Histamine, Bradykinin, and
Their Antagonists
Randal A. Skidgel, Allen P. Kaplan,
and Ervin G. Erdös
The biogenic amine, histamine, is a major mediator of
inflammation, anaphylaxis, and gastric acid secretion;
in addition, histamine plays a role in neurotransmission.
Our understanding of the physiological and pathophys-
iological roles of histamine has been enhanced by the
development of subtype-specific receptor antagonists
and by the cloning of four receptors for histamine.
Competitive antagonists of H1 receptors have diverse
actions and are used therapeutically in treating aller-
gies, urticaria, anaphylactic reactions, nausea, motion
sickness, insomnia, and some symptoms of asthma.
Antagonists of the H2 receptor are effective in reducing
gastric acid secretion. The peptide, bradykinin, has car-
diovascular effects similar to those of histamine and
plays prominent roles in inflammation and nociception.
This chapter presents the physiology and patho-
physiology of histamine and kinins and the pharmacol-
ogy of the antagonists that inhibit responses to these
mediators.
HISTAMINE
History. The history of histamine (β-aminoethylimidazole) parallels
that of acetylcholine (ACh). Both were chemically synthesized
before their biological significance was recognized; they were first
detected as uterine stimulants in, and isolated from, extracts of ergot,
where they proved to be contaminants derived from bacterial action
(Dale, 1953).
Dale and Laidlaw subjected histamine to intensive pharmaco-
logical study (Dale, 1953), discovering that it stimulated a host of
smooth muscles and had an intense vasodepressor action.
Importantly, they observed that when a sensitized animal was
injected with a normally inert protein, the immediate responses
closely resembled those of poisoning by histamine. These observa-
tions anticipated by many years the finding that endogenous hista-
mine contributes to immediate hypersensitivity reactions and to
responses to cellular injury. Best and colleagues (1927) isolated
histamine from fresh samples of liver and lung, thereby establish-
ing it as a natural constituent of mammalian tissues, hence the name
histamine after the Greek word for tissue, histos. The presence of
histamine in tissue extracts delayed the acceptance of the discovery
of some peptide and protein hormones (e.g., gastrin) until the tech-
nology for separating the naturally occurring substances was suffi-
ciently advanced (Grossman, 1966).
Lewis and colleagues (Lewis, 1927) proposed that a sub-
stance with the properties of histamine (“H substance”) was liberated
from the cells of the skin by injurious stimuli, including the reaction
of antigen with antibody. We now know that endogenous histamine
plays a role in the immediate allergic response and is an important
regulator of gastric acid secretion. More recently, a role for hista-
mine as a modulator of neurotransmitter release in the central and
peripheral nervous systems has emerged.
Early suspicions that histamine acts through more than one
receptor have been borne out by the elucidation of four classes of
receptors, designated H1 (Ash and Schild, 1966), H2 (Black et al.,
1972), H3 (Arrang et al., 1987), and H4 (Leurs et al., 2009). H1 recep-
tors are blocked selectively by the classical “antihistamines.”
Second-generation H1 antagonists are collectively referred to as
nonsedating antihistamines. The term third generation has been
applied to some recently developed antihistamines, such as active
metabolites of first- or second-generation antihistamines that are not
further metabolized (e.g., cetirizine derived from hydroxyzine or fex-
ofenadine from terfenadine) or to antihistamines that have additional
therapeutic effects. However, the Consensus Group on New-
Generation Antihistamines concluded that none of the currently
available antihistamines can be classified as true third-generation
drugs, defined as lacking in cardiotoxicity, drug-drug interactions,
and CNS effects or with possible additional beneficial effects (e.g.,
anti-inflammatory) (Holgate et al., 2003). The discovery of H2 antag-
onists and their ability to inhibit gastric secretion has contributed
greatly to the resurgence of interest in histamine in biology and clin-
ical medicine (Chapter 45). H3 receptors were discovered as presy-
naptic autoreceptors on histamine-containing neurons that mediate
feedback inhibition of the release and synthesis of histamine. The
development of selective H3 receptor agonists and antagonists has
led to an increased understanding of the importance of H3 receptors
in histaminergic neurons in vivo. None of these H3 agonists or
912 antagonists has yet emerged as a therapeutic agent (Sander et al., mammalian tissues contain histamine in amounts
2008). The H4 receptor is most similar to the H3 receptor but is ranging from <1 to >100 μg/g. Concentrations in
expressed in cells of hematopoietic lineage; the availability of H4-
plasma and other body fluids generally are very low,
specific antagonists with anti-inflammatory properties should help to
but human cerebrospinal fluid (CSF) contains signif-
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS

define the biological roles of the H4 receptor (Thurmond et al., 2008).

Chemistry. Histamine is a hydrophilic molecule consisting of an
imidazole ring and an amino group connected by two methylene
groups. The pharmacologically active form is the monocationic
Nγ–H tautomer, which is the charged form of the species depicted in
Figure 32–1 (Ganellin and Parsons, 1982). H3 and H4 receptors have
a much higher affinity for histamine than H1 and H2 receptors, and
the four histamine receptors can be activated differently by analogs
of histamine (Venable and Thurmond, 2006) (Figure 32–1 and
Table 32–1). The specificities of histamine analogs were re-evalu-
ated after the discovery of the H4 receptor. Thus, 4-methylhistamine
and dimaprit, originally classified as H2 receptors (Black et al.,
1972), are full H4 agonists with a ~100-fold higher affinity for the
H4 receptor. A number of H3 agonists also are weaker agonists of
the H4 receptor (Lim et al., 2005; Venable and Thurmond, 2006).
Distribution and Biosynthesis of Histamine
Distribution. Histamine is widely, if unevenly, dis-
tributed throughout the animal kingdom and is pres-
ent in many venoms, bacteria, and plants. Almost all
icant amounts. The mast cell is the predominant stor-
age site for histamine in most tissues; the concentration
of histamine is particularly high in tissues that con-
tain large numbers of mast cells, such as skin,
bronchial mucosa, and intestinal mucosa.
Synthesis, Storage, and Metabolism. Histamine is
formed by the decarboxylation of the amino acid histi-
dine by the enzyme L-histidine decarboxylase (Figure
32-2), found in every mammalian tissue that contains
histamine. The chief site of histamine storage in most
tissues is the mast cell; in the blood, it is the basophil.
These cells synthesize histamine and store it in secre-
tory granules.
At the secretory granule pH of ~5.5, histamine is positively
charged and ionically complexed with negatively charged acidic
groups on other granule constituents, primarily proteases and
heparin or chondroitin sulfate proteoglycans. The turnover rate of

CH2CH2NH2

HN N

HISTAMINE

H1 RECEPTOR AGONISTS H2 RECEPTOR AGONISTS H3 + H4 RECEPTOR AGONISTS

CH2CH2NH2 H2N N NH2

C
C SCH2CH2CH2N(CH3)2
HN N N N NH3 H
HN
CH3 DIMAPRIT α-METHLYHISTAMINE
(R)-α

2-METHLYHISTAMINE

CH2CH2NH2 N H3C CH2CH2NH2

N H2N
S NH2 HN N

2-PYRIDYLETHYLAMINE AMTHAMINE 4-METHLYHISTAMINE

H3C CH2SCH2CH2HNCNHCH2CH2CH2 S NH2

S
NH NH
N HN N N NH HN N

2-THIAZOLYLETHYLAMINE IMPROMIDINE IMETIT

Figure 32–1. Structure of histamine and some H1, H2, H3, and H4 agonists- Dimaprit and 4-methylhistamine, originally identified as
specific H2 agonists, have a much higher affinity for the H4 receptor; 4-methylhistamine is the most specific available H4 agonist, with
~10-fold higher affinity than dimaprit, a partial H4 agonist. Impromidine is among the most potent H2 agonists but also is an antago-
nist at H1 and H3 receptors and a partial agonist at H4 receptors. (R)-α-Methylhistamine and imetit are high-affinity agonists of H3
receptors and lower-affinity full agonists at H4 receptors.
Table 32–1
Characteristics of Histamine Receptors
H1 H2 H3∗ H4
Size (amino acids) 487 359 329-445 390
G protein coupling Gq/11 Gs Gi/o Gi/o
(second messengers) (a Ca ; a NO
2+
(a cAMP) (b cAMP; (b cAMP; a Ca2+)
and a cGMP) a MAP kinase)
Distribution Smooth muscle, Gastric parietal CNS: presynaptic Cells of hematopoietic
endothelial cells, cells, cardiac origin
CNS muscle, mast
cells, CNS
Representative agonist 2-CH3-histamine Amthamine (R)-α-CH3-histamine 4-CH3-histamine
Representative Chlorpheniramine Ranitidine Tiprolisant JNJ7777120
antagonist
cAMP, cyclic AMP; cGMP, cyclic GMP; CNS, central nervous system; NO, nitric oxide.
*At least 20 alternately spliced H3 isoforms have been detected at the mRNA level. Eight of these isoforms, ranging in size from 329-445 residues,
were found to be functionally competent by binding or signaling assays (see Esbenshade et al., 2008)

histamine in secretory granules is slow, and when tissues rich in

COOH
mast cells are depleted of their histamine stores, it may take weeks
before concentrations return to normal levels. Non–mast cell sites CH2CH2NH2
of histamine formation include the epidermis, the gastric mucosa,
neurons within the CNS, and cells in regenerating or rapidly grow- HN N

ing tissues. Turnover is rapid at these non–mast cell sites because HISTIDINE
the histamine is released continuously rather than stored. Non–mast L-Histidine
cell sites of histamine production contribute significantly to the decarboxylase
daily excretion of histamine metabolites in the urine. Because
CH2CH2NH2
L -histidine decarboxylase is an inducible enzyme, the histamine-
forming capacity at such sites is subject to regulation. Histamine HN N
that is ingested or formed by bacteria in the gastrointestinal (GI)
HISTAMINE
tract does not contribute to the body’s stores; rather, it is rapidly
metabolized, and the metabolites are eliminated in the urine. N-Methyltransferase Diamine Oxidase
There are two major paths of histamine metabolism in
humans (Figure 32–2). The more important is ring methylation to
CH2CH2NH2 CH2COOH
form N-methylhistamine, catalyzed by histamine-N-methyltrans-
ferase, which is distributed widely. Most of the N-methylhistamine H3CN N HN N
formed is then converted to N-methylimidazole acetic acid by
monoamine oxidase (MAO), and this reaction can be blocked by N-METHYLHISTAMINE IMIDAZOLEACETIC ACID

MAO inhibitors (Chapters 8, 15, and 22). Alternatively, histamine Ribose Phosphoribosyl
may undergo oxidative deamination catalyzed mainly by the non- MAO-B transferase
specific enzyme diamine oxidase, yielding imidazole acetic acid, CH2COOH CH2COOH
which is then converted to imidazole acetic acid riboside. These
metabolites have little or no activity and are excreted in the urine. H3CN N Ribose—N N
Measurement of N-methylhistamine in urine affords a more reli-
N-METHYLIMIDAZOLE IMIDAZOLEACETIC ACID
able index of histamine production than assessment of histamine ACETIC ACID RIBOSIDE
itself. Artifactually elevated levels of histamine in urine arise from
Figure 32–2. Pathways of histamine synthesis and metabolism
genitourinary tract bacteria that can decarboxylate histidine. In in humans. Histamine is synthesized from histidine by decar-
addition, the metabolism of histamine appears to be altered in boxylation. Histamine is metabolized via two pathways, predom-
patients with mastocytosis such that determination of histamine inantly by methylation of the ring followed by oxidative
metabolites is a more sensitive diagnostic indicator of the disease deamination (left side of figure), and secondarily by oxidative
than histamine. deamination and then conjugation with ribose.
914 Release and Functions
of Endogenous Histamine
Histamine has important physiological roles. After its
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
release from storage granules as a result of the interac-
tion of antigen with immunoglobulin E (IgE) antibod-
ies on the mast cell surface, histamine plays a central
role in immediate hypersensitivity and allergic responses.
The actions of histamine on bronchial smooth muscle
and blood vessels account for many of the symptoms
of the allergic response. In addition, some drugs act
directly on mast cells to release histamine, causing
untoward effects. Histamine has a major role in regulat-
ing gastric acid secretion and also modulates neuro-
transmitter release.
Role in Allergic Responses. The principal target cells
of immediate hypersensitivity reactions are mast cells
and basophils (Schwartz, 1994). As part of the allergic
response to an antigen, IgE antibodies are generated
and bind to the surfaces of mast cells and basophils via
specific high-affinity Fc receptors. This receptor,
FcεRI, consists of α, β, and two γ chains (Chapter 35).
Atopic individuals develop IgE antibodies to com-
monly inhaled antigens. This is a heritable trait, confer-
ring a predilection to rhinitis, asthma, and atopic
dermatitis.
Antigen bridges the IgE molecules and via FcεRI activates
signaling pathways in mast cells or basophils involving tyrosine
kinases and subsequent phosphorylation of multiple protein sub-
strates within 5-15 seconds of contact with antigen. Protein kinases
implicated include the Src-related kinases Lyn and Syk. Prominent
among the phosphorylated proteins are the β and γ subunits of FcεRI,
itself, and phospholipase C (PLC)γ1 and PLCγ2, with consequent
production of inositol trisphosphate (IP3) and mobilization of intra-
cellular Ca2+ (Chapter 3). These events trigger the exocytosis of the
contents of secretory granules.
Release of Other Autacoids. The release of histamine
only partially explains the biological effects that ensue
from immediate hypersensitivity reactions because a
broad spectrum of other inflammatory mediators is
released on mast cell activation.
Stimulation of IgE receptors also activates phos-
pholipase A2 (PLA2), leading to the production of a host
of mediators, including platelet-activating factor (PAF)
and metabolites of arachidonic acid such as leukotrienes
C4 and D4, which contract the smooth muscles of the
bronchial tree ( Chapters 33 and 36). Kinins also are gen-
erated during some allergic responses. Thus, the mast
cell secretes a variety of inflammatory mediators in addi-
tion to histamine, each contributing to the major symp-
toms of the allergic response (see below).
Regulation of Mediator Release. The wide variety of
mediators released during the allergic response can
explain the ineffectiveness of drug therapy focused on a
single mediator. Agents that act at muscarinic or α-
adrenergic receptors increase the release of mediators,
an effect of little clinical significance. Epinephrine and
related drugs that act through β2 adrenergic receptors
increase cellular cyclic AMP and thereby inhibit the
secretory activities of mast cells. However, the benefi-
cial effects of β adrenergic agonists in allergic states such
as asthma are due mainly to relaxing bronchial smooth
muscle (Chapters 12 and 36).
Histamine Release by Drugs, Peptides, Venoms, and
Other Agents. Many compounds, including a large
number of therapeutic agents, stimulate the release of
histamine from mast cells directly and without prior
sensitization. Responses of this sort are most likely to
occur following intravenous injections of certain cate-
gories of substances, particularly organic bases such as
amides, amidines, quaternary ammonium compounds,
pyridinium compounds, piperidines, and alkaloids
(Rothschild, 1966). Tubocurarine, succinylcholine,
morphine, some antibiotics, radiocontrast media, and
certain carbohydrate plasma expanders also may elicit
the response. The phenomenon is one of clinical con-
cern, and may account for unexpected anaphylactoid
reactions. For example, vancomycin-induced red-man
syndrome, involving hypotension and flushing in the
upper body and face, may be mediated through hista-
mine release.
In addition to therapeutic agents, certain experimental com-
pounds stimulate the release of histamine as their dominant pharma-
cological characteristic. The archetype is the polybasic substance
known as compound 48/80. This is a mixture of low-molecular-
weight polymers of p-methoxy-N-methylphenethylamine, of which
the hexamer is most active.
Basic polypeptides often are effective histamine releasers,
and over a limited range, their potency generally increases with the
number of basic groups. For example, bradykinin is a poor hista-
mine releaser, whereas kallidin (Lys-bradykinin) and substance P,
with more positively charged amino acids, are more active. Some
venoms, such as that of the wasp, contain potent histamine-releasing
peptides (Johnson and Erdös, 1973). Polymyxin B also is very active.
Basic polypeptides released upon tissue injury constitute pathophys-
iological stimuli to secretion for mast cells and basophils.
Within seconds of the intravenous injection of a histamine
liberator, human subjects experience a burning, itching sensation.
This effect, most marked in the palms of the hand and in the face,
scalp, and ears, is soon followed by a feeling of intense warmth. The
skin reddens, and the color rapidly spreads over the trunk. Blood
pressure falls, the heart rate accelerates, and the subject usually com-
plains of headache. After a few minutes, blood pressure recovers, and
crops of hives usually appear on the skin. Colic, nausea, hypersecretion
of acid, and moderate bronchospasm also frequently occur. The
effect becomes less intense with successive injections as the mast
cell stores of histamine are depleted. Histamine liberators do not
deplete tissues of non–mast cell histamine.
Mechanism of Histamine-Releasing Agents. Histamine-
releasing substances activate the secretory responses of
mast cells and basophils by causing a rise in intracellular
Ca2+. Some are ionophores and directly facilitate the entry
of Ca2+ into the cell; others, such as neurotensin, act on
specific G protein–coupled receptors (GPCRs). In con-
trast, the precise mechanism by which basic secreta-
gogues (e.g., substance P, mastoparan, kallidin,
compound 48/80, and polymyxin B) release histamine
still is unclear. These agents can directly activate Gi pro-
teins after being taken up by the cell (Ferry et al., 2002),
but more recent evidence indicates the involvement of a
cell-surface GPCR in the Mas-related gene family or inte-
grin-associated protein CD47 coupled to Gi (Sick et al.,
2009). The downstream effectors appear to be βγ subunits
released from Gαi, which activate the PLCβ–IP3–Ca2+
pathway. Antigen–IgE complexes lead to mobilization of
stored Ca2+ and activation of isoforms of PLCγ, as
described in “Role in Allergic Responses.”
Histamine Release by Other Means. Clinical conditions related to
histamine release include cold, cholinergic, and solar urticaria. Some
of these involve specific secretory responses of the mast cells and
cell-fixed IgE. However, nonspecific cellular damage from any cause
can release histamine. The redness and urticaria that follow scratch-
ing of the skin is a familiar example.
Increased Proliferation of Mast Cells and Basophils and Gastric
Carcinoid Tumors. In urticaria pigmentosa (cutaneous mastocyto-
sis), mast cells aggregate in the upper corium and give rise to pig-
mented cutaneous lesions that sting when stroked. In systemic
mastocytosis, overproliferation of mast cells also is found in other
organs. Patients with these syndromes suffer a constellation of signs
and symptoms attributable to excessive histamine release, including
urticaria, dermographism, pruritus, headache, weakness, hypoten-
sion, flushing of the face, and a variety of GI effects, such as diar-
rhea or peptic ulceration. Episodes of mast cell activation with
attendant systemic histamine release are precipitated by a variety of
stimuli, including exertion, insect stings, exposure to heat, and expo-
sure to drugs that release histamine directly or to which patients are
allergic. In myelogenous leukemia, excessive numbers of basophils
are present in the blood, raising its histamine content to high levels
that may contribute to chronic pruritus. Gastric carcinoid tumors
secrete histamine, which is responsible for episodes of vasodilation
as part of the patchy “geographical” flush.
Gastric Acid Secretion. Histamine acting at H2 receptors is a pow-
erful gastric secretagogue, evoking a copious secretion of acid from
parietal cells (see Figure 45–1); it also increases the output of pepsin
and intrinsic factor. The secretion of gastric acid from parietal cells
also is caused by stimulation of the vagus nerve and by the enteric
hormone gastrin. However, histamine undoubtedly is the dominant
physiological mediator of acid secretion; blockade of H2 receptors 915
not only antagonizes acid secretion in response to histamine but also
inhibits responses to gastrin and vagal stimulation. (For regulation of
gastric acid secretion and the clinical utility of H2 antagonists, see
CHAPTER 32 HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
Chapter 45.)
Central Nervous System. There is substantial evidence that histamine
functions as a neurotransmitter in the CNS. Histamine-containing
neurons control both homeostatic and higher brain functions, includ-
ing regulation of the sleep-wake cycle, circadian and feeding
rhythms, immunity, learning, memory, drinking, and body tempera-
ture (see Haas et al., 2008). However, knockout animals lacking his-
tamine or its receptors exhibit only subtle defects unless challenged,
and no human disease has yet been directly linked to dysfunction of
the brain histamine system. Histamine, histidine decarboxylase,
enzymes that metabolize histamine, and H1, H2, and H3 receptors are
distributed widely but non-uniformly in the CNS (see Haas et al.,
2008). H1 receptors are associated with both neuronal and non-
neuronal elements (e.g., glia, blood cells, vessels) and are concen-
trated in regions that control neuroendocrine function, behavior, and
nutritional state. Distribution of H2 receptors is more consistent with
histaminergic projections than H1 receptors, suggesting that they
mediate many of the postsynaptic actions of histamine. H3 receptors
also are heterogeneously concentrated in areas known to receive his-
taminergic projections, consistent with their function as presynaptic
autoreceptors. Histamine inhibits appetite and increases wakefulness
via H1 receptors, explaining sedation by classical antihistamines
(Haas et al., 2008).
Pharmacological Effects
Receptor–Effector Coupling and Mechanisms of Action.
Histamine receptors are GPCRs (Leurs et al., 2009; Haas
et al., 2008; Thurmond et al., 2008) (Table 32–1). H1
receptors couple to Gq/11 and activate the PLC–IP3–Ca2+
pathway and its many possible sequelae, including
activation of PKC, Ca2+– calmodulin– dependent enzymes
(eNOS and various protein kinases), and PLA2. H2 recep-
tors link to Gs to activate the adenylyl cyclase–cyclic
AMP–PKA pathway, whereas H3 and H4 receptors cou-
ple to Gi/o to inhibit adenylyl cyclase and decrease cellu-
lar cyclic AMP. Activation of H3 receptors also can
activate MAP kinase and inhibit the Na+/H+ exchanger,
and activation of H4 receptors mobilizes stored Ca2+ in
some cells (Leurs et al., 2009; Haas et al., 2008;
Thurmond et al., 2008; Esbenshade et al., 2008). Armed
with this information, knowledge of the cellular expres-
sion of H receptor subtypes, and an understanding of the
differentiated functions of a particular cell type, one can
predict a cell’s response to histamine. Of course, in a
physiological setting, a cell is exposed to a myriad of hor-
mones simultaneously, and significant interactions may
occur between signaling pathways, such as the Gq → Gs
cross-talk described in a number of systems (Meszaros
et al., 2000). Furthermore, the differential expression
916 of H receptor subtypes on neighboring cells and the
unequal sensitivities of H receptor–effector response path-
ways can cause parallel and opposing cellular responses
to occur together, complicating interpretation of the over-
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
all response of a tissue. For example, activation of H1
receptors on vascular endothelium stimulates the Ca2+-
mobilizing pathway (Gq–PLC–IP3) and activates eNOS
to produce nitric oxide (NO), which diffuses to nearby
smooth muscle cells to increase cyclic GMP and cause
relaxation. Stimulation of H1 receptors on smooth muscle
also will mobilize Ca2+ but cause contraction, whereas
activation of H2 receptors on the same smooth muscle cell
will link via Gs to enhanced cyclic AMP accumulation,
activation of PKA, and thence to relaxation.
The existence of multiple histamine receptors was predicted
by the studies of Ash and Schild (1966) and Black and colleagues
(1972) a generation before the cloning of histamine receptors.
Similarly, heterogeneity of H3 receptors, predicted by kinetic and
radioligand-binding studies, has been confirmed by cloning, which
revealed H3 isoforms differing in the third intracellular loop, trans-
membrane helices 6 and 7, and C-terminal tail, and in their capacity
to couple Gi, inhibit adenylyl cyclase, and activate MAP kinase.
Molecular cloning studies also identified the H4 receptor.
As Figure 32–1 and Table 32–1 indicate, the pharmacologi-
cal definition of H1, H2, and H3 receptors is clear because relatively
specific agonists and antagonists are available. However, the H4
receptor exhibits 35-40% homology to isoforms of the H3 receptor,
and the two were harder to distinguish pharmacologically because
many high-affinity H3 ligands also interact with H4 receptors. Several
non-imidazole compounds that are more selective H3 antagonists
have been developed (Sander et al., 2008), and there are now several
selective H4 antagonists (Leurs et al., 2009; Venable and Thurmond,
2006). 4-Methylhistamine and dimaprit, previously identified as spe-
cific H2 agonists (Black et al., 1972), are actually more potent H4
agonists (Venable and Thurmond, 2006).
H1 and H2 Receptors. H1 and H2 receptors are distrib-
uted widely in the periphery and in the CNS.
Histamine can exert local or widespread effects on
smooth muscles and glands. It causes itching and stim-
ulates secretion from nasal mucosa. It contracts many
smooth muscles, such as those of the bronchi and gut,
but markedly relaxes others, including those in small
blood vessels. Histamine also is a potent stimulus of
gastric acid secretion (see “Gastric Acid Secretion”).
Other, less prominent effects include formation of
edema and stimulation of sensory nerve endings.
Bronchoconstriction and contraction of the gut are
mediated by H1 receptors. Gastric secretion results
from the activation of H2 receptors and, accordingly,
can be inhibited by H2 receptor antagonists. Some
responses, such as vascular dilation, are mediated by
both H1 and H2 receptor stimulation.
H3 and H4 Receptors. H3 receptors are expressed mainly
in the CNS (Arrang et al., 1987), especially in the basal
ganglia, hippocampus, and cortex. H3 receptors func-
tion as autoreceptors on histaminergic neurons, much
like presynaptic α2 receptors, inhibiting histamine release
and modulating the release of other neurotransmitters.
Because H3 receptors have high constitutive activity,
histamine release is tonically inhibited, and inverse ago-
nists will thus reduce receptor activation and increase
histamine release from histaminergic neurons. H3 ago-
nists promote sleep; thus, H3 antagonists promote
wakefulness. H4 receptors primarily are found in cells
of hematopoietic origin such as eosinophils, dendritic
cells, mast cells, monocytes, basophils, and T cells but
has also been detected in the GI tract, dermal fibrob-
lasts, CNS, and primary sensory afferent neurons
(Leurs et al., 2009). Activation of H4 receptors in some
of these cell types has been associated with induction of
cellular shape change, chemotaxis, secretion of
cytokines and upregulation of adhesion molecules, sug-
gesting that H4 antagonists may be useful inhibitors of
allergic and inflammatory responses (Thurmond et al.,
2008.
Effects on Histamine Release. H2 receptor stimulation
increases cyclic AMP and leads to feedback inhibition
of histamine release from mast cells and basophils,
whereas activation of H3 and H4 receptors has the oppo-
site effect by decreasing cellular cyclic AMP (Oda et al.,
2000). Activation of presynaptic H3 receptors also
inhibits histamine release from histaminergic neurons.
Histamine Toxicity from Ingestion. Histamine is the toxin in food poi-
soning from spoiled scombroid fish such as tuna (Morrow et al.,
1991). The high histidine content combines with a large bacterial
capacity to decarboxylate histidine, generating a lot of histamine.
Ingestion of the fish causes severe nausea, vomiting, headache, flush-
ing, and sweating. Histamine toxicity, manifested by headache and
other symptoms, also can follow red wine consumption in persons
with a diminished ability to degrade histamine. The symptoms of his-
tamine poisoning can be suppressed by H1 antagonists.
Cardiovascular System. Histamine characteristically
dilates resistance vessels, increases capillary permeabil-
ity, and lowers systemic blood pressure. In some vascu-
lar beds, histamine constricts veins, contributing to the
extravasation of fluid and edema formation upstream
in capillaries and postcapillary venules.
Vasodilation. This is the most important vascular effect
of histamine in humans. Vasodilation involves both H1
and H2 receptors distributed throughout the resistance
vessels in most vascular beds; however, quantitative dif-
ferences are apparent in the degree of dilation that
occurs in various beds. Activation of either the H1 or H2
receptor can elicit maximal vasodilation, but the
responses differ. H1 receptors have a higher affinity for
histamine and cause Ca2+-dependent activation of
eNOS in endothelial cells; NO diffuses to vascular
smooth muscle, increasing cyclic GMP (Table 32–1)
and causing relaxation that results in a relatively rapid
and short-lived vasodilation. By contrast, activation of
H2 receptors on vascular smooth muscle stimulates the
cyclic AMP–PKA pathway, causing dilation that devel-
ops more slowly and is more sustained. As a result, H1
antagonists effectively counter small dilator responses
to low concentrations of histamine but only blunt the
initial phase of larger responses to higher concentra-
tions of the amine. In addition, there is a variable distri-
bution of H1 receptors on vascular smooth muscle,
resulting in direct vasoconstrictor responses in vein,
skin, and skeletal muscle and in larger coronary arteries.
Increased “Capillary” Permeability. Histamine’s effect on
small vessels results in efflux of plasma protein and
fluid into the extracellular spaces and an increase lymph
flow, causing edema. H1 receptors on endothelial cells
are the major mediators of this response; the role of H2
receptors is uncertain.
Increased permeability results from histamine
activation of H1 receptors on postcapillary venules. This
contracts the endothelial cells, disrupts interendothelial
junctions, and exposes the basement membrane, which
is freely permeable to plasma proteins and fluid. The
gaps between endothelial cells also may permit passage
of circulating cells recruited to tissues during the mast
cell response. Recruitment of circulating leukocytes is
enhanced by H1 receptor–mediated expression of adhe-
sion molecules (e.g., P-selectin) on endothelial cells
(Thurmond et al., 2008).
Triple Response of Lewis. If histamine is injected intra-
dermally, it elicits a characteristic phenomenon known
as the triple response (Lewis, 1927). This consists of:
• a localized red spot extending for a few millimeters
around the site of injection that appears within a few
seconds and reaches a maximum in ~1 minute
• a brighter red flush, or “flare,” extending ~1 cm
beyond the original red spot and developing more
slowly
• a wheal that is discernible in 1-2 minutes and occu-
pies the same area as the original small red spot at
the injection site.
The initial red spot results from the direct vasodi-
lating effect of histamine (H1 receptor–mediated NO
production), the flare is due to histamine-induced
stimulation of axon reflexes that cause vasodilation 917
indirectly, and the wheal reflects histamine’s capacity to
increase capillary permeability (edema formation).
CHAPTER 32 HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
Constriction of Larger Vessels. Histamine tends to con-
strict larger blood vessels, in some species more than
in others. In rodents, the effect extends to the arterioles
and may overshadow dilation of the finer blood vessels,
leading to an elevation in blood pressure. As noted ear-
lier, H1 receptor–mediated constriction may occur in
some veins and in conduit coronary arteries.
Heart. Histamine affects both cardiac contractility and
electrical events directly. It increases the force of con-
traction of both atrial and ventricular muscle by pro-
moting the influx of Ca2+, and it speeds heart rate by
hastening diastolic depolarization in the sinoatrial (SA)
node. It also directly slows atrioventricular (AV) con-
duction to increase automaticity and, in high doses, can
elicit arrhythmias. The slowed AV conduction involves
mainly H1 receptors, while the other effects are largely
attributable to H2 receptors and cyclic AMP accumula-
tion. The direct cardiac effects of histamine given intra-
venously are overshadowed by baroreceptor reflexes
due to reduced blood pressure.
Histamine Shock. Histamine given in large doses or
released during systemic anaphylaxis causes a pro-
found and progressive fall in blood pressure. As the
small blood vessels dilate, they trap large amounts of
blood, their permeability increases, and plasma
escapes from the circulation. Resembling surgical or
traumatic shock, these effects diminish effective blood
volume, reduce venous return, and greatly lower car-
diac output.
Extravascular Smooth Muscle. Histamine directly con-
tracts or, more rarely, relaxes various extravascular
smooth muscles. Contraction is due to activation of H1
receptors on smooth muscle to increase intracellular
Ca2+ (in contrast to intact vessels, where endothelium-
derived NO causes vasodilation; see “Vasodilation”),
and relaxation is mainly due to activation of H2 recep-
tors. Responses vary widely among species and even
among humans. Bronchial smooth muscle of guinea
pigs is exquisitely sensitive. Minute doses of histamine
also will evoke intense bronchoconstriction in patients
with bronchial asthma and certain other pulmonary dis-
eases, but in normal humans, the effect is much less.
Although the spasmogenic influence of H1 receptors is
dominant in human bronchial muscle, H2 receptors with
dilator function also are present. Thus, histamine-
induced bronchospasm in vitro is potentiated slightly
918 by H2 blockade. In asthmatic subjects in particular, his-
tamine-induced bronchospasm may involve an addi-
tional reflex component that arises from irritation of
afferent vagal nerve endings (Nadel and Barnes, 1984).
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
The uterus of some species is contracted by histamine; in the
human uterus, gravid or not, the response is negligible. Responses of
intestinal muscle also vary with species and region, but the classical
effect is contraction. Bladder, ureter, gallbladder, iris, and many other
smooth muscle preparations are affected little or inconsistently by
histamine.
Peripheral Nerve Endings: Pain, Itch, and Indirect Effects. Histamine
stimulates various nerve endings and sensory effects. In the epider-
mis, it causes itch; in the dermis, it evokes pain, sometimes accom-
panied by itching. Stimulant actions on nerve endings, including
autonomic afferents and efferents, contribute to the “flare” compo-
nent of the triple response and to indirect effects of histamine on the
bronchi and other organs. In the periphery, neuronal receptors for
histamine are generally of the H1 type (see Rocha e Silva, 1978;
Ganellin and Parsons, 1982).
Clinical Uses
The practical application of histamine is limited to use
as a diagnostic agent, such as to assess nonspecific
bronchial hyperreactivity in asthmatics or as a positive
control injection during allergy skin testing.
H1 RECEPTOR ANTAGONISTS
History. Antihistamine activity was first demonstrated by Bovet
and Staub in 1937 with one of a series of amines with a phenolic
ether moiety. The substance 2-isopropyl-5-methylphenoxy-ethyl-
diethyl-amine protected guinea pigs against several lethal doses of
histamine but was too toxic for clinical use. By 1944, Bovet and his
colleagues had described pyrilamine maleate, an effective histamine
antagonist of this category. The discovery of the highly effective
diphenhydramine and tripelennamine soon followed (Ganellin and
Parsons, 1982). In the 1980s, nonsedating H1 histamine receptor
antagonists were developed for treatment of allergic diseases.
Despite success in blocking allergic responses to histamine, the H1
antihistamines failed to inhibit a number of other responses, notably
gastric acid secretion. The discovery of H2 receptors and H2 antag-
onists by Black and colleagues provided a new class of agents that
antagonized histamine-induced acid secretion (Black et al., 1972).
The pharmacology of these drugs (e.g., cimetidine, famotidine) is
described in Chapter 45.
Pharmacological Properties
Chemistry. All the available H1 receptor “antagonists” are
actually inverse agonists (see Chapter 3) that reduce con-
stitutive activity of the receptor and compete with hista-
mine (Haas et al., 2008): Whereas histamine binding to
the receptor induces a fully active conformation, antihis-
tamine binding yields an inactive conformation. At the
tissue level, the effect seen is proportional to receptor
occupancy by the antihistamine. Like histamine, many H1
antagonists contain a substituted ethylamine moiety.
C C N
Unlike histamine, which has a primary amino
group and a single aromatic ring, most H1 antagonists
have a tertiary amino group linked by a two-or three-
atom chain to two aromatic substituents and conform
to the general formula
Ar1
X C C N
Ar2
where Ar is aryl and X is a nitrogen or carbon atom or
a —C—O— ether linkage to the β-aminoethyl side
chain. Sometimes the two aromatic rings are bridged, as
in the tricyclic derivatives, or the ethylamine may be
part of a ring structure (Figure 32–3) (Ganellin and
Parsons, 1982).
Mechanism of Action. Most H1 antagonists have simi-
lar pharmacological actions and therapeutic applica-
tions. Their effects are largely predictable from
knowledge of the consequences of the activation of H1
receptors by histamine.
Effects on Physiological Systems.
Smooth Muscle. H1 antagonists inhibit most of the effects
of histamine on smooth muscles, especially the con-
striction of respiratory smooth muscle. For example, a
small dose of histamine causes death by asphyxia in
guinea pigs, yet the animal may survive a hundred
lethal doses of histamine if given an H1 antagonist. In
the same species, striking protection also is afforded
against anaphylactic bronchospasm. This is not so in
humans, where allergic bronchoconstriction appears to
be caused by a variety of alternative mediators, such as
leukotrienes (Chapter 33).
H1 antagonists inhibit both the vasoconstrictor
effects of histamine and, to a degree, the more rapid
vasodilator effects mediated by activation of H1 recep-
tors on endothelial cells (synthesis/release of NO and
other mediators). Residual vasodilation is due to H2
receptors on smooth muscle; administration of an H2
antagonist suppresses the effect. The efficacy of the his-
tamine antagonists on histamine-induced changes in
systemic blood pressure parallels these vascular effects.
Capillary Permeability. H1 antagonists strongly block the
increased capillary permeability and formation of
edema and wheal caused by histamine.

CH3
H C O CH2 CH2 N
CH3
DIPHENHYDRAMINE (an ethanolamine)
H3CO CH2
CH3
N CH2 CH2 N
CH3
N
PYRILAMINE (an ethylenediamine)
CH3
S N CH2 CH N
CH3
CH3
PROMETHAZINE (a phenothiazine)
Figure 32–3. Representative H1 antagonists.
Flare and Itch. H1 antagonists suppress the action of histamine on
nerve endings, including the flare component of the triple response
and the itching caused by intradermal injection.
Exocrine Glands. H1 antagonists do not suppress gastric secretion;
they do inhibit histamine-evoked salivary, lacrimal, and other
exocrine secretions, but with variable success. However, the antimus-
carinic properties of many H1 antagonists may contribute to lessened
secretion in cholinergically innervated glands and reduce ongoing
secretion in, e.g., the respiratory tree. Nasal sprays of some H1 antag-
onists can be used to treat allergic rhinitis.
Immediate Hypersensitivity Reactions: Anaphylaxis and
Allergy. During hypersensitivity reactions, histamine is
one of the many potent autacoids released (see “Release
of Other Autacoids”), and its relative contribution to the
ensuing symptoms varies widely with species and tis-
sue. The protection afforded by H1 antagonists thus also
varies accordingly. In humans, edema formation and
itch are effectively suppressed. Other effects, such as
hypotension, are less well antagonized. This may be
explained by the participation of other types of H recep-
tors and by effects of other mast cell mediators, chiefly
eicosanoids (Thurmond et al., 2008; Campbell and
Falck, 2007) (Chapter 25). Bronchoconstriction is
reduced little, if at all.
919
Cl
CH3
H C CH2 CH2 N
CH3
CHAPTER 32 HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
H
N
CHLORPHENIRAMINE (an alkylamine)
H C N N CH3
Cl
CHLORCYCLIZINE (a piperazine)
O OC2H5
C
N
N
Cl
LORATADINE (a tricyclic piperidine)
Central Nervous System. The first-generation H1 antago-
nists can both stimulate and depress the CNS.
Stimulation occasionally is encountered in patients
given conventional doses; they become restless, nerv-
ous, and unable to sleep. Central excitation also is a
striking feature of overdose, which commonly results
in convulsions, particularly in infants. Central depres-
sion, on the other hand, usually accompanies therapeu-
tic doses of the older H1 antagonists. Diminished
alertness, slowed reaction times, and somnolence are
common manifestations. Patients vary in their suscep-
tibility and responses to individual drugs. The
ethanolamines (e.g., diphenhydramine; Figure 32–3)
are particularly prone to causing sedation. Because of
the sedation that occurs with first-generation antihista-
mines, these drugs cannot be tolerated or used safely
by many patients except at bedtime. Even then, patients
may experience an antihistamine “hangover” in the
morning, resulting in sedation with or without psy-
chomotor impairment (Simons, 2003). Whether toler-
ance to such adverse effects results from protracted use
when administered in divided doses to patients with
chronic urticarial syndromes is unclear (Richardson
920 et al., 2002). Thus, the development of second-genera-
tion “nonsedating” antihistamines was an important
advance that allowed their general use. These newer H1
antagonists do not cross the blood-brain barrier appre-
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
ciably. Their sedative effects are similar to those of
placebo.
Many antipsychotic agents are H1 and H2 recep-
tor antagonists, but it is unclear whether this property
plays a role in the anti-psychotic effects of these agents.
The atypical anti-psychotic agent clozapine is an effec-
tive H1 antagonist and a weak H3 antagonist but an H4
receptor agonist in the rat. The H1 antagonist activity
of typical and atypical antipsychotic drugs is responsi-
ble for the effect of these agents to cause weight gain
(see Haas et al., 2008).
Anticholinergic Effects. Many of the first-generation H1 antago-
nists tend to inhibit responses to ACh that are mediated by mus-
carinic receptors and may be manifest during clinical use (see
below). Some H1 antagonists also can be used to treat motion sick-
ness (Chapters 9 and 46). Because scopolamine potently prevents
motion sickness, the anticholinergic properties of H1 antagonists
may be largely responsible for this effect. Indeed, promethazine has
perhaps the strongest muscarinic-blocking activity among these
agents and is the most effective H1 antagonist in combating motion
sickness. The second-generation H1 antagonists have no effect on
muscarinic receptors.
Local Anesthetic Effect. Some H1 antagonists have local anesthetic
activity, and a few are more potent than procaine. Promethazine
(phenergan) is especially active. However, the concentrations
required for this effect are much higher than those that antagonize
histamine’s interactions with its receptors.
Absorption, Distribution, and Elimination. The H1 antag-
onists are well absorbed from the GI tract. Following
oral administration, peak plasma concentrations are
achieved in 2-3 hours, and effects usually last 4-6
hours; however, some of the drugs are much longer act-
ing (Table 32–2).
Studies of the metabolic fate of the older H1 antagonists are
limited. Diphenhydramine, given orally, reaches a maximal concen-
tration in the blood in ~2 hours, remains there for another 2 hours,
then falls exponentially with a plasma elimination t1/2 of ~4-8 hours.
The drug is distributed widely throughout the body, including the
CNS. Little, if any, is excreted unchanged in the urine; most appears
there as metabolites. Other first-generation H1 antagonists can be
eliminated in much the same way (see Paton and Webster, 1985).
Peak concentrations of these drugs in the skin may persist after
plasma levels have declined. Thus, inhibition of “wheal and flare”
responses to the intradermal injection of histamine or allergen can
persist for ≥36 hours after treatment, even when the concentration in
plasma is low.
Like other extensively metabolized drugs, H1 antagonists are
eliminated more rapidly by children than by adults and more slowly
in those with severe liver disease. H1-receptor antagonists also
induce hepatic CYPs and thus may facilitate their own metabolism
(Paton and Webster, 1985).
The second-generation H1 antagonist loratadine is absorbed
rapidly from the GI tract and metabolized in the liver to an active
metabolite by CYPs (Chapter 6). Consequently, metabolism of lorata-
dine can be affected by other drugs that compete for the P450
enzymes. Two other second-generation H1 antagonists that were
marketed previously, terfenadine and astemizole, also were con-
verted by CYPs to active metabolites. Both of these drugs were
found in rare cases to induce a potentially fatal arrhythmia, torsades
de pointes, when their metabolism was impaired, such as by liver
disease or drugs that inhibit the CYP3A family (Chapter 29). This
led to the withdrawal of terfenadine and astemizole from the market
in 1998 and 1999, respectively. The active metabolite of terfenadine,
fexofenadine, is its replacement. Fexofenadine lacks the toxic side
effects of terfenadine, is not sedating, and retains the anti-allergic
properties of the parent compound (Meeves and Appajosyula, 2003).
Another antihistamine developed using this strategy is deslorata-
dine, an active metabolite of loratadine. Cetirizine, loratadine, and
fexofenadine are all well absorbed and are excreted mainly in the
unmetabolized form. Cetirizine and loratadine are excreted primarily
into the urine, whereas fexofenadine is excreted primarily in the
feces. Levocetirizine represents the active enantiomer of cetirizine.
Therapeutic Uses
H1 antagonists have an established place in the sympto-
matic treatment of various immediate hypersensitivity
reactions. The central properties of some of the drugs
also are of therapeutic value for suppressing motion
sickness or for sedation.
Allergic Diseases. H1 antagonists are most useful in
acute types of allergy that present with symptoms of
rhinitis, urticaria, and conjunctivitis. Their effect is con-
fined to the suppression of symptoms attributable to the
histamine released by the antigen-antibody reaction. In
bronchial asthma, histamine antagonists have limited
efficacy and are not used as sole therapy (Chapter 36).
In the treatment of systemic anaphylaxis, where auta-
coids other than histamine are important, the mainstay
of therapy is epinephrine; histamine antagonists have
only a subordinate and adjuvant role. The same is true
for severe angioedema, in which laryngeal swelling
constitutes a threat to life.
Other allergies of the respiratory tract are more amenable to
therapy with H1 antagonists. The best results are obtained in sea-
sonal rhinitis and conjunctivitis (hay fever, pollinosis), in which
these drugs relieve the sneezing, rhinorrhea, and itching of eyes,
nose, and throat. A gratifying response is obtained in most patients,
especially at the beginning of the season when pollen counts are low;
however, the drugs are less effective when the allergens are most
abundant, when exposure to them is prolonged, and when nasal con-
gestion is prominent. Nasal sprays or topical ophthalmic prepara-
tions of antihistamines such as levocabastine (discontinued in the
Table 32–2
Preparations and Dosage of Representative H1 Receptor Antagonistsa
CLASS AND DURATION
NONPROPRIETARY OF ACTION, SINGLE DOSE
NAME TRADE NAME HOURSb PREPARATIONSc (ADULT)
First-Generation Agents
Tricyclic Dibenzoxepins
Doxepin HCl SINEQUAN 6-24 O, L, T 10-150 mg
Ethanolamines
Carbinoxamine maleate RONDEC,fothers 3-6 O, L 4-8 mg
Clemastine fumarate TAVIST,
others 12 O, L 1.34-2.68 mg
Diphenhydramine HCl BENADRYL, others 12 O, L, I, T 25-50 mg
Dimenhydrinatee DRAMAMINE, others 4-6 O, L, I 50-100 mg
Ethylenediamines
Pyrilamine maleate POLY–HISTINE-Df 4-6 O, L, T 25-50 mg
Tripelennamine HCl PBZ 4-6 O 25-50 mg, 100 mg
(SR)
Tripelennamine citrate PBZ 4-6 L 37.5-75 mg
Alkylamines
Chlorpheniramine CHLOR-TRIMETON, 24 O, L, I 4 mg
maleate others 8-12 mg (SR)
5-20 mg (I)
Brompheniramine BROMPHEN, 4-6 O, L, I 4 mg
maleate others 8-12 mg (SR)
5-20 mg (I)
Piperazines
Hydroxyzine HCl ATARAX, others 6-24 O, L, I 25-100 mg
Hydroxyzine pamoate VISTARIL 6-24 O, L 25-100 mg
Cyclizine HCl MAREZINE 4-6 O 50 mg
Cyclizine lactate MAREZINE 4-6 I 50 mg
Meclizine HCl ANTIVERT, others 12-24 O 12.5-50 mg
Phenothiazines
Promethazine HCl PHENERGAN, others 4-6 O, L, I, S 12.5-50 mg
Piperidines
Cyproheptadine HClg PERIACTIN 4-6 O, L 4 mg
Phenindamine tartrate NOLAHIST 4-6 O 25 mg
Second-Generation Agents
Tricyclic
Dibenzoxepins PATANOL 6-8 T One drop/eye
Olopatadine HCl PATANASE 6-8 T Two sprays/nostril
Alkylamines
Acrivastined SEMPREX-Df 6-8 O 8 mg
Piperazines
Cetirizine HCld ZYRTEC 12-24 O 5-10 mg
Levocetirizine HCl XYZAL 12-24 O 2.5-5 mg

(Continued )
Table 32–2
Preparations and Dosage of Representative H1 Receptor Antagonistsa (Continued)
CLASS AND DURATION
NONPROPRIETARY OF ACTION, SINGLE DOSE
NAME TRADE NAME HOURSb PREPARATIONSc (ADULT)
Phthalazinones
Azelastine HCld ASTELIN 12-24 T Two sprays/nostril
Piperidines
Levocabastine HCl LIVOSTIN 6-12 T One drop/eye
Ketotifen fumarate ZADITOR 8-12 T One drop/eye
Loratadine CLARITIN 24 O, L 10 mg
Desloratadine CLARINEX, AERIUS 24 O 5 mg
Ebastine EBASTEL 24 O 10-20 mg
Mizolastine MIZOLLEN 24 O 10 mg
Fexofenadine HCl ALLEGRA, TELFAST 12-24 O 60-180 mg
HCl, hydrochloride.
a
For a discussion of phenothiazines, see Chapter 16.
b
The duration of action of H1 antihistamines by objective assessment of suppression of histamine- or allergen-induced symptoms is longer than might
be expected from measurement of plasma concentrations or terminal elimination t1/2 values. For a more complete discussion, see Simons, 2003.
c
Preparations are designated as follows: O, oral solids; L, oral liquids; I, injection; S, suppository; SR, sustained release; T, topical. Many H1 receptor
antagonists also are available in preparations that contain multiple drugs.
d
Has mild sedating effects.
e
Dimenhydrinate is a combination of diphenhydramine and 8-chlorotheophylline in equal molecular proportions.
f
Trade-name drug also contains other medications.
g
Also has anti-serotonin properties.

U.S.), azelastine (ASTELIN, ASTEPRO, nasal spray; OPTIVAR, ophthalmic
drops), emedastine (EMADINE, drops), epinastine (ELESTAT, drops),
ketotifen (ZADITOR, drops), and olopatadine (PATANOL, drops;
PATANASE, spray) are effective in allergic conjunctivitis and rhinitis.
H1 antihistamines have been investigated for potential anti-inflam-
matory properties because histamine releases inflammatory
cytokines and eicosanoids, increases expression of endothelial adhe-
sion molecules, and activates the pro-inflammatory transcription
factor NF-κB (Holgate et al., 2003; Thurmond et al., 2008).
Although H1 antihistamines do exhibit a variety of anti-inflamma-
tory effects in vitro and in animal models, in many cases the doses
required are higher than those normally achieved therapeutically,
and clinical effectiveness has not been proven (Holgate et al., 2003;
Thurmond et al., 2008). Rupatadine is a second-generation H1
antagonist (available in many countries outside the U.S.) that also
blocks receptors for the inflammatory phospholipid, PAF (Mullol et
al., 2008). Although rupatadine appears to have broader anti-inflam-
matory effects than other antihistamines, the clinical relevance of
these properties is unclear.
Certain allergic dermatoses respond favorably to H1 antago-
nists. The benefit is most striking in acute urticaria. Chronic urticaria
can be less responsive but also may require higher doses than has
been approved for rhinitis (Siebenhaar et al., 2009; Kaplan, 2002).
Furthermore, the combined use of H1 and H2 antagonists sometimes
is effective when therapy with an H1 antagonist alone has failed.
Angioedema also responds to treatment with H1 antagonists, but the
paramount importance of epinephrine in the severe attack must be
re-emphasized, especially in life-threatening laryngeal edema
(Chapter 12). In this setting, it may be appropriate to also adminis-
ter an H1 antagonist intravenously.
H1 antagonists have a place in the treatment of pruritus. Some
relief may be obtained in many patients with atopic and contact der-
matitis (although topical corticosteroids are more effective) and in
such diverse conditions as insect bites and poison ivy. Pruritus with-
out an allergic basis sometimes responds to antihistamine therapy.
However, the possibility of producing allergic dermatitis with local
application of H1 antagonists must be recognized. The urticarial and
edematous lesions of serum sickness respond to H1 antagonists, but
fever and arthralgia often do not.
Many drug reactions attributable to allergic phenomena
respond to therapy with H1 antagonists, particularly those character-
ized by itch, urticaria, and angioedema. However, explosive release
of histamine generally calls for treatment with epinephrine, with H1
antagonists being accorded a subsidiary role. Nevertheless, prophylactic
treatment with an H1 antagonist may reduce symptoms to a tol-
erable level when a drug known to be a histamine liberator is to
be given.
Common Cold. H1 antagonists are without value in combating the
common cold. The weak anticholinergic effects of the older agents
may tend to lessen rhinorrhea, but this drying effect may do more
harm than good, as may their tendency to induce somnolence.
Motion Sickness, Vertigo, and Sedation. Scopolamine, the muscarinic
antagonist, given orally, parenterally, or transdermally, is the most
effective drug for the prophylaxis and treatment of motion sickness.
Some H1 antagonists are useful for milder cases and have fewer
adverse effects. These drugs include dimenhydrinate and the piper-
azines (e.g., cyclizine, meclizine). Promethazine, a phenothiazine,
is more potent and more effective; its additional antiemetic proper-
ties may be of value in reducing vomiting, but its pronounced seda-
tive action usually is disadvantageous. Whenever possible, the
various drugs should be administered ~1 hour before the anticipated
motion. Treatment after the onset of nausea and vomiting rarely is
beneficial.
Some H1 antagonists, notably dimenhydrinate and meclizine,
often are of benefit in vestibular disturbances such as Meniere’s dis-
ease and in other types of true vertigo. Only promethazine is useful
in treating the nausea and vomiting subsequent to chemotherapy or
radiation therapy for malignancies; however, other, more effective
anti-emetic drugs (e.g., 5-HT3 antagonists) are available (Chapter
46). Diphenhydramine can reverse the extrapyramidal side effects
caused by phenothiazines ( Chapter 16).
The tendency of some H1 receptor antagonists to produce
somnolence has led to their use as hypnotics. H1 antagonists, prin-
cipally diphenhydramine, often are present in various proprietary
over-the-counter remedies for insomnia. Although these drugs gen-
erally are ineffective in the recommended doses, some sensitive indi-
viduals may derive benefit. The sedative and mild anti-anxiety
activities of hydroxyzine contribute to its use as a weak anxiolytic.
Adverse Effects. The most frequent side effect in first-
generation H1 antagonists is sedation. Although seda-
tion may be a desirable adjunct in the treatment of some
patients, it may interfere with the patient’s daytime
activities. Concurrent ingestion of alcohol or other CNS
depressants produces an additive effect that impairs
motor skills. Other untoward central actions include
dizziness, tinnitus, lassitude, incoordination, fatigue,
blurred vision, diplopia, euphoria, nervousness, insom-
nia, and tremors.
The next most frequent side effects involve the digestive tract
and include loss of appetite, nausea, vomiting, epigastric distress, and
constipation or diarrhea. Taking the drug with meals may reduce their
incidence. H1 antagonists such as cyproheptadine may increase
appetite and cause weight gain. Other side effects, owing to the
antimuscarinic actions of some first-generation H1 antagonists, include
dryness of the mouth and respiratory passages (sometimes inducing
cough), urinary retention or frequency, and dysuria. These effects are
not observed with second-generation H1 antagonists.
Drug allergy may develop when H1 antagonists are given
orally but occurs more commonly after topical application. Allergic
dermatitis is not uncommon; other hypersensitivity reactions include
drug fever and photosensitization. Hematological complications,
such as leukopenia, agranulocytosis, and hemolytic anemia, are very
rare. Because H1 antihistamines cross the placenta, caution is advised
for women who are or may become pregnant. Several antihistamines
(e.g., azelastine, hydroxyzine, fexofenadine) had teratogenic
effects in animal studies, whereas others (e.g., chlorpheniramine,
diphenhydramine, cetirizine, loratadine) did not (see Simons, 2003). 923
Antihistamines can be excreted in small amounts in breast milk, and
first-generation antihistamines taken by lactating mothers may cause
symptoms such as irritability, drowsiness, or respiratory depression
CHAPTER 32 HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
in the nursing infant (Simons, 2003). Because H1 antagonists inter-
fere with skin tests for allergy, they must be withdrawn well before
such tests are performed.
In acute poisoning with H1 antagonists, their central excita-
tory effects constitute the greatest danger. The syndrome includes
hallucinations, excitement, ataxia, incoordination, athetosis, and con-
vulsions. Fixed, dilated pupils with a flushed face, together with
sinus tachycardia, urinary retention, dry mouth, and fever, lend the
syndrome a remarkable similarity to that of atropine poisoning.
Terminally, there is deepening coma with cardiorespiratory collapse
and death usually within 2-18 hours. Treatment is along general
symptomatic and supportive lines.
Pediatric and Geriatric Indications and Problems. Although little clin-
ical testing has been done, second-generation antihistamines are rec-
ommended for elderly patients (>65 years of age), especially those
with impaired cognitive function, because of the sedative and anti-
cholinergic effects of first-generation drugs. Therapy should be
approached cautiously, possibly at reduced dosages, because of the
greater likelihood of compromised renal and hepatic function in
these patients, which can reduce drug elimination.
First-generation antihistamines are not recommended for use
in children because their sedative effects can impair learning and
school performance. The second-generation drugs loratadine, deslo-
ratadine, fexofenadine, cetirizine, levocetirizine, and azelastine
(intranasal) have been approved by the FDA for use in children and
are available in appropriate lower-dose formulations (e.g., chewable
or rapidly dissolving tablets, syrup).
Use of over-the-counter cough and cold medicines (containing
mixtures of antihistamines, decongestants, antitussives, expectorants)
in young children has been associated with serious side effects and
deaths (Kuehn, 2008). In 2008, the FDA recommended that they not be
used in children <2 years of age, and drug manufacturers affiliated with
the Consumer Healthcare Products Association voluntarily re-labeled
products “do not use” for children <4 years of age. The FDA is review-
ing the safety of these medicines in children aged 2-11 years.
Available H1 Antagonists. Summarized below are the
therapeutic side effects of a number of H1 antagonists,
grouped by their chemical structures. Representative
preparations are listed in Table 32–2.
Dibenzoxepin Tricyclics (Doxepin). Doxepin, the only drug in this
class, is marketed as a tricyclic antidepressant (Chapter 16). It also is
one of the most potent H1 antagonists and has significant H2 antagonist
activity, but this does not translate into greater clinical effectiveness.
It can cause drowsiness and is associated with anticholinergic effects.
Doxepin is better tolerated by patients with depression than those
who are not depressed, where even small doses (e.g., 20 mg) may
cause disorientation and confusion.
Ethanolamines (Prototype: Diphenhydramine). These drugs possess
significant antimuscarinic activity and have a pronounced tendency
to induce sedation. About half of those treated acutely with conven-
tional doses experience somnolence. The incidence of GI side
effects, however, is low with this group.
924 Ethylenediamines (Prototype: Pyrilamine). These include some of
the most specific H1 antagonists. Although their central effects are
relatively feeble, somnolence occurs in a fair proportion of patients.
GI side effects are quite common.
SECTION IV INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Alkylamines (Prototype: Chlorpheniramine). These are among the
most potent H1 antagonists. The drugs are less prone to produce
drowsiness and are more suitable for daytime use, but a significant
proportion of patients do experience sedation. Side effects involv-
ing CNS stimulation are more common than with other groups.
First-Generation Piperazines. The oldest member of this group, chlor-
cyclizine, has a more prolonged action and produces a comparatively
low incidence of drowsiness. Hydroxyzine is a long-acting com-
pound that is used widely for skin allergies; its considerable CNS-
depressant activity may contribute to its prominent anti-pruritic
action. Cyclizine and meclizine have been used primarily to counter
motion sickness, although promethazine and diphenhydramine are
more effective (as is the antimuscarinic scopolamine; see “H1
Antihistamines”).
Second-Generation Piperazines (Cetirizine). Cetirizine is the only
drug in this class. It has minimal anticholinergic effects. It also has
negligible penetration into the brain but is associated with a
somewhat higher incidence of drowsiness than the other second-gen-
eration H1 antagonists. The active enantiomer levocetirizine has
slightly greater potency and may be used at half the dose with less
resultant sedation.
Phenothiazines (Prototype: Promethazine). Most drugs of this class
are H1 antagonists and also possess considerable anticholinergic
activity. Promethazine, which has prominent sedative effects, and its
many congeners are used primarily for their antiemetic effects
(Chapter 37).
First-Generation Piperidines (Cyproheptadine, Phenindamine).
Cyproheptadine uniquely has both antihistamine and anti-serotonin
activity. Cyproheptadine and phenindamine cause drowsiness and
also have significant anticholinergic effects and can increase appetite.
Second-Generation Piperidines (Prototype: Terfenadine). Terfenadine
and astemizole were withdrawn from the market. Current drugs in
this class include loratadine, desloratadine, and fexofenadine. These
agents are highly selective for H1 receptors, lack significant anti-
cholinergic actions, and penetrate poorly into the CNS. Taken
together, these properties appear to account for the low incidence of
side effects of piperidine antihistamines.
H2 RECEPTOR ANTAGONISTS
The pharmacology and clinical utility of H2 antagonists to
inhibit gastric acid secretion are described in Chapter 45.
THE HISTAMINE H3 RECEPTOR
AND ITS ANTAGONISTS
The H3 receptor was characterized as a novel Gi-coupled
receptor using (R)-α-methylhistamine, a selective H3
agonist, and thioperamide, an antagonist (Arrang et al.,
1987). The cloning of its cDNA revealed it to be a
GPCR with low sequence identity (~20%) to H1 and H2
receptors (Lovenberg et al., 1999). Further studies on
the H3 receptor uncovered a variety of functional iso-
forms resulting from alternative splicing, many within
a pseudo-intron in the third intracellular loop that may
control constitutive activity (Arrang et al., 2007); this,
combined with the influence of cell type, signaling
pathway, and interspecies differences, yields H3 recep-
tors with a variety of binding and signaling properties
(Esbenshade et al., 2008).
H3 receptors are presynaptic autoreceptors on histaminergic
neurons that originate in the tuberomammillary nucleus in the hypo-
thalamus and project throughout the CNS, most prominently to the
hippocampus, amygdala, nucleus accumbens, globus pallidus, stria-
tum, hypothalamus, and cortex (Haas et al., 2008; Sander et al.,
2008). The activated H3 receptor depresses neuronal firing at the
level of cell bodies/dendrites and decreases histamine release from
depolarized terminals. Thus, H3 agonists decrease histaminergic
transmission, and antagonists increase it. H3 receptors also are presy-
naptic heteroreceptors on a variety of neurons in brain and periph-
eral tissues, and their activation inhibits release from noradrenergic,
serotoninergic, GABA-ergic, cholinergic, and glutamatergic neu-
rons, as well as pain-sensitive C fibers. H3 receptors in the brain have
significant constitutive activity in the absence of agonist, which
varies according to splicing isoform, cell type, and signaling path-
way stimulated; consequently, inverse agonists will activate these
neurons.
In the enterochromaffin-like cells of the stomach, H3 recep-
tors inhibit gastrin-induced release of histamine and, therefore,
decrease HCl secretion mediated by H2 receptors, but the effect is not
large enough to warrant development of therapeutic agents. H3 ago-
nists decrease tachykinin release from capsaicin-sensitive C-fiber
terminals and thereby reduce capsaicin-induced plasma extravasa-
tion and are antinociceptive. H3 agonists also depress exaggerated
catecholamine release in the heart (e.g., during ischemia).
By blocking H3 autoreceptors on histaminergic neurons and
H3 heteroreceptors on other neurons, H3 antagonists/inverse agonists
have a wide range of central effects; for example, they promote
wakefulness, improve cognitive function (e.g., enhance memory,
learning, and attention), and reduce food intake (Esbenshade et al.,
2008; Sander et al., 2008). As a result, there is considerable interest
in developing H3 antagonists for possible treatment of sleeping dis-
orders, attention-deficit hyperactivity disorder (ADHD), epilepsy,
cognitive impairment, schizophrenia, obesity, neuropathic pain, and
Alzheimer’s disease (Esbenshade et al., 2008; Sander et al., 2008).
However, this task is complicated by the heterogeneity in receptor
isoforms and signaling pathways, varying levels of constitutive H3
activity, species differences in ligand affinities, and the effects of H3
antagonists/inverse agonists on the release of neurotransmitters in
addition to histamine (e.g., DA, ACh, NE, GABA, glutamate, and
substance P) (Sander et al., 2008; Esbenshade et al., 2008). Although
drug development is focused on inverse agonists to block basal and
agonist-stimulated H3 activity, it is not yet clear that such drugs will
necessarily be clinically superior to neutral antagonists.