNS) Effects
Inhibition of After standard doses, there is potential impairment of alertness, cognition, Minimal or no adverse effects reported with bilastine
neurotransmitter effect learning, memory, and performance (especially of complex sensorimotor 10 mg, cetirizine 5 mg, desloratadine 5 mg,
of histamine at CNS tasks), with or without drowsiness, somnolence, fatigue, or sedation. fexofenadine 120 mg or 240 mg (standard doses),
H1 receptors Other potential CNS adverse effects include headache, dizziness, fexofenadine 360 mg (off-label dose), levocetirizine
confusion, agitation, behavioral changes (children), and less often, 5 mg, loratadine 10 mg, or rupatadine 10 mg.
dystonia, dyskinesia, and hallucinations. Except for fexofenadine, at higher doses these H1
antihistamines might cause dose-related CNS
effects in some adults with some allergic diseases.
Cardiac Effects
Antimuscarinic effects, Dose-related sinus tachycardia; reflex tachycardia, prolonged atrial Concerns are minimal in countries where regulatory
anti-α-adrenergic refractive period, and supraventricular arrhythmias potentially occur. agencies scrutinize second (new)-generation H1
effects, and blockade Prolongation of the QTc interval and ventricular arrhythmias reported antihistamines for potential cardiac toxicity and do
of cardiac ion currents after standard doses but more likely after overdose (see Toxicity after not approve them for use if identified.
(IKr, INa, Ito, IKi, and IKs) Overdose).
Other Potential Adverse Effects

Blockade of muscarinic, After standard doses: potential antimuscarinic effects include mydriasis None
serotonin, and (dilation of pupils), blurred vision, dry eyes, dry mouth, urinary retention/
α-adrenergic receptors hesitancy, constipation, erectile dysfunction, and memory deficits; these
Unknown mechanismsd H1 antihistamines are contraindicated in patients with glaucoma or
prostatic hypertrophy. Antiserotonin effects include appetite stimulation
and weight gain, especially with cyproheptadine and ketotifen.
Anti-α-adrenergic effects include peripheral vasodilation, orthostatic
hypotension, and dizziness.
Toxicity After Overdose

Multiple mechanisms In adults, potential CNS effects include extreme drowsiness, confusion, Up to 30-fold overdoses of cetirizine, fexofenadine,
delirium, coma, and respiratory depression. In infants and young children, and loratadine have not been causally associated
paradoxic excitation, irritability, hyperactivity, insomnia, hallucinations, with serious adverse events or fatality.
and seizures can precede coma and respiratory depression. Prolongation
of QTc interval and ventricular arrhythmias reported after overdose of
cyproheptadine, diphenhydramine, doxepin, hydroxyzine, promethazine,
and others. Adverse CNS effects typically predominate over adverse
cardiac effects. In untreated patients, death can occur within hours.
Drug Abuse
Through H1 receptors Euphoria, hallucinations, and “getting high” are reported for cyclizine, None reported
and other CNS diphenhydramine, dimenhydrinate, and others.
receptors
IKr, Rapid component of the delayed outward rectifying potassium current; INa, rapid component of the inward rectifying sodium current; Ito,
transient outward potassium current; IKi, inward rectifying current; IKs, slow component of the delayed rectifying potassium current.
a
Information about adverse effects and toxicity of first (old)-generation H1 antihistamines is based largely on descriptions in case reports and
case series since the 1940s. For example, promethazine is no longer recommended because it may cause sedation and respiratory depression/
arrest and by the intravenous route, vascular irritation, local necrosis, and gangrene. Applied topically to the skin, diphenhydramine or doxepin
may cause contact dermatitis, and when applied to abraded or thin skin, may also cause systemic adverse effects and rarely, death.
b
Nasal and ophthalmic formulations of H1 antihistamines are minimally absorbed and seldom cause systemic adverse effects. Some are
associated with a transient bitter or unpleasant taste sensation. Ophthalmic H1 antihistamines can cause stinging or burning on application.
These H1 antihistamines should be applied at least 10 minutes before contact lens insertion because the preservative benzalkonium chloride
0.01% in the formulations can cloud the lenses.
c
Information about relative lack of adverse effects from second (new)-generation H1 antihistamines is from prospective randomized placebo-
controlled trials in patients with allergic rhinitis or chronic urticaria and from occasional case reports of overdose with remarkable absence of
toxicity.
d
Both first (old)-generation and second (new)-generation H1 antihistamines are reported to cause rare adverse effects for which the mechanisms
are incompletely understood. These include agranulocytosis, fever, urticaria, anaphylaxis, hepatic enzyme elevation/hepatitis, fixed-drug
eruptions, and photosensitivity. Rhabdomyolysis has been reported after overdose with diphenhydramine and doxylamine.
Non-sedating
90
80
Bilastine (20 mg) 70
H1 receptor occupancy (%)

Olopatadine eye drop*
Fexofenadine (60 mg) 60
Fexofenadine (120 mg) 50
Levocetirizine (5 mg)
Epinastine (20 mg) 40
Ebastine (10 mg)
30
Loratadine (10 mg)
Terfenadine (60 mg) 20
Cetirizine (10 mg)
Olopatadine (5 mg) 10
Bepotastine (10 mg) 0
Azelastine (1 mg) 0 1 2 3
Mequitazine (3 mg) Proportional impairment ratio (2008)
Cetirizine (20 mg)
Astemizole (10 mg)
d-Chlorpheniramine (2 mg)
Oxatomide (30 mg)
Ketotifen eye drop*
Diphenhydramine (30 mg)
Hydroxyzine (30 mg)
Ketotifen (1 mg)
d-Chlorpheniramine (5 mg iv)
–10 0 10 20 30 40 50 60 70 80 90 100
Histamine H1 receptor occupancy (%)
Fig. 92.17 The sedative effects of H1 antihistamines is proportional to their CNS H1 receptor occupancy,
which varies considerably among drugs in this class. H1 receptor occupancy also varies with dose and route
of administration. First-generation H1 antihistamines such as chlorpheniramine, diphenhydramine, hydroxyzine,
ketotifen, and oxatomide have the highest CNS H1 receptor occupancy. (From Yanai K, Zhang D, Tashiro M,
et al. Positron emission tomography evaluation of sedative properties of antihistamines. Expert Opin Drug
Saf 2011;10:613-22.)
sleep-wake cycle, as well as to energy and endocrine homeostasis. First of H1 receptors occupied. More than 50% occupancy was detected upon
(old)-generation H1 antihistamines cross the BBB and interfere with application of eye drops of sedating antihistamines.176,177
neurotransmission in the histaminergic system.74,75,167–173 Impairment can be documented in the absence of CNS symptoms,
regardless of the patient population studied, the test used, the first-
First (Old)-Generation H1 Antihistamines. Use of positron emission generation H1 antihistamine given, or the dose given. Even in low doses
tomography (PET) to document H1 antihistamine penetration into the such as 2 mg of chlorpheniramine 2 mg or diphenhydramine 25 mg,
human brain provides objective criteria by which occupancy of H1 old H1 antihistamines potentially impair alertness, cognition, learning,
receptors can be directly related to effects on CNS function75,167,170–172,174 and rapid response/waking memory, especially during multitasking and
(Fig. 92.17). PET studies with 11C-doxepin as the positron-emitting performance of complex sensorimotor tasks, including divided-attention,
ligand (positive control) confirm that in standard or even low doses, critical tracking, and attention-switch tasks such as objectively monitored
first (old)-generation H1 antihistamines cross the BBB and occupy greater car driving.168,169,173,178–181
than 50% to 70% of the H1 receptors located on the presynaptic mem- The likelihood of CNS adverse effects is high; after ingestion of a
branes of histaminergic neurons throughout the CNS, especially in the first-generation H1 antihistamine in randomized double-blind crossover
frontal cortex, temporal cortex, hippocampus, and pons. High H1-receptor studies, only six participants are needed to demonstrate significant dif-
occupancy is associated with decreased histaminergic neurotransmission ferences between an old H1 antihistamine versus placebo or versus a
and impaired CNS function on objective testing, with or without associ- new H1 antihistamine169 (Fig. 92.18). This contrasts with the hundreds
ated sedation, drowsiness, fatigue, or somnolence.168 Based on the degree of participants per treatment group typically required in clinical trials
of H1-receptor occupancy after single-dose application, antihistamines to demonstrate clinical efficacy versus placebo, as in allergic rhinitis.
can be classified as sedating (more than 50%), less sedating (20% to Few studies involve objective tests of CNS function in children or elderly
50%), and nonsedating (Fig. 92.17). Percentages may increase upon patients, and the results are more variable in the studies in these age
repetitive application and drugs initially classified as nonsedating.175 groups.
No significant increase was observed in case of fexofenadine or bilas- The CNS adverse effects of the first (old)-generation H1 antihista-
tine.176 Because of the lack of a first-pass effect topical antihistamines mines are underestimated by health care professionals and by patients.
in the form of eye drops or nasal sprays result in a very high percentage As with ethanol and other CNS-active chemicals and medications,
Placebo
Fexofenadine 120 mg
14 Fexofenadine 180 mg 20
13 Fexofenadine 240 mg
* *
12
* Promethazine 10 mg
11 *p < .05
% Incorrect responses
15
Sleep latency (min)

10
9
8
7 10
6
5
4 5 * *
3 * * * *
0 0
–1.0 0.5 1.5 2.5 3.5 5.0 6.5 8.0 1.0 0.5 1.5 2.5 3.5 5.0 6.5 8.0
Pre-drug Post-drug Pre-drug Post-drug
A Time of test session (hr) B Time of test session (hr)
Fig. 92.18 Central nervous system effects of first (old)-generation versus second (new)-generation H1 anti-
histamines. First (old)-generation promethazine impairs psychomotor performance and increases sedation;
second (new)-generation fexofenadine does not. In a single-dose double-blind placebo controlled crossover
study in six participants, psychomotor performance tests included visual vigilance (A) and multiple sleep
latency tests (B). Compared with fexofenadine (120, 180, and 240 mg) or placebo, promethazine (10 mg)
significantly impaired vigilance at 2.5 to 5 hours and increased the likelihood of falling asleep, as assessed
by electroencephalograms in the multiple sleep latency tests between 1.5 and 3.5 hours after administration.
In contrast, at all test times, the effect of fexofenadine (120, 180, and 240 mg) did not differ from placebo
on any test. (Modified from data in Nicholson AN, Stone BM, Turner C, Mills SL. Antihistamines and aircrew:
usefulness of fexofenadine. Aviat Space Environ Med 2000;71:2-6.)
impairment is often subclinical and occurs long before drowsiness is effects of the antihistamine, although the sedative effects typically
perceived. The warnings contained in the package insert for these medi- predominate.
cations (e.g., may cause drowsiness; avoid activities requiring mental
alertness) are critically important in this high-technology era, in which Second (New)-Generation H1 Antihistamines. By definition, second-
mental alertness is required for most activities of daily life. Impaired generation H1 antihistamines do not cross the BBB readily.75 These
performance on school examinations, loss of productivity in the work- drugs are relatively free from adverse effects in standard doses and free
place, and on-the-job injuries are attributed to first (old)-generation from toxicity and fatality in overdose (Table 92.4). High-dose data is
H1 antihistamines. These medications are implicated as a cause of civil only available for fexofenadine in PET studies. Even in a high, off-label
(i.e., noncommercial, nonmilitary) aviation accidents and fatalities, and dose of 360 mg, it occupies CNS receptors minimally and does not
traffic accidents and fatalities, based on documentation of elevated impair cognitive function or cause sedation.169,181 By definition, all the
levels of H1 antihistamine (e.g., chlorpheniramine) in postmortem blood new H1 antihistamines impair CNS function significantly less than their
and tissue samples. In some jurisdictions, motorists faulted for causing predecessors,182 and in standard doses can be coadministered with alcohol,
traffic fatalities can be fined or imprisoned if they have taken a first lorazepam, and other CNS-active chemicals without exacerbation of
(old)-generation H1 antihistamine. For obvious reasons, commercial the impairment or sedation associated with these agents.183 Some,
and military aircraft pilots are prohibited from using these medications however, such as cetirizine may have CNS activity at higher doses.171
before or during flights.168,169,173,178–180 Regulatory agencies do not require screening of second (new)-
The adverse CNS effects of first-generation H1 antihistamines are generation H1 antihistamines for potential CNS adverse effects. Infor-
potentially exacerbated by concurrently ingested ethanol, benzodiaz- mation about the CNS safety of these medications can be obtained
epines, and other CNS-active chemicals. Driving performance has been from pharmacokinetic studies performed in healthy adults, elderly
reported to be worse after diphenhydramine ingestion than after alcohol patients, and those with impaired renal or hepatic function; from reported
ingestion sufficient to produce blood alcohol levels of 0.1%.181 adverse events in clinical trials; and from Phase-4 prescription event-
Some physicians recommend giving the old H1 antihistamine only monitoring studies in clinical practice.184
at bedtime so that somnolence will occur during the night. When taken
at bedtime, however, these H1 antihistamines increase the latency to Nasal and Ophthalmic H1 Antihistamines. Nasal and ophthalmic
onset of rapid eye movement sleep and reduce the duration of rapid formulations of H1 antihistamines are minimally absorbed through the
eye movement sleep.74,75,172 As noted in the previous section on Urti- nasal mucosa or conjunctivae, respectively. After application to the nasal
caria, the morning after, in patients who have CNS residual effects mucosa or the conjunctivae, first (old)-generation H1 antihistamines
such as impairment with or without sedation (antihistamine hangover), (e.g., ketotifen) are significantly less sedating than after administration
PET documents residual H1-receptor occupancy.174 Other physicians in oral formulations, where available for comparison.74
advise regular daytime use to develop tolerance to the adverse CNS
effects; however, on objective testing, tolerance may or may not be Cardiac Effects
confirmed. First (old)-generation H1 antihistamines are available in H1 antihistamines are among many medications that potentially prolong
fixed-dose combination with a decongestant to counteract the sedative the QTc interval and lead to cardiac arrhythmias, including polymorphic
ventricular tachycardia, with torsades de pointes, ventricular fibrillation, pointes develops, cardioversion and pacing should be instituted. In
and even death.39,185 Cardiac toxicity from H1 antihistamines is not an patients with H1 antihistamine-induced cardiac toxicity, some anti
HR1 effect but rather is caused by blockade of cardiac ion currents, arrhythmics are contraindicated because they also potentiate the QTc
such as the rapid component of the delayed outward rectifying potas- interval further.5,185
sium channel (IKr) or the rapid component of the inward rectifying In contrast, intentional or accidental overdose of second (new)-
sodium channel (INa)185 (Table 92.4). generation H1 antihistamines has not been reported to cause toxicity
In overdose, first (old)-generation H1 antihistamines poten- or fatality. A 6-year-old child who ingested 300 mg of loratadine and
tially cause cardiac effects such as prolongation of the QTc interval a 13-month-old child who ingested 180 mg of cetirizine developed only
and atrial and ventricular arrhythmias and may cause torsades de minimal symptoms.3,74
pointes.144,186,187
Several years after the second (new)-generation H1 antihistamines Vulnerable Patients
astemizole and terfenadine were introduced for clinical use, sporadic Many first (old)-generation H1 antihistamines remain in widespread
reports linked their administration with occurrence of torsades de pointes use in vulnerable patients with impaired hepatic or renal function,
and other potentially fatal ventricular arrhythmias. Subsequently, in elderly people, pregnant women, infants, and children, in whom
most countries, regulatory approval was withdrawn for these medica- their unfavorable benefit/risk ratio has been well documented195–210
tions. During the past 2 decades, regulatory agencies have mandated (Table 92.5).
extensive testing for potential cardiac toxicity of second (new)-generation Diphenhydramine and doxylamine are not expected to increase the
H1 antihistamines. This scrutiny begins during the preclinical and early risk of congenital malformations based on human and animal studies.
clinical studies of each H1 antihistamine and continues through Phase-2, Nevertheless some reports, which were either retrospective or hypothesis
3, and 4 studies, including long-term pharmacovigilance.39,185 generating, found associations of diphenhydramine with neural tube
Second (new)-generation H1 antihistamines such as bilastine,188 effects, facial clefts, or hypospadias. Importantly there was a signifi-
cetirizine, desloratadine, fexofenadine, levocetirizine,189 loratadine, and cant number of studies that did not report these findings or were not
rupatadine190 have been extensively investigated for potential cardiac able to replicate these findings. Some reports in rodents suggested an
toxicity, which has not been detected even when therapeutic doses are involvement of hydroxyzine in palate and skeletal malformations when
greatly exceeded. Lack of cardiac toxicity has also been confirmed in applied early in pregnancy and is considered to be contraindicated in
thousands of patients by using drug prescription event monitoring in early pregnancy. Based on available human data, no evidence of an
postmarketing surveillance studies. In the rare clinical reports where increased risk of teratogenicity was reported (www.reprotox.org). Preg-
cardiac toxicity has been attributed to one of these medications, causal- nant women who receive large therapeutic doses or take an overdose
ity has been deemed unlikely.5,189–192 of a first (old)-generation H1 antihistamine (e.g., diphenhydramine)
can experience oxytocin-like effects and uterine contractions as well as
Overdose Toxicity and Fatality other symptoms and signs of toxicity. Maternal ingestion of a first (old)-
Toxicity and fatality after overdose of first (old)-generation H1 antihis- generation H1 antihistamine before parturition can lead to irritability,
tamines were reported soon after these medications were introduced tremulousness, seizures, and respiratory depression in the neonate. A
for clinical use 70 years ago160 and still lead to tens of thousands of report describes a neonatal withdrawal syndrome in the context of
phone calls to poison control centers and emergency department visits a mother who took diphenhydramine in pregnancy because of her
in the United States every year. Evidence-based guidelines detail triage seasonal rhinitis.211
and management of diphenhydramine poisoning in adults and chil- H1 antihistamines are excreted in small amounts (less than 0.1% of
dren193,194 (Table 92.4). a maternal dose) in breast milk. Nursing infants whose mothers have
First (old)-generation H1 antihistamines such as brompheniramine, ingested first-generation H1 antihistamines can experience irritability
chlorpheniramine, cyproheptadine, dimenhydrinate, diphenhydramine, or drowsiness.212,213 In contrast, after maternal ingestion of second (new)-
and doxylamine remain widely available without prescription and are generation H1 antihistamines, neonates and nursing infants have not
used in suicide attempts. Palatable liquid formulations have been impli- been reported to develop symptoms.
cated in homicides of infants and young children. After accidental or
intentional overdose in infants and young children, paradoxic excitation Children
with irritability, hyperalertness, hallucinations, and seizures typically Adverse effects, toxicity, and fatalities from first (old)-generation H1
precedes drowsiness, confusion, delirium, coma, and respiratory depres- antihistamines such as diphenhydramine in infants and children have
sion. In patients of all ages, prominent features of overdose include been reported since the 1940s and 1950s.214 In this population, few
anticholinergic effects such as dryness of the mucous membranes, fever, short-term and no long-term RCTs of efficacy and safety of old H1
flushed face, pupillary dilation, urinary retention, decreased gastro- medications are available. Most publications relate to their adverse
intestinal motility, hypotension, and tachycardia.144,160,182–187 In patients effects. First-generation drugs are widely used off-label in atopic der-
with thin or abraded epidermis, topical H1 antihistamines such as matitis, cough, colds, and otitis media, despite lack of evidence for their
diphenhydramine or promethazine can produce toxic effects.160 efficacy and safety in these disorders. They are often given in mixtures
After H1 antihistamine overdose, monitoring of vital signs, includ- containing decongestants, analgesics, and other drugs. In some countries,
ing continuous electrocardiographic monitoring, should be instituted, regulatory agencies have mandated that many of these medications be
and CNS function should be monitored. Supportive measures should withdrawn from the market or relabeled as “not safe for use in children
be implemented promptly when needed. Rarely, hemodialysis is effec- less than 6 years of age.”195,197,203,205,209
tive in facilitating H1 antihistamine elimination.144,185–187,195 In patients In contrast, second (new)-generation H1 antihistamines such as
who have overdosed on a first (old)-generation H1 antihistamine such cetirizine, desloratadine, levocetirizine, loratadine, bilastine,215 and
as diphenhydramine, although CNS signs usually predominate, dose- rupatadine have been relatively well studied in the pediatric population,
dependent cardiac toxicity, including increased QTc interval and tor- including a short-term RCT of cetirizine in infants age 6 to 11 months.206
sades de pointes, can occur.144,185–187 If the QTc interval is prolonged, In randomized DBPC studies in atopic children age 1 to 3 years, no
the patient should be monitored until it normalizes. If torsades de long-term effects on behavioral, cognitive, or psychomotor development
TABLE 92.5 H1 Antihistamines: Potential Adverse Effects in Vulnerable Patients

Population First (Old)-Generation H1 Antihistamines Second (New)-Generation H1 Antihistamines
Patients with Few prospective studies are available. In these patients, including Clinical pharmacology (absorption, distribution, metabolism,
impaired hepatic those receiving hemodialysis, use of standard doses may be elimination) of most medications has been studied prospectively
or renal function associated with adverse effects, including central nervous system in these patients; specific instructions for reduction in dose or
(CNS) effects (e.g., impaired cognitive function, drowsiness). dose frequency are provided where relevant.
Elderly people Few randomized controlled trials of first (old)-generation H1 Clinical pharmacology of most medications has been studied
antihistamines are available. Elderly patients often use these prospectively in elderly patients; specific instructions for
drugs, which may impair cognition and memory and cause reduction in dose or dose frequency are provided where
inattention, disorganized speech, falls, incontinence, sedation, relevant.
altered consciousness, and delirium.
Pregnant and Pregnancy considerations: diphenhydramine (FDA label B) and for Pregnancy considerations: alcaftadine (FDA B), emedastine
lactating womena hydroxyzine, ketotifen and chlorpheniramine descriptive (FDA B), azelastine (FDA C), desloratadine (FDA C), epinastine
information is available (PLLR) (FDA C), levocetirizine (FDA B), olopatadine (FDA C) are categorized
In nursing infants, these drugs potentially cause irritability or in the old system and descriptive information is available for
drowsiness. fexofenadine, cetirizine, loratadine and bepotastine (PLLR).
No adverse CNS effects reported in nursing infants.
Neonates When given to the mother immediately before parturition, these No CNS adverse effects reported in neonates.
medications potentially cause irritability, seizures, drowsiness,
and respiratory depression in the neonate.
Infants and young These drugs are often assumed to be effective and safe in infants Long-term safety of cetirizine, desloratadine, fexofenadine,
children and children with allergies, coughs, and colds, either alone or in levocetirizine, and loratadine has been confirmed in young
a mixture with other medications, but are often associated with children.
adverse effects and occasionally with fatalities.b Since 2006,
regulatory agencies in the US and other countries have mandated
that more than 1500 pediatric oral allergy, cough, and cold
formulations containing first (old)-generation H1 antihistamines be
withdrawn from the market or relabeled as “not safe for use in
children less than 6 years.”
a
No medications, including H1 antihistamines, are classified as Pregnancy Category A (no risk) by the U.S. Food and Drug Administration (FDA).
The Pregnancy Category B designation means that medications are not teratogenic in animals and are therefore thought to be relatively low risk
in humans. Pregnancy Category C designates “teratogenicity in animals/adequate information about use in human pregnancies not yet available/
should therefore be used during pregnancy only if the expected benefits to the mother exceed the unknown risks to the fetus.”
b
First (old)-generation H1 antihistamines, particularly the phenothiazine class, have been associated with sudden infant death syndrome and
apparent life-threatening events, although causality has never been proved.
Pregnancy and Lactation Labeling Final Rule (PLLR) is effective since 2015, and the former classifications of A, B, C, D and X will be gradually
reorganized till 2020; for some drugs the descriptive information is available and is hallmarked with PLLR in the table.
have been found after cetirizine or levocetirizine administration daily tissue sites and affect their maturation, activation, polarization, and
for 18 months.191,198,208,216 A 12-month RCT of loratadine in young chil- other functions, leading to chronic inflammation. Histamine also regu-
dren documented no safety concerns198 (Table 92.5). Rupatadine displayed lates dendritic cells, T cells, and B cells; regulates related antibody isotype
comparable efficacy and safety in 2- to 11-year-old children with chronic responses; and, through HR2, it positively interferes with the peripheral
urticaria.217 antigen tolerance induced by T reg cells. The diverse effects of histamine
on immune regulation are caused by differential expression and regula-
Elderly Patients tion of four types of histamine receptors and their distinct intracellular
The brain is a sensitive target in old age, and elderly people are vulnerable signals. In addition, differences in affinity of these receptors for histamine
to adverse effects from any CNS-active chemical, including first (old)- are decisive for the biologic effects of histamine and drugs that target
generation H1 antihistamines. In hospitalized elderly patients, diphenhy- histamine receptors.
dramine administration has been associated with an increased risk of At H1 receptors, the molecular mechanisms of action of histamine
cognitive decline/dementia, delirium, inattention, disorganized speech, and H1 antihistamines involve inverse agonism. Second (new)-generation
altered consciousness, and need for urinary catheter placement.196,200,201,218 H1 antihistamines are preferred to first (old)-generation H1 antihista-
mines in the treatment of allergic rhinitis, allergic conjunctivitis, and
urticaria because the new H1 antihistamines have been investigated
SUMMARY AND FUTURE DIRECTIONS extensively with regard to clinical pharmacology, efficacy, and safety.
The cells involved in the regulation of immune responses and hema- They are significantly less likely to impair CNS function or cause seda-
topoiesis express histamine receptors and also secrete histamine. Mast tion or other adverse effects. The second-generation drugs are not caus-
cells and basophils are not the sole but are among the best-characterized ally linked with fatalities after overdose. Important advances include
sources of histamine release in the context of IgE-mediated allergic introduction of high (up to fourfold) doses of some second (new)-
responses. Histamine can selectively recruit the major effector cells into generation H1 antihistamines for effective and safe chronic urticaria
treatment and nasal and ophthalmic formulations with rapid onset of 11. Barcik W, Pugin B, Westermann P, et al. Histamine-secreting microbes
action (minutes) for allergic rhinitis and conjunctivitis. Using PET to are increased in the gut of adult asthma patients. J Allergy Clin
study H1 antihistamine penetration in the human brain, CNS H1-receptor Immunol 2016;138(5):1491–4.e7.
occupancy can now be directly related to CNS functional effects. Oral 12. Barcik W, Wawrzyniak M, Akdis CA, et al. Immune regulation by
histamine and histamine-secreting bacteria. Curr Opin Immunol
first (old)-generation H1 antihistamines are contraindicated in anyone
2017;48:108–13.
who requires alertness and ability to learn, remember, and perform 13. Sokolowska M, Akdis CA. Highlights in immune response, microbiome
complex tasks. Despite safety concerns, the old H1 antihistamines remain and precision medicine in allergic disease and asthma. Curr Opin
in use for insomnia and other CNS disorders as well as for motion Immunol 2017;48:iv–ix.
sickness and other vestibular disorders. 14. Dy M, Schneider E. Histamine-cytokine connection in immunity and
Further research is needed into the molecular mechanisms of action hematopoiesis. Cytokine Growth Factor Rev 2004;15(5):393–410.
of H1 antihistamines as inverse agonists and the molecular basis of their 15. MacGlashan D Jr. Histamine: a mediator of inflammation. J Allergy Clin
specificity for the H1 receptor. Additional clinical pharmacology studies Immunol 2003;112(4 Suppl.):S53–9.
and high-quality RCTs of H1 antihistamine efficacy and safety are needed, 16. Schneider E, Rolli-Derkinderen M, Arock M, et al. Trends in histamine
especially comparative studies of different second (new)-generation H1 research: new functions during immune responses and hematopoiesis.
Trends Immunol 2002;23(5):255–63.
antihistamines in allergic rhinitis, allergic conjunctivitis, chronic urti-
17. Akdis CA, Blaser K. Histamine in the immmune regulation of allergic
caria, and prevention of allergic reactions and additional RCTs in infants, inflammation. J Allergy Clin Immunol 2003;112:15–22.
children, and the elderly. Further comparative PET studies of old and 18. Jutel M, Watanabe T, Akdis M, et al. Immune regulation by histamine.
new H1 antihistamines need to correlate BBB penetration and CNS Curr Opin Immunol 2002;14(6):735–40.
H1-receptor occupancy as well as CNS functional effects. Ongoing pro- 19. Nakagawa S, Okaya Y, Yatsunami K, et al. Identification of multiple
spective observational studies of the safety of second (new)-generation regulatory elements of human L-histidine decarboxylase gene. J
H1 antihistamines are required in pregnancy.45,112 Biochem 1997;121(5):935–40.
Regarding other HR antihistamines, the H3 antihistamines lead to 20. Kuramasu A, Saito H, Suzuki S, et al. Mast cell-/basophil-specific
an increase in norepinephrine and might have an advantageous decon- transcriptional regulation of human L-histidine decarboxylase gene by CpG
gestant effect in patients with allergic rhinitis, administered with or methylation in the promoter region. J Biol Chem 1998;273(47):31607–14.
21. Yoshimoto T, Tsutsui H, Tominaga K, et al. IL-18, although antiallergic
without H1 antihistamines. The H4 antihistamines might play an impor-
when administered with IL-12, stimulates IL-4 and histamine release by
tant role in the downregulation of inflammation in patients with allergic basophils. Proc Natl Acad Sci USA 1999;96:13962–6.
rhinitis, administered with or without H1 antihistamines, in patients 22. Ohtsu H, Tanaka S, Terui T, et al. Mice lacking histidine decarboxylase
with atopic dermatitis, asthma, and other chronic inflammatory diseases. exhibit abnormal mast cells. FEBS Lett 2001;502:53–6.
Accelerated investigation of H3 antihistamines and H4 antihistamines 23. Tanaka S, Takasu Y, Mikura S, et al. Antigen-independent induction of
in allergic diseases is needed.219–222 histamine synthesis by immunoglobulin E in mouse bone
marrow-derived mast cells. J Exp Med 2002;196:229–35.
Acknowledgments 24. Yang XD, Ai W, Asfaha S, et al. Histamine deficiency promotes
The authors thank Dr. Mübeccel Akdis, Dr. Marek Jutel, and Dr. Keith inflammation-associated carcinogenesis through reduced myeloid
J. Simons for insightful discussions and long-term collaboration. They maturation and accumulation of CD11b+Ly6G+ immature myeloid
cells. Nat Med 2011;17(1):87–95.
also acknowledge the assistance of Lori McNiven.
25. Ash AS, Schild HO. Receptors mediating some actions of histamine.
1966. Br J Pharmacol 1997;120(4 Suppl.):302–14, discussion 300–1.
REFERENCES 26. Lovenberg TW, Roland BL, Wilson SJ, et al. Cloning and functional
expression of the human histamine H3 receptor. Mol Pharmacol
1. Jutel M, Blaser K, Akdis CA. Histamine receptors in immune regulation 1999;55(6):1101–7.
and allergen-specific immunotherapy. Immunol Allergy Clin North Am 27. Oda T, Morikawa N, Saito Y, et al. Molecular cloning and
2006;26(2):245–59, vii. characterization of a novel type of histamine receptor preferentially
2. O’Mahony L, Akdis M, Akdis CA. Regulation of the immune response expressed in leukocytes. J Biol Chem 2000;275:36781–6.
and inflammation by histamine and histamine receptors. J Allergy Clin 28. Le Coniat M, Traiffort E, Ruat M, et al. Chromosomal localization of the
Immunol 2011;128(6):1153–62. human histamine H1-receptor gene. Hum Genet 1994;94(2):186–8.
3. Simons FE. Advances in H1-antihistamines. N Engl J Med 29. Nakamura T, Itadani H, Hidaka Y, et al. Molecular cloning and
2004;351(21):2203–17. characterization of a new human histamine receptor, HH4R. Biochem
4. Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating a Biophys Res Commun 2000;279(2):615–20.
century of progress. J Allergy Clin Immunol 2011;128(6):1139–50.e4. 30. Kashiwakura JC, Ando T, Matsumoto K, et al. Histamine-releasing factor
5. Simons FER, Akdis AC. Histamine and H1-antihistamines. In: Adkinson has a proinflammatory role in mouse models of asthma and allergy. J
NF Jr, Bochner BS, Burks AW, et al, editors. Middleton’s allergy: Clin Invest 2012;122(1):218–28.
principles & practice. St. Louis: Mosby; 2013. p. 1503–33. 31. Yeh YC, Xie L, Langdon JM, et al. The effects of overexpression of
6. Akdis CA, Simons FE. Histamine receptors are hot in histamine releasing factor (HRF) in a transgenic mouse model. PLoS
immunopharmacology. Eur J Pharmacol 2006;533(1–3):69–76. ONE 2010;5(6):e11077.
7. Banu Y, Watanabe T. Augmentation of antigen receptor-mediated 32. Ando T, Kashiwakura JI, Itoh-Nagato N, et al. Histamine-releasing factor
responses by histamine H1 receptor signaling. J Exp Med enhances food allergy. J Clin Invest 2017;127(12):4541–3.
1999;189(4):673–82. 33. Togias A. H1-receptors: localization and role in airway physiology and in
8. Shimamura T, Shiroishi M, Weyand S, et al. Structure of the human immune functions. J Allergy Clin Immunol 2003;112(4 Suppl.):S60–8.
histamine H1 receptor complex with doxepin. Nature 34. Bakker RA, Schoonus SB, Smit MJ, et al. Histamine H(1)-receptor
2011;475(7354):65–70. activation of nuclear factor-kappa B: roles for G beta gamma- and G
9. Jutel M, Watanabe T, Klunker S, et al. Histamine regulates T-cell and alpha(q/11)-subunits in constitutive and agonist-mediated signaling.
antibody responses by differential expression of H1 and H2 receptors. Mol Pharmacol 2001;60(5):1133–42.
Nature 2001;413:420–5. 35. Aoki Y, Qiu D, Zhao GH, et al. Leukotriene B4 mediates histamine
10. Nijmeijer S, Leurs R, Vischer HF. Constitutive activity of the histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells.
H(1) receptor. Methods Enzymol 2010;484:127–47. Am J Physiol 1998;274(6 Pt 1):L1030–9.
36. Vanbervliet B, Akdis M, Vocanson M, et al. Histamine receptor H1 58. Morgan RK, McAllister B, Cross L, et al. Histamine 4 receptor activation
signaling on dendritic cells plays a key role in the IFN-gamma/IL-17 induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a
balance in T cell-mediated skin inflammation. J Allergy Clin Immunol murine model. J Immunol 2007;178(12):8081–9.
2011;127(4):943–53.e1–10. 59. Muller U, Hari Y, Berchtold E. Premedication with antihistamines may
37. Johansen P, Weiss A, Bünter A, et al. Clemastine causes immune suppression enhance efficacy of specific-allergen immunotherapy. J Allergy Clin
through inhibition of extracellular signal-regulated kinase-dependent Immunol 2001;107(1):81–6.
proinflammatory cytokines. J Allergy Clin Immunol 2011;128:1286–94. 60. Jutel M. Histamine receptor expression on peripheral blood CD4+
38. Del Valle J, Gantz I. Novel insights into histamine H2 receptor biology. lymphocytes is influenced by ultrarush bee venom immunotherapy.
Am J Physiol 1997;273(5 Pt 1):G987–96. Allergy 1997;52(Suppl. 37):88.
39. Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse 61. Müller UR, Jutel M, Reimers A, et al. Clinical and immunologic effects
agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy of H1 antihistamine preventive medication during honeybee venom
2002;32(4):489–98. immunotherapy. J Allergy Clin Immunol 2008;122(5):1001–7.e4.
40. Novak N, Mete N, Bussmann C, et al. Early suppression of basophil 62. Ferstl R, Frei R, Schiavi E, et al. Histamine receptor 2 is a key influence
activation during allergen-specific immunotherapy by histamine in immune responses to intestinal histamine-secreting microbes. J
receptor 2. J Allergy Clin Immunol 2012;130(5):1153–8.e2. Allergy Clin Immunol 2014;134(3):744–6.e3.
41. Frei R, Ferstl R, Konieczna P, et al. Histamine receptor 2 modifies 63. Smolinska S, Groeger D, Perez NR, et al. Histamine receptor 2 is
dendritic cell responses to microbial ligands. J Allergy Clin Immunol required to suppress innate immune responses to bacterial ligands in
2013;132(1):194–204. patients with inflammatory bowel disease. Inflamm Bowel Dis
42. Ferstl R, Frei R, Barcik W, et al. Histamine receptor 2 modifies iNKT cell 2016;22(7):1575–86.
activity within the inflamed lung. Allergy 2017;72(12):1925–35. 64. Church MK. Efficacy and tolerability of rupatadine at four times the
43. Leurs R, Bakker RA, Timmerman H, et al. The histamine H3 receptor: recommended dose against histamine- and platelet-activating
from gene cloning to H3 receptor drugs. Nat Rev Drug Discov factor-induced flare responses and ex vivo platelet aggregation in healthy
2005;4(2):107–20. males. Br J Dermatol 2010;163(6):1330–2.
44. Teuscher C, Subramanian M, Noubade R, et al. Central histamine H3 65. Church MK. Comparative inhibition by bilastine and cetirizine of
receptor signaling negatively regulates susceptibility to autoimmune histamine-induced wheal and flare responses in humans. Inflamm Res
inflammatory disease of the CNS. Proc Natl Acad Sci USA 2011;60(12):1107–12.
2007;104(24):10146–51. 66. Horak F, Zieglmayer P, Zieglmayer R, et al. The effects of bilastine
45. Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1 and compared with cetirizine, fexofenadine, and placebo on allergen-induced
H4 receptors in allergic inflammation: the search for new nasal and ocular symptoms in patients exposed to aeroallergen in the
antihistamines. Nat Rev Drug Discov 2008;7(1):41–53. Vienna Challenge Chamber. Inflamm Res 2010;59(5):391–8.
46. Brandes LJ, Queen GM, LaBella FS. Displacement of histamine from 67. Peña J1, Carbo ML, Solans A, et al. Antihistaminic effects of rupatadine and
liver cells and cell components by ligands for cytochromes P450. J Cell PKPD modelling. Eur J Drug Metab Pharmacokinet 2008;33(2):107–16.
Biochem 2002;85(4):820–4. 68. Abelson MB, Torkildsen GL, Williams JI, et al. Time to onset and
47. Tamási V, Fülöp AK, Hegyi K, et al. Upregulation of CYP2e1 and CYP3a duration of action of the antihistamine bepotastine besilate ophthalmic
activities in histamine-deficient histidine decarboxylase gene targeted solutions 1.0% and 1.5% in allergic conjunctivitis: a phase III,
mice. Cell Biol Int 2003;27(12):1011–15. single-center, prospective, randomized, double-masked,
48. Kazumori H, Ishihara S, Rumi MA, et al. Transforming growth placebo-controlled, conjunctival allergen challenge assessment in adults
factor-alpha directly augments histidine decarboxylase and vesicular and children. Clin Ther 2009;31(9):1908–21.
monoamine transporter 2 production in rat enterochromaffin-like cells. 69. Bohets H, McGowan C, Mannens G, et al. Clinical pharmacology of
Am J Physiol Gastrointest Liver Physiol 2004;286(3):G508–14. alcaftadine, a novel antihistamine for the prevention of allergic
49. Abernathy-Carver KJ, Sampson HA, Picker LJ, et al. Milk-induced conjunctivitis. J Ocul Pharmacol Ther 2011;27(2):187–95.
eczema is associated with the expansion of T cells expressing cutaneous 70. Torkildsen GL, Williams JI, Gow JA, et al. Bepotastine besilate
lymphocyte antigen. J Clin Invest 1995;95:913–18. ophthalmic solution for the relief of nonocular symptoms provoked by
50. Akdis M, Simon HU, Weigl L, et al. Skin homing (Cutaneous conjunctival allergen challenge. Ann Allergy Asthma Immunol
Lymphocyte-Associated Antigen-positive) CD8+ T cells respond to 2010;105(1):57–64.
superantigen and contribute to eosinophilia and IgE production in 71. Leurs R, Smit MJ, Timmerman H. Molecular and pharmacological
atopic dermatitis. J Immunol 1999;163:466–75. aspects of histamine receptors. Pharmacol Ther 1995;66:413–63.
51. Takahashi HK, Iwagaki H, Mori S, et al. Histamine inhibits 72. Yanai K, Son LZ, Endou M, et al. Targeting disruption of histamine H1
lipopolysaccharide-induced interleukin (IL)-18 production in human receptors in mice: behavioral and neurochemical characterization. Life
monocytes. Clin Immunol 2004;112(1):30–4. Sci 1998;62(17–18):1607–10.
52. Mazzoni A, Young HA, Spitzer JH, et al. Histamine regulates cytokine 73. Chen C, Hanson E, Watson JW, et al. P-glycoprotein limits the brain
production in maturing dendritic cells, resulting in altered T cell penetration of nonsedating but not sedating H1-antagonists. Drug
polarization. J Clin Invest 2001;108(12):1865–73. Metab Dispos 2003;31(3):312–18.
53. Ohtani T, Aiba S, Mizuashi M, et al. H1 and H2 histamine receptors are 74. Church MK, Maurer M, Simons FE, et al. Risk of first-generation
absent on Langerhans cells and present on dermal dendritic cells. J H(1)-antihistamines: a GA(2)LEN position paper. Allergy
Invest Dermatol 2003;121:1073–9. 2010;65(4):459–66.
54. Dijkstra D, Stark H, Chazot PL, et al. Human inflammatory dendritic 75. Yanai K, Zhang D, Tashiro M, et al. Positron emission tomography
epidermal cells express a functional histamine H(4) receptor. J Invest evaluation of sedative properties of antihistamines. Expert Opin Drug
Dermatol 2008;128(7):1696–703. Saf 2011;10(4):613–22.
55. Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta cooperate in the 76. Bailey DG. Fruit juice inhibition of uptake transport: a new type of
regulatory T cell response to mucosal allergens in normal immunity and food-drug interaction. Br J Clin Pharmacol 2010;70(5):645–55.
specific immunotherapy. Eur J Immunol 2003;33:1205–14. 77. Church MK, Gillard M, Sargentini-Maier ML, et al. From
56. Meiler F, Zumkehr J, Klunker S, et al. In vivo switch to IL-10-secreting T pharmacokinetics to therapeutics. Drug Metab Rev 2009;41(3):455–74.
regulatory cells in high dose allergen exposure. J Exp Med 78. Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and
2008;205(12):2887–98. pharmacodynamics of desloratadine, fexofenadine and levocetirizine: a
57. Simon T, Gogolák P, Kis-Tóth K, et al. Histamine modulates multiple comparative review. Clin Pharmacokinet 2008;47(4):217–30.
functional activities of monocyte-derived dendritic cell subsets via 79. Gupta SK, Kantesaria B, Banfield C, et al. Desloratadine dose selection
histamine receptor 2. Int Immunol 2012;24(2):107–16. in children aged 6 months to 2 years: comparison of population
pharmacokinetics between children and adults. Br J Clin Pharmacol 100. Simons KJ, Benedetti MS, Simons FE, et al. Relevance of H1-receptor
2007;64(2):174–84. occupancy to H1-antihistamine dosing in children. J Allergy Clin
80. Phan H, Moeller ML, Nahata MC. Treatment of allergic rhinitis in Immunol 2007;119(6):1551–4.
infants and children: efficacy and safety of second-generation 101. Jones DH, Romero FA, Casale TB. Time-dependent inhibition of
antihistamines and the leukotriene receptor antagonist montelukast. histamine-induced cutaneous responses by oral and intramuscular
Drugs 2009;69(18):2541–76. diphenhydramine and oral fexofenadine. Ann Allergy Asthma Immunol
81. Rodrigues WC, Castro C, Catbagan P, et al. Immunoassay screening of 2008;100(5):452–6.
diphenhydramine (Benadryl(R)) in urine and blood using a newly 102. Papadopoulos NG, Bernstein JA, Demoly P, et al. Phenotypes and
developed assay. J Anal Toxicol 2012;36(2):123–9. endotypes of rhinitis and their impact on management: a PRACTALL
82. Shon JH, Yoon YR, Hong WS, et al. Effect of itraconazole on the report. Allergy 2015;70(5):474–94.
pharmacokinetics and pharmacodynamics of fexofenadine in relation to the 103. Drugs for allergic disorders. Treat Guidel Med Lett 2010;8(90):9–18,
MDR1 genetic polymorphism. Clin Pharmacol Ther 2005;78(2):191–201. quiz 2 p following 18.
83. Simons FE, Simons KJ. Levocetirizine: pharmacokinetics and 104. Benninger M, Farrar JR, Blaiss M, et al. Evaluating approved
pharmacodynamics in children age 6 to 11 years. J Allergy Clin medications to treat allergic rhinitis in the United States: an
Immunol 2005;116(2):355–61. evidence-based review of efficacy for nasal symptoms by class. Ann
84. Nomeir AA, Mojaverian P, Kosoglou T, et al. Influence of food on the Allergy Asthma Immunol 2010;104(1):13–29.
oral bioavailability of loratadine and pseudoephedrine from 105. Bousquet J, Bachert C, Canonica GW, et al. Unmet needs in severe
extended-release tablets in healthy volunteers. J Clin Pharmacol chronic upper airway disease (SCUAD). J Allergy Clin Immunol
1996;36(10):923–30. 2009;124(3):428–33.
85. Solans A, Carbó ML, Peña J, et al. Influence of food on the oral 106. Brożek JL, Bousquet J, Agache I, et al. Allergic Rhinitis and its Impact on
bioavailability of rupatadine tablets in healthy volunteers: a single-dose, Asthma (ARIA) guidelines-2016 revision. J Allergy Clin Immunol
randomized, open-label, two-way crossover study. Clin Ther 2017;140(4):950–8.
2007;29(5):900–8. 107. Carr W, Bernstein J, Lieberman P, et al. A novel intranasal therapy of
86. Wolthers OD. Bilastine: a new nonsedating oral H1 antihistamine for azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy
treatment of allergic rhinoconjunctivitis and urticaria. Biomed Res Int Clin Immunol 2012;129(5):1282–9.e10.
2013;2013:626837. 108. Fantin S, Maspero J, Bisbal C, et al. A 12-week placebo-controlled study of
87. Paśko P, Rodacki T, Domagała-Rodacka R, et al. Second generation H1 rupatadine 10 mg once daily compared with cetirizine 10 mg once daily,
- antihistamines interaction with food and alcohol-A systematic review. in the treatment of persistent allergic rhinitis. Allergy 2008;63(7):924–31.
Biomed Pharmacother 2017;93:27–39. 109. Hellings PW, Dobbels F, Denhaerynck K, et al. Explorative study on patient’s
88. Day JH, Ellis AK, Rafeiro E, et al. Experimental models for the perceived knowledge level, expectations, preferences and fear of side effects for
evaluation of treatment of allergic rhinitis. Ann Allergy Asthma treatment for allergic rhinitis. Clin Transl Allergy 2012;2(1):9.
Immunol 2006;96(2):263–77, quiz 277–8, 315. 110. Kaliner MA, Berger WE, Ratner PH, et al. The efficacy of intranasal
89. Ellis AK, Soliman M, Steacy L, et al. The Allergic Rhinitis - Clinical antihistamines in the treatment of allergic rhinitis. Ann Allergy Asthma
Investigator Collaborative (AR-CIC): nasal allergen challenge protocol Immunol 2011;106(2 Suppl.):S6–11.
optimization for studying AR pathophysiology and evaluating novel 111. Lieberman P, Meltzer EO, LaForce CF, et al. Two-week comparison study
therapies. Allergy Asthma Clin Immunol 2015;11(1):16. of olopatadine hydrochloride nasal spray 0.6% versus azelastine
90. Ellis AK, Steacy LM, Hobsbawn B, et al. Clinical validation of controlled hydrochloride nasal spray 0.1% in patients with vasomotor rhinitis.
grass pollen challenge in the Environmental Exposure Unit (EEU). Allergy Asthma Proc 2011;32(2):151–8.
Allergy Asthma Clin Immunol 2015;11(1):5. 112. Stokes JR, Romero FA Jr, Allan RJ, et al. The effects of an H3 receptor
91. Hyo S, Fujieda S, Kawada R, et al. The efficacy of short-term antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis
administration of 3 antihistamines vs placebo under natural exposure to symptoms. J Allergy Clin Immunol 2012;129(2):409–12.e1–2.
Japanese cedar pollen. Ann Allergy Asthma Immunol 2005;94(4):457–64. 113. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and
92. Kitamura Y, Nakagawa H, Fujii T, et al. Effects of antihistamine on management of rhinitis: an updated practice parameter. J Allergy Clin
up-regulation of histamine H1 receptor mRNA in the nasal mucosa of Immunol 2008;122(2 Suppl.):S1–84.
patients with pollinosis induced by controlled cedar pollen challenge in 114. Bachert C, Bousquet J, Canonica GW, et al. Levocetirizine improves
an environmental exposure unit. J Pharmacol Sci 2015;129(3):183–7. quality of life and reduces costs in long-term management of persistent
93. Pfaar O, Calderon MA, Andrews CP, et al. Allergen exposure chambers: allergic rhinitis. J Allergy Clin Immunol 2004;114(4):838–44.
harmonizing current concepts and projecting the needs for the future 115. Canonica GW, Fumagalli F, Guerra L, et al. Levocetirizine in persistent
- an EAACI Position Paper. Allergy 2017;72(7):1035–42. allergic rhinitis: continuous or on-demand use? A pilot study. Curr Med
94. Tenn MW, Steacy LM, Ng CC, et al. Onset of action for loratadine Res Opin 2008;24(10):2829–39.
tablets for the symptomatic control of seasonal allergic rhinitis in adults 116. Laekeman G, Simoens S, Buffels J, et al. Continuous versus on-demand
challenged with ragweed pollen in the Environmental Exposure Unit: a pharmacotherapy of allergic rhinitis: evidence and practice. Respir Med
post hoc analysis of total symptom score. Allergy Asthma Clin Immunol 2010;104(5):615–25.
2018;14:5. 117. Grubbe RE, Lumry WR, Anolik R. Efficacy and safety of desloratadine/
95. Church MK, Maurer M. H(1)-antihistamines and urticaria: how can we pseudoephedrine combination vs its components in seasonal allergic
predict the best drug for our patient? Clin Exp Allergy rhinitis. J Investig Allergol Clin Immunol 2009;19(2):117–24.
2012;42(10):1423–9. 118. Hay JW, Kaliner MA. Costs of second-generation antihistamines in the
96. Frossard N, Strolin-Benedetti M, Purohit A, et al. Inhibition of treatment of allergic rhinitis: US perspective. Curr Med Res Opin
allergen-induced wheal and flare reactions by levocetirizine and 2009;25(6):1421–31.
desloratadine. Br J Clin Pharmacol 2008;65(2):172–9. 119. Bielory L. American Academy of Allergy, Asthma & Immunology–2008
97. Simons FE, Silver NA, Gu X, et al. Skin concentrations of H1-receptor annual meeting. IDrugs 2008;11(5):309–11.
antagonists. J Allergy Clin Immunol 2001;107(3):526–30. 120. Greiner JV, Edwards-Swanson K, Ingerman A. Evaluation of alcaftadine
98. Gillman S, Gillard M, Strolin Benedetti M. The concept of receptor 0.25% ophthalmic solution in acute allergic conjunctivitis at 15 minutes
occupancy to predict clinical efficacy: a comparison of second and 16 hours after instillation versus placebo and olopatadine 0.1. Clin
generation H1 antihistamines. Allergy Asthma Proc 2009;30(4):366–76. Ophthalmol 2011;5:87–93.
99. Simons FE, Early G. Prevention of Asthma in Atopic Children Study, 121. Mahvan TD, Buckley WA, Hornecker JR. Alcaftadine for the prevention
H1-antihistamine treatment in young atopic children: effect on of itching associated with allergic conjunctivitis. Ann Pharmacother
urticaria. Ann Allergy Asthma Immunol 2007;99(3):261–6. 2012;46(7–8):1025–32.
122. Mantelli F, Lambiase A, Bonini S, et al. Clinical trials in allergic 143. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis–a practice
conjunctivits: a systematic review. Allergy 2011;66(7):919–24. parameter update 2015. Ann Allergy Asthma Immunol
123. Torkildsen G, Shedden A. The safety and efficacy of alcaftadine 0.25% 2015;115(5):341–84.
ophthalmic solution for the prevention of itching associated with 144. Park JH, Godbold JH, Chung D, et al. Comparison of cetirizine and
allergic conjunctivitis. Curr Med Res Opin 2011;27(3):623–31. diphenhydramine in the treatment of acute food-induced allergic
124. Lambiase A, Micera A, Bonini S. Multiple action agents and the eye: do reactions. J Allergy Clin Immunol 2011;128(5):1127–8.
they really stabilize mast cells? Curr Opin Allergy Clin Immunol 145. de Silva HA, Pathmeswaran A, Ranasinha CD, et al. Low-dose
2009;9(5):454–65. adrenaline, promethazine, and hydrocortisone in the prevention of acute
125. Gong L, Sun X, Qu J, et al. Loteprednol etabonate suspension 0.2% adverse reactions to antivenom following snakebite: a randomised,
administered QID compared with olopatadine solution 0.1% double-blind, placebo-controlled trial. PLoS Med 2011;8(5):e1000435.
administered BID in the treatment of seasonal allergic conjunctivitis: a 146. Chang AB, Peake J, McElrea MS. Anti-histamines for prolonged
multicenter, randomized, investigator-masked, parallel group study in non-specific cough in children. Cochrane Database Syst Rev
Chinese patients. Clin Ther 2012;34(6):1259–72.e1. 2008;(2):CD005604.
126. Liu RF, Wu XX, Wang X, et al. Efficacy of olopatadine hydrochloride 147. Coleman C, Moore M. Decongestants and antihistamines for acute otitis
0.1%, emedastine difumarate 0.05%, and loteprednol etabonate 0.5% media in children. Cochrane Database Syst Rev 2008;(3):CD001727.
for Chinese children with seasonal allergic conjunctivitis: a randomized 148. De Sutter AI, van Driel ML, Kumar AA, et al. Oral
vehicle-controlled study. Int Forum Allergy Rhinol 2017;7(4):393–8. antihistamine-decongestant-analgesic combinations for the common
127. Simons FE. Prevention of acute urticaria in young children with atopic cold. Cochrane Database Syst Rev 2012;(2):CD004976.
dermatitis. J Allergy Clin Immunol 2001;107(4):703–6. 149. Griffin G, Flynn CA. Antihistamines and/or decongestants for otitis
128. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2)LEN/EDF/ media with effusion (OME) in children. Cochrane Database Syst Rev
WAO Guideline for the Definition, Classification, Diagnosis and 2011;(9):CD003423.
Management of Urticaria. The 2017 Revision and Update. Allergy 150. Meltzer EO, Hamilos DL. Rhinosinusitis diagnosis and management for
2018;73(7):1393–414. the clinician: a synopsis of recent consensus guidelines. Mayo Clin Proc
129. Guillen-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, et al. 2011;86(5):427–43.
Updosing nonsedating antihistamines in patients with chronic 151. Shaikh N, Wald ER, Pi M. Decongestants, antihistamines and nasal
spontaneous urticaria: a systematic review and meta-analysis. Br J irrigation for acute sinusitis in children. Cochrane Database Syst Rev
Dermatol 2016;175(6):1153–65. 2012;(9):CD007909.
130. Weller K, Ardelean E, Scholz E, et al. Can on-demand non-sedating 152. Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications
antihistamines improve urticaria symptoms? A double-blind, for acute cough in children and adults in ambulatory settings. Cochrane
randomized, single-dose study. Acta Derm Venereol 2013;93(2):168–74. Database Syst Rev 2012;(8):CD001831.
131. Potter PC, Kapp A, Maurer M, et al. Comparison of the efficacy of 153. Egan TJ, Kaschula CH. Strategies to reverse drug resistance in malaria.
levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic Curr Opin Infect Dis 2007;20(6):598–604.
urticaria patients. Allergy 2009;64(4):596–604. 154. Riemann D, Baglioni C, Bassetti C, et al. European guideline for the
132. Zuberbier T, Oanta A, Bogacka E, et al. Comparison of the efficacy and diagnosis and treatment of insomnia. J Sleep Res 2017;26(6):675–700.
safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of 155. Vande Griend JP, Anderson SL. Histamine-1 receptor antagonism for
chronic idiopathic urticaria: a multi-centre, double-blind, randomized, treatment of insomnia. J Am Pharm Assoc (2003) 2012;52(6):e210–19.
placebo-controlled study. Allergy 2010;65(4):516–28. 156. Roach CL, Husain N, Zabinsky J, et al. Moderate sedation for
133. Staevska M, Gugutkova M, Lazarova C, et al. Night-time sedating echocardiography of preschoolers. Pediatr Cardiol 2010;31(4):469–73.
H1-antihistamine increases daytime somnolence but not treatment 157. Golding JF, Gresty MA. Motion sickness. Curr Opin Neurol
efficacy in chronic spontaneous urticaria: a randomized controlled trial. 2005;18(1):29–34.
Br J Dermatol 2014;171(1):148–54. 158. Krystal AD, Durrence HH, Scharf M, et al. Efficacy and safety of
134. Cornillier H, Giraudeau B, Munck S, et al. Chronic spontaneous doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient
urticaria in children - a systematic review on interventions and trial of elderly subjects with chronic primary insomnia. Sleep
comorbidities. Pediatr Allergy Immunol 2018;29(3):303–10. 2010;33(11):1553–61.
135. Vena GA, Cassano N, Colombo D, et al. Cyclosporine in chronic 159. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety
idiopathic urticaria: a double-blind, randomized, placebo-controlled disorder. Cochrane Database Syst Rev 2010;(12):CD006815.
trial. J Am Acad Dermatol 2006;55(4):705–9. 160. Wyngaarden JB, Seevers MH. The toxic effects of antihistaminic drugs.
136. Siebenhaar F, Förtsch A, Krause K, et al. Rupatadine improves quality of J Am Med Assoc 1951;145(5):277–82.
life in mastocytosis: a randomized, double-blind, placebo-controlled 161. Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and
trial. Allergy 2013;68(7):949–52. detoxification: a brief review and case report. J Psychopharmacol
137. Karppinen A, Kautiainen H, Petman L, et al. Comparison of cetirizine, 2009;23(1):101–5.
ebastine and loratadine in the treatment of immediate mosquito-bite 162. Ratliff JC, Barber JA, Palmese LB, et al. Association of prescription H1
allergy. Allergy 2002;57(6):534–7. antihistamine use with obesity: results from the National Health and
138. Reunala T, Brummer-Korvenkontio H, Petman L, et al. Effect of ebastine Nutrition Examination Survey. Obesity (Silver Spring)
on mosquito bites. Acta Derm Venereol 1997;77(4):315–16. 2010;18(12):2398–400.
139. Karppinen A, Brummer-Korvenkontio H, Petman L, et al. Levocetirizine 163. Shi SJ, Platts SH, Ziegler MG, et al. Effects of promethazine and midodrine
for treatment of immediate and delayed mosquito bite reactions. Acta on orthostatic tolerance. Aviat Space Environ Med 2011;82(1):9–12.
Derm Venereol 2006;86(4):329–31. 164. St Peter SD, Sharp SW, Ostlie DJ. Influence of histamine receptor
140. Karppinen A, Brummer-Korvenkontio H, Reunala T, et al. Rupatadine antagonists on the outcome of perforated appendicitis: analysis from a
10 mg in the treatment of immediate mosquito-bite allergy. J Eur Acad prospective trial. Arch Surg 2010;145(2):143–6.
Dermatol Venereol 2012;26(7):919–22. 165. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system.
141. He A, Feldman SR, Fleischer AB Jr. An assessment of the use of Physiol Rev 2008;88(3):1183–241.
antihistamines in the management of atopic dermatitis. J Am Acad 166. Thakkar MM. Histamine in the regulation of wakefulness. Sleep Med
Dermatol 2018;79(1):92–6. Rev 2011;15(1):65–74.
142. Schmitt J, Buske-Kirschbaum A, Tesch F, et al. Increased 167. Kubo N, Senda M, Ohsumi Y, et al. Brain histamine H1 receptor
attention-deficit/hyperactivity symptoms in atopic dermatitis are occupancy of loratadine measured by positron emission topography:
associated with history of antihistamine use. Allergy 2018;73(3): comparison of H1 receptor occupancy and proportional impairment
615–26. ratio. Hum Psychopharmacol 2011;26(2):133–9.
168. McDonald K, Trick L, Boyle J. Sedation and antihistamines: an update. 190. Donado E, Izquierdo I, Pérez I, et al. No cardiac effects of therapeutic
Review of inter-drug differences using proportional impairment ratios. and supratherapeutic doses of rupatadine: results from a ‘thorough QT/
Hum Psychopharmacol 2008;23(7):555–70. QTc study’ performed according to ICH guidelines. Br J Clin Pharmacol
169. Nicholson AN, Stone BM, Turner C, et al. Antihistamines and aircrew: 2010;69(4):401–10.
usefulness of fexofenadine. Aviat Space Environ Med 2000;71(1):2–6. 191. Simons FE, Early G. Prevention of Asthma in Atopic Children Study,
170. Tashiro M, Duan X, Kato M, et al. Brain histamine H1 receptor Safety of levocetirizine treatment in young atopic children: an 18-month
occupancy of orally administered antihistamines, bepotastine and study. Pediatr Allergy Immunol 2007;18(6):535–42.
diphenhydramine, measured by PET with 11C-doxepin. Br J Clin 192. Tyl B, Kabbaj M, Azzam S, et al. Lack of significant effect of bilastine
Pharmacol 2008;65(6):811–21. administered at therapeutic and supratherapeutic doses and
171. Tashiro M, Kato M, Miyake M, et al. Dose dependency of brain concomitantly with ketoconazole on ventricular repolarization: results
histamine H(1) receptor occupancy following oral administration of of a thorough QT study (TQTS) with QT-concentration analysis. J Clin
cetirizine hydrochloride measured using PET with [11C]doxepin. Hum Pharmacol 2012;52(6):893–903.
Psychopharmacol 2009;24(7):540–8. 193. Bebarta VS, Blair HW, Morgan DL, et al. Validation of the American
172. Yanai K, Rogala B, Chugh K, et al. Safety considerations in the Association of Poison Control Centers out of hospital guideline for
management of allergic diseases: focus on antihistamines. Curr Med Res pediatric diphenhydramine ingestions. Clin Toxicol (Phila)
Opin 2012;28(4):623–42. 2010;48(6):559–62.
173. Zhuo X, Cang Y, Yan H, et al. The prevalence of drugs in motor vehicle 194. Scharman EJ, Erdman AR, Wax PM, et al. Diphenhydramine and
accidents and traffic violations in Shanghai and neighboring cities. Accid dimenhydrinate poisoning: an evidence-based consensus guideline for
Anal Prev 2010;42(6):2179–84. out-of-hospital management. Clin Toxicol (Phila) 2006;44(3):205–23.
174. Zhang D, Tashiro M, Shibuya K, et al. Next-day residual sedative effect 195. McKeown NJ, West PL, Hendrickson RG, et al. Survival after
after nighttime administration of an over-the-counter antihistamine diphenhydramine ingestion with hemodialysis in a toddler. J Med
sleep aid, diphenhydramine, measured by positron emission Toxicol 2011;7(2):147–50.
tomography. J Clin Psychopharmacol 2010;30(6):694–701. 196. Chang CM, Chen MJ, Tsai CY, et al. Medical conditions and medications
175. Senda M, Kubo N, Adachi K, et al. Cerebral histamine H1 receptor as risk factors of falls in the inpatient older people: a case-control study.
binding potential measured with PET under a test dose of olopatadine, Int J Geriatr Psychiatry 2011;26(6):602–7.
an antihistamine, is reduced after repeated administration of 197. Dart RC, Paul IM, Bond GR, et al. Pediatric fatalities associated with
olopatadine. J Nucl Med 2009;50(6):887–92. over the counter (nonprescription) cough and cold medications. Ann
176. Yanai K, Yoshikawa T, Yanai A, et al. The clinical pharmacology of Emerg Med 2009;53(4):411–17.
non-sedating antihistamines. Pharmacol Ther 2017;178:148–56. 198. Grimfeld A, Holgate ST, Canonica GW, et al. Prophylactic management
177. Inami A, Matsuda R, Grobosch T, et al. A simulated car-driving study on of children at risk for recurrent upper respiratory infections: the
the effects of acute administration of levocetirizine, fexofenadine, and Preventia I Study. Clin Exp Allergy 2004;34(11):1665–72.
diphenhydramine in healthy Japanese volunteers. Hum 199. Kurella Tamura M, Larive B, Unruh ML, et al. Prevalence and correlates
Psychopharmacol 2016;31(3):167–77. of cognitive impairment in hemodialysis patients: the Frequent
178. Canfield DV, Dubowski KM, Chaturvedi AK, et al. Drugs and alcohol Hemodialysis Network trials. Clin J Am Soc Nephrol 2010;5(8):1429–38.
found in civil aviation accident pilot fatalities from 2004-2008. Aviat 200. McEvoy LK, Smith ME, Fordyce M, et al. Characterizing impaired
Space Environ Med 2012;83(8):764–70. functional alertness from diphenhydramine in the elderly with
179. Officer J. Trends in drug use of Scottish drivers arrested under Section 4 performance and neurophysiologic measures. Sleep 2006;29(7):957–66.
of the Road Traffic Act–a 10 year review. Sci Justice 2009;49(4):237–41. 201. Meurer WJ, Potti TA, Kerber KA, et al. Potentially inappropriate
180. Walker BE, Patterson A. Induction of cleft palate in mice by tranquilizers medication utilization in the emergency department visits by older
and barbiturates. Teratology 1974;10(2):159–63. adults: analysis from a nationally representative sample. Acad Emerg
181. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, Med 2010;17(3):231–7.
diphenhydramine, and alcohol on driving performance. A randomized, 202. Ostroff C, Lee CE, McMeekin J. Unapproved prescription cough, cold,
placebo-controlled trial in the Iowa driving simulator. Ann Intern Med and allergy drug products: recent US Food and Drug Administration
2000;132(5):354–63. regulatory action on unapproved cough, cold, and allergy medications.
182. Tzanetos DB, Fahrenholz JM, Scott T, et al. Comparison of the sedating Chest 2011;140(2):295–300.
effects of levocetirizine and cetirizine: a randomized, double-blind, 203. Rimsza ME, Newberry S. Unexpected infant deaths associated with use
placebo-controlled trial. Ann Allergy Asthma Immunol 2011;107(6):517–22. of cough and cold medications. Pediatrics 2008;122(2):e318–22.
183. Garcia-Gea C, Ballester MR, Martínez J, et al. Rupatadine does not 204. Schwarz EB, Moretti ME, Nayak S, et al. Risk of hypospadias in offspring
potentiate the CNS depressant effects of lorazepam: randomized, of women using loratadine during pregnancy: a systematic review and
double-blind, crossover, repeated dose, placebo-controlled study. Br J meta-analysis. Drug Saf 2008;31(9):775–88.
Clin Pharmacol 2010;69(6):663–74. 205. Shehab N, Schaefer MK, Kegler SR, et al. Adverse events from cough and
184. Layton D, Osborne V, Gilchrist A, et al. Examining the utilization and cold medications after a market withdrawal of products labeled for
tolerability of the non-sedating antihistamine levocetirizine in England infants. Pediatrics 2010;126(6):1100–7.
using prescription-event monitoring data. Drug Saf 2011;34(12):1177–89. 206. Simons FE, Silas P, Portnoy JM, et al. Safety of cetirizine in infants 6 to
185. Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol 11 months of age: a randomized, double-blind, placebo-controlled
Toxicol 1996;36:233–52. study. J Allergy Clin Immunol 2003;111(6):1244–8.
186. Jo SH, Hong HK, Chong SH, et al. H(1) antihistamine drug promethazine 207. So M, Bozzo P, Inoue M, et al. Safety of antihistamines during
directly blocks hERG K(+) channel. Pharmacol Res 2009;60(5):429–37. pregnancy and lactation. Can Fam Physician 2010;56(5):427–9.
187. Nia AM, Fuhr U, Gassanov N, et al. Torsades de pointes tachycardia 208. Stevenson J, Cornah D, Evrard P, et al. Long-term evaluation of the
induced by common cold compound medication containing impact of the h1-receptor antagonist cetirizine on the behavioral,
chlorpheniramine. Eur J Clin Pharmacol 2010;66(11):1173–5. cognitive, and psychomotor development of very young children with
188. Graff C, Struijk JJ, Kanters JK, et al. Effects of bilastine on T-wave atopic dermatitis. Pediatr Res 2002;52(2):251–7.
morphology and the QTc interval: a randomized, double-blind, 209. Vassilev ZP, Kabadi S, Villa R. Safety and efficacy of over-the-counter
placebo-controlled, thorough QTc study. Clin Drug Investig cough and cold medicines for use in children. Expert Opin Drug Saf
2012;32(5):339–51. 2010;9(2):233–42.
189. Hulhoven R, Rosillon D, Letiexhe M, et al. Levocetirizine does not 210. Weber-Schoendorfer C, Schaefer C. The safety of cetirizine during
prolong the QT/QTc interval in healthy subjects: results from a pregnancy. A prospective observational cohort study. Reprod Toxicol
thorough QT study. Eur J Clin Pharmacol 2007;63(11):1011–17. 2008;26(1):19–23.
211. Parkin DE. Probable Benadryl withdrawal manifestations in a newborn 217. Potter P, Mitha E, Barkai L, et al. Rupatadine is effective in the treatment
infant. J Pediatr 1974;85(4):580. of chronic spontaneous urticaria in children aged 2-11 years. Pediatr
212. Ito S, Blajchman A, Stephenson M, et al. Prospective follow-up of Allergy Immunol 2016;27(1):55–61.
adverse reactions in breast-fed infants exposed to maternal medication. 218. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong
Am J Obstet Gynecol 1993;168(5):1393–9. anticholinergics and incident dementia: a prospective cohort study.
213. Moretti ME, Ito S, Koren G. Disposition of maternal ketoconazole in JAMA Intern Med 2015;175(3):401–7.
breast milk. Am J Obstet Gynecol 1995;173(5):1625–6. 219. Beaton G, Moree WJ. The expanding role of H1 antihistamines: a patent
214. Baker AM, Johnson DG, Levisky JA, et al. Fatal diphenhydramine survey of selective and dual activity compounds 2005-2010. Expert Opin
intoxication in infants. J Forensic Sci 2003;48(2):425–8. Ther Pat 2010;20(9):1197–218.
215. Novák Z, Yáñez A, Kiss I, et al. Safety and tolerability of bilastine 10 mg 220. Huang JF, Thurmond RL. The new biology of histamine receptors. Curr
administered for 12 weeks in children with allergic diseases. Pediatr Allergy Asthma Rep 2008;8(1):21–7.
Allergy Immunol 2016;27(5):493–8. 221. Walter M, Kottke T, Stark H. The histamine H(4) receptor: targeting
216. Simons FE. Prospective, long-term safety evaluation of the H1-receptor inflammatory disorders. Eur J Pharmacol 2011;668(1–2):1–5.
antagonist cetirizine in very young children with atopic dermatitis. 222. Yu F, Bonaventure P, Thurmond RL. The future antihistamines:
ETAC Study Group. Early Treatment of the Atopic Child. J Allergy Clin histamine H3 and H4 receptor ligands. Adv Exp Med Biol
Immunol 1999;104(2 Pt 1):433–40. 2010;709:125–40.
CHAPTER 92 Histamine and Antihistamines 1517.e1
SELF-ASSESSMENT QUESTIONS
1. Henrik is a 15-year-old adolescent with a known peanut, walnut, that requires a commute in the car, she schedules an appointment
and pecan allergy and a history of severe anaphylaxis to walnut with her allergist to ask for alternative treatments. Which treatment
requiring overnight hospital admission and two epinephrine appli- option is appropriate?
cations. He accidently ingested a baked product with walnut. Imme- a. Nonsedating, second-generation antihistamines are recommended
diately after ingestion he experiences coughing, tingling in the mouth, instead of a first-generation sedating antihistamine.
generalized pruritus, and some hives. What is the role of antihista- b. Topical nasal antihistamines are as effective as oral antihistamines.
mines in the acute management of this reaction? c. A combination of intranasal H1 antihistamines with intranasal
a. Sedating, first generation H1 antihistamines are useful tools to steroids or intranasal steroids alone is suggested if topical anti-
manage an acute anaphylaxis before the ambulance arrives since histamines do not show good clinical response.
they match intravenous formulations available in the emergency d. Patients on first-generation, sedating antihistamines should not
room and stop the allergic reaction. drive a car.
b. Antihistamines should always be given with epinephrine to make e. In addition to the symptomatic treatment, allergen-specific
sure they start working when epinephrine loses its effect. immunotherapy may be considered.
c. Antihistamines (H1 and H2) or corticosteroids should not be con- f. All of the above.
sidered as initial therapy for anaphylaxis instead of epinephrine. 3. Kathrin is a 2-year-old child with a body weight of 12 kg who drank
d. Antihistamines and corticosteroids should be given immediately about half of a bottle of diphenhydramine that was mistakenly left
to treat the respiratory symptoms and the pruritus. open; she consumed about 250 mg. Her mother brings her to the
e. None of the above. emergency department. What clinical symptoms may arise as a result
2. Stella is a 35-year-old woman who suffers each year from severe of such an overdose?
allergic rhinitis during the birch pollen season. For more than a. Somnolence
10 years she has self-medicated with oral diphenhydramine. She was b. QT prolongation
initially told that oral antihistamines are more effective and stayed c. Dry mouth, flushing, mydriasis
on her medication despite fatigue and sleepiness associated with the d. Vomiting
intake. Inspired by a friend and the fact that she is starting a new job e. All of the above

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92

Histamine and Antihistamines

SUMMARY OF IMPORTANT CONCEPTS INTRODUCTION

1900 1950 1990 2000

NH2 O HISTAMINE RECEPTORS

TABLE 92.1 Histamine Receptor Subtypes

both adenylate cyclase and phosphoinositide second-messenger systems

IgE+ memory B cell

IL-4 Th2 switch IgE

HR1 blocks humoral immunity, induces cellular immunity

H3R neuronal activation alters

H1R enhances IFN-γ H1R promotes H2R suppresses

Immune Regulation by Histamine-Secreting Bacteria. In addition Inactive

TABLE 92.2 H1 Antihistamines: Chemical and Functional Classification

TABLE 92.3 H1 Antihistamines: Pharmacokinetics and Pharmacodynamics in Healthy Adults

Second (New) Generation

Nasal/Ophthalmic H1 Antihistamine Formulationsd

100 of medication washout by continuous bathing of the nasal mucosa and

Percent wheal/flare suppression

Wheal or flare area (cm2)

Wheal or flare area (cm2)

Wheal suppression (%)

100 10h 8h 6h 4h 3h 2h 100 10h 8h 6h 4h

Flare suppression (%)

Beneficial Effects of H1 Antihistamines

Direct effects NF-κB– and calcium ion channel–modulated anti-allergic effects

CONTROL MEDICATION STEPS

Number of symptom-free patients

Potential Adverse Effects of First (Old)-Generation H1 Antihistamines

TABLE 92.4 H1 Antihistamines: Potential Adverse Effects

Other Potential Adverse Effects

Toxicity After Overdose

Bilastine (20 mg) 70

H1 receptor occupancy (%)

Sleep latency (min)

TABLE 92.5 H1 Antihistamines: Potential Adverse Effects in Vulnerable Patients

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