PHARMACOLOGY
Histamine and
antihistamines
Amr M Mahdy
Nigel R Webster
Abstract
Histamine is one of the most extensively studied biological amines in
medicine. It stimulates smooth muscle contraction and gastric acid secre-
tion, increases vascular permeability, functions as a neurotransmitter, and
plays various roles in immunomodulation, allergy, inflammation, haema-
topoiesis and cell proliferation. Histamine exerts its effects through four
receptors, designated H1eH4. H1 and H2 receptors are widely distrib-
uted, H3 receptors are mainly presynaptic, and H4 receptors are mainly
haematopoietic. H1 antihistamines are classified as first- and second-
generation compounds. First-generation compounds lack specificity and
cross the bloodebrain barrier causing sedation. Second-generation
compounds are less sedating and highly specific. H1 antihistamines
have well-documented anti-allergic and anti-inflammatory effects and
are well established in the treatment of a variety of allergic disorders.
First-generation antihistamines are also used in the treatment of vestib-
ular disorders and can be used as sedatives, sleeping aids and anti-
emetics. H2 antihistamines are widely used in the treatment of gastric
acid-related disorders; however, proton pump inhibitors are becoming
the drugs of first choice in some of these disorders. H3 antihistamines
are expected to be of potential value in the treatment of some cognitive
disorder. H4 antihistamines could be of potential therapeutic benefit in
the management of various immune and inflammatory disorders.
Keywords Antihistamines; histamine; histamine receptors
Histamine, 2-(4-imidazole)-ethylamine, was chemically synthe-
sized for the first time by Windaus and Vogt in 1907; however, it
was not until 1910 that Henry Dale and Patrick Laidlaw charac-
terized its biological effects. Since that date histamine has
become one of the most extensively studied biological amines in
medicine.
In addition to its well-known three functions (smooth muscle
contraction, increased vascular permeability and stimulation of
gastric acid secretion), histamine plays various roles in immu-
nomodulation, inflammation, regulation of cell proliferation and
differentiation, haematopoiesis, embryonic development, regen-
eration and wound healing. Moreover, as a neurotransmitter,
histamine is involved in the regulation of sleep and wakefulness,
Amr M Mahdy FRCA MD is a Consultant Anaesthetist at Aberdeen Royal
Infirmary and an Honorary Senior Lecturer at the University of
Aberdeen, UK. Conflict of interest: none declared.
Nigel R Webster FRCP FRCS is a Professor of Anaesthesia and Intensive
Care at the University of Aberdeen, UK. Conflict of interest: none
declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:7
Learning objectives
After reading this article you should be able to:
C describe the role of histamine in health and disease
C describe the four classes of histamine receptors
C understand the current and future clinical application of
antihistamine
cognition, memory, and energy and endocrine homeostasis. It
also modulates the release of several neurotransmitters through
presynaptic receptors located on histaminergic and non-
histaminergic neurones of the central and peripheral nervous
system.
Histamine also plays a pivotal role in the pathogenesis of
allergic inflammation. In response to an antigen, reaginic anti-
bodies of the immunoglobulin (Ig)E type are generated. These
antibodies bind to specific receptors expressed on the surface of
mast cells and basophils. The binding triggers a complex chain of
intracellular reactions leading to exocytosis and release of hista-
mine along with tryptase, leukotrienes and prostaglandins as well
as other mediators. Alternatively, histamine can be directly dis-
placed and released from its storage granules upon exposure to
certain organic bases, including drugs such as morphine and
tubocurarine. Subsequent binding of histamine to central and
peripheral histamine receptors leads to immediate, concentration-
dependent smooth muscle contraction in the respiratory and
gastrointestinal tracts, vasodilatation and sensory nerve stimula-
tion. These actions of histamine manifest clinically as erythema,
pruritus, nasal congestion, flushing, headache, hypotension,
tachycardia and bronchoconstriction. Moreover, in addition to its
role in the early allergic response, histamine acts as a stimulatory
signal for the production of cytokines and the expression of cell
adhesion molecules and class II antigens, thereby contributing to
the late allergic response.
Histamine is formed by decarboxylation of the amino acid
L-histidine in a reaction catalysed by the enzyme histidine decar-
boxylase (HDC). Mast cells, basophils, enterochromaffin-like cells
of the gastric mucosa, and histaminergic neurones synthesize
considerable amounts of histamine and store the mediator in
special storage granules inside the cells. Upon appropriate stimu-
lation, these cells can rapidly release relatively large amounts of
histamine and thereby efficiently activate suitable effector mech-
anisms. Apart from these histamine-storing cell types, many other
cells including epithelial cells and lymphocytes can express HDC
and synthesize histamine. However, in these cells, histamine is
immediately released and is not stored.
In humans, histamine is metabolized by histamine N-meth-
yltransferase to N-methylhistamine, which can be further
metabolized to N-methyl-imidazole acetic acid by the enzyme
monoamine oxidase. Alternatively, histamine can be metabo-
lized by diamine oxidase (DAO) to imidazole acetic acid, which
can be further conjugated to form imidazole acetic acid ribose. In
the gut wall, DAO is responsible for metabolizing dietary hista-
mine present in considerable amounts in certain foods, pre-
venting its uptake into the circulation. However, the DAO
pathway is not active in the central nervous system (CNS).
324 Ó 2011 Elsevier Ltd. All rights reserved.
 PHARMACOLOGY

Histamine receptors The histamine H3 receptor is found mainly in the central

nervous system (basal ganglia, hippocampus and cortical areas),
Histamine exerts its diverse biologic effects through four types of
but can also be found in the peripheral nervous system, airways,
receptors; H1, H2, H3 and H4 receptors (Table 1). Additionally,
the cardiovascular system, and the gastrointestinal tract. Acting
low-affinity intracellular non-H1, -H2, -H3, or -H4 receptors,
through presynaptic H3 receptor, histamine regulates its own
have been recently described in cell nuclei and microsomes,
release as well as the release of other neurotransmitters such as
although biologic functions at these receptors is still somewhat
noradrenaline, dopamine, serotonin, acetylcholine, and gamma-
unclear.
amino-butyric acid. In the lower airways, H3 receptors are
The H1 receptor is widely distributed throughout the body, with
located on postganglionic cholinergic nerves and defend against
well-documented expression in the CNS, smooth muscle, sensory
excess bronchoconstriction and in the upper airways, histamine
nerves, heart, adrenal medulla, and immune, endothelial, and
may play a role in nasal congestion through its activity at H3
epithelial cells. The H1 receptor mediates most of the postsynaptic
receptors.
effects of histamine within the central nervous system. Moreover,
The H4 receptor has been detected in bone marrow, periph-
through its activity at H1 receptors, histamine stimulates smooth
eral blood, spleen, thymus, lung, gastrointestinal tract, liver,
muscle contraction in the respiratory and gastrointestinal tract,
peripheral nerves, and central neurones. Nevertheless, cells that
stimulates sensory nerves leading to pruritus and sneezing, and
clearly express functional H4 receptors are mainly haemato-
increase vascular permeability leading to oedema. Simultaneous
poietic and include: mast cells, eosinophils, basophils, dendritic
activation of H1 and H2 receptor can also result in hypotension,
cells, and T cells. H4 receptor activation induces calcium mobi-
tachycardia, flushing, and headache.
lization in mast cells and mediates mast cells migration towards
The H2 receptor is also widely expressed and can be found in
histamine. Moreover the receptor plays a significant role in
gastric mucosal cells, heart, CNS, immune cells, and smooth
regulating dendritic and T-cell function.
muscles of the airway, vasculature, and uterus. H2 receptor
In general terms, the four histamine receptors can be
activation stimulates hydrochloric acid secretion from the acid-
described as heptahelical G-protein coupled receptors. They
secreting parietal cells of the gastric mucosa, leads to smooth
transduce extracellular signals through various G proteins, which
muscle relaxation in the vasculature and airways, increases
function as mediators between the cell surface receptors and the
cardiac rate and contractility, and mediates some of the immu-
intracellular second messenger systems.
nomodulatory effects of histamine.

Histamine receptor subtypes along with their selective agonists, inverse agonists/antagonists, G-protein coupling and
signal transduction
Receptor subtype H1 H2 H3 H4

G-protein coupling Gq/11 Gs Gi/o Gi/o

Signal transduction C Phospholipase C activation / C Adenylate cyclase C Adenylate cyclase inhibition / C Adenylate cyclase

[ IP3 and DAG / activation / Y cAMP inhibition /

[ Intracellular Ca and protein [ cAMP / C MAPK pathway activation Y cAMP
kinase C activation Protein kinase A C Phospholipase A2 C MAPK pathway

C Phospholipase A2 activation activation / activation

activation / [ Arachidonic acid
[ Arachidonic acid C Inhibition of Na/H

C NOS activation exchanger

C Phospholipase D activation C Y Intracellular Ca

Selective agonists Histaprodifen Amthamine alpha-Methyl-histamine Clobenopropit

Dimaprit Imetit (partial agonist)
Impromidine Immepip Imetit
Immepip
4-Methylhistamine
Antagonists/inverse Chlorphenamine Cimetidine Thioperamide JNJ-7777120
agonists (examples) Promethazine Ranitidine BF2.649 JNJ-10191584
Loratidine Famotidine PF-03654746
Fexofenidine Nizatidine GSK189254
MK-0249
JNJ-17216498

IP3, inositol triphosphate; DAG, diacylglycerol; NOS, nitric oxide synthase; cAMP, cyclic adenosine monophosphate; MAPK, mitogen-activated protein kinase.

Table 1

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 PHARMACOLOGY

Figure 1 The two-state model of histamine receptors. a In the resting state, a balance exists between the active receptors R* and the inactive receptors R;
b Agonists bind to the active state shifting the equilibrium towards R*; c Inverse agonists bind to the inactive state shifting the equilibrium towards R;
d True antagonists bind to both active and inactive receptors interfering with agonist binding but with no effect on R/R* equilibrium.

Histamine receptors exist in an equilibrium between two
conformational states (Figure 1), active (R*) or inactive (R).
Moreover, they all have constitutive activity, which is defined as
the ability to trigger downstream events even in the absence of
ligand binding (receptors changing from R to R* in the absence of
a ligand). Based on this two-state model, ligands at the histamine
receptors can be classified into agonists (bind to the active state
and shift the equilibrium towards R*), true antagonists (bind to
both active and inactive state interfering with agonist binding but
with no effect on equilibrium or intrinsic receptor activity), and
inverse agonists (bind to the inactive state shifting the equilib-
rium towards R, and reduce the intrinsic activity of the receptor
in the absence of an agonist).
Most currently known antihistamines have been reclassified
as inverse agonists and the term histamine antagonists is only
reserved for those compounds that function as true antagonists.
In the following paragraphs the term antihistamines is used to
describe drugs with inverse agonist or antagonist activity at
a given histamine receptor.
H1 antihistamines
In 1937, the first H1 antihistamine (thymo-ethyl-diethylamine)
was synthesized. However, because of weak activity and high
toxicity, this compound was not used in clinical practice. Clinically
useful H1 antihistamines such as phenbenzamine, pyrilamine, and
diphenhydramine were introduced in the 1940s. Currently, H1
antihistamines constitute the second most commonly used class of
medications after antibiotics, with more than 40 varieties of H1
antihistamines used in clinical practice worldwide.
As mentioned earlier, the vast majority of H1 antihistamines
exert their antihistaminic action by acting as inverse agonists at
the H1 receptors; binding to and stabilizing the inactive state of
the H1 receptor and reducing the intrinsic activity of the receptor
even in the absence of an agonist.
Based on their pharmacological structure, H1 antihistamines
are traditionally classified into six groups: ethanolamines, ethylene
diamines, alkylamines, piperazines, piperidines, and phenothia-
zines. This classification is, however, of limited clinical relevance,
and currently H1 antihistamines are classified as ‘first generation’,
also known as ‘sedating antihistamines’, and ‘second generation’,
which are relatively non-sedating (Table 2). The terms ‘third
generation’ and ‘new generation’ antihistamines are sometimes
used to describe some newly produced antihistamines that are
selective isomers or active metabolites of older second-generation
antihistamines. However, there is currently no consensus on such
terminology, and for the purpose of this review these newer agents
will still be considered as second-generation antihistamines.
First-generation H1 antihistamines such as alimemazine,
chlorphenamine, clemastine, cyproheptadine, hydroxyzine, and
promethazine are non-selective in binding to the H1 receptor. Most
of these drugs have weak antimuscarinic anticholinergic effects,
some have alpha-adrenergic blocking effects (promethazine), and
others can inhibit both histamine and 5-hydroxytryptamine
activity (cyproheptadine). Owing to their lipophilicity, relatively
low molecular weight, and lack of recognition by the P-glycopro-
tein efflux pump, first-generation H1 antihistamines readily
penetrate the non-fenestrated capillaries of the central nervous
system (CNS; bloodebrain barrier) and bind to central H1 recep-
tors, interfering with the actions of histamine on these receptors.
Second-generation H1 antihistamines such as cetirizine,
desloratadine, fexofenadine, levocetirizine, loratadine and miz-
olastine have significantly less affinity for muscarinic cholin-
ergic, alpha-adrenergic and 5-hydroxytryptaminergic receptors

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 PHARMACOLOGY

Comparison between first- and second-generation H1 antihistamines

First generation Second generation

Receptor selectivity Inverse agonists at H1 receptors Highly selective for H1 receptors

Weak antimuscarinic
a-anti-adrenergic (promethazine)
anti-serotonergic (cyproheptadine)
Central H1 occupation High occupancy 0e30% occupancy
Examples Alimemazine Cetirizine
Chlorphenamine Levocetirizine (isomer of cetirizine)
Clemastine Loratadine
Cyproheptadine Desloratadine (metabolite of loratadine)
Hydroxyzine Mizolastine
Promethazine Astemizole (not currently used)
Cyclizine Terfenadine (not currently used)
Cinnarizine Fexofenadine (metabolite of terfenadine)
Clinical uses Allergic rhinitis Allergic rhinitis
Atopic dermatitis Atopic dermatitis
Acute and chronic urticaria Acute and chronic urticaria
Insect bites and stings Insect bites and stings
Anaphylaxis (intravenous chlorphenamine) Seasonal asthma with allergic rhinitis
URT infection (no evidence) URT infection (no evidence)
Insomnia
Sedative premedication (promethazine)
Vertigo and motion sickness (cinnarizine)
Treatment/prevention of PONV (cyclizine)

Side effects CNS depression (somnolence, impaired Minimal or no CNS depression

cognitive and psychomotor performance);
other CNS effects (seizures, dyskinesia,
dystonia, hallucinations)
Anticholinergic effects (dry mouth, blurred Minimal or no anticholinergic effects
vision, urine retention)
Drugs of abuse Polymorphic ventricular tachycardias with
torsade de pointes and ventricular
fibrillation (astemizole and terfenadine;
both not in clinical use)
Drugs of suicide and infants’ homicide
Weight gain (cyproheptadine)

CNS, central nervous system; URT, upper respiratory tract; PONV, postoperative nausea and vomiting.

Table 2

and penetrate poorly into the CNS because of their low lipid
solubility, relatively high molecular weight and affinity for the
P-glycoprotein efflux pump. Their propensity to occupy central
nervous system H1 receptors varies from none for fexofenadine
to 30% for cetirizine.
H1 antihistamines, both first and second generation, have
well-documented anti-allergic and anti-inflammatory effects.
They exert these effects through their inverse agonist activity at
peripheral H1 receptors and through other non-receptor-
mediated mechanisms (e.g. inhibition of mast cell and basophil
histamine release and inhibition of inflammatory cell activation).
They are currently well established as first- or second-line
treatments for a variety of allergic disorders.
All H1 antihistamines are of potential value in the manage-
ment of seasonal (intermittent) and perennial (persistent) allergic
rhinitis in which they relieve nasal and conjunctival itching,
sneezing and rhinorrhoea and improve the quality of life. They
are also useful in the treatment of acute and chronic urticaria as
they provide symptomatic relief of itching and reduce the
number, size and duration of individual hives. However, the
evidence for using first-generation drugs in the treatment of these
disorders remains surprisingly small by current standards and
most available evidence is derived from large randomized,
controlled trials using second-generation drugs. Moreover, first-
generation H1 antihistamines have an unsatisfactory benefit-
to-risk ratio owing to their sedating effects, and although

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 PHARMACOLOGY
generally less expensive than second-generation drugs, when
costs attributed to their adverse effects are considered, the
difference may be less than expected. Second-generation H1
antihistamines should, therefore, be the preferred choice in the
treatment of these disorders because of their lack of sedative,
cognitive and psychomotor performance-impairing and anti-
muscarinic anticholinergic adverse effects.
H1 antihistamines are also used in the management of atopic
dermatitis both for relief of itching and for their glucocorticoid-
sparing effects; however, the evidence in support of their effi-
cacy is considerably weaker than it is in allergic rhinitis and
urticaria. They are also administered to treat local allergic reac-
tions to insect bites and stings.
H1 antihistamines, usually in combination with a deconges-
tant, are widely used to relieve symptoms in upper respiratory tract
infections, otitis media and sinusitis. However, the published
evidence does not support this practice and it is currently thought
that the beneficial effects sometimes reported with first-generation
drugs are due at least in part to their sedating and antimuscarinic
effects. Similarly, current evidence does not support the use of H1
antihistamines in persistent asthma. However, in patients with
allergic rhinitis and asthma, the use of second-generation H1
antihistamines has been shown to relieve co-existing mild
seasonal asthma symptoms, reduce beta-2 adrenergic agonist
requirements and improve pulmonary function.
First-generation H1 antihistamines such as chlorphenamine
and promethazine are used intravenously for the management of
anaphylaxis when hypotension is unresponsive to epinephrine.
Since most second-generation H1 antihistamines have low
aqueous solubility, they are not available in formulations for
injection and hence cannot be used in such circumstances.
Owing to their ability to cross the bloodebrain barrier, first-
generation H1 antihistamines such as promethazine are used as
non-prescription sleeping aids; promethazine is commonly used
as a sedative premedication in children; and cinnarizine, prom-
ethazine and cyclizine, are used for the prevention and treatment
of symptoms of vertigo and motion sickness. Moreover, cyclizine
has a well-established role in the prevention and management of
postoperative nausea and vomiting. The anti-emetic effect of
these drugs stems from their antimuscarinic properties and from
their ability to block the histaminergic signal from the vestibular
nucleus to the vomiting centre in the medulla.
A wide variety of adverse effects has been attributed to first-
generation H1 antihistamines. They readily penetrate the
bloodebrain barrier and hence have the potential to cause CNS
depression, which usually manifests as somnolence and
impaired cognitive and psychomotor performance. Their use can
also lead to a variety of other adverse CNS effects, including
seizures, dyskinesia, dystonia and hallucinations. First-
generation H1 antihistamines have also been associated with
fatalities in accidental or intentional overdose, and are potential
agents of suicide and of infants’ homicide. Moreover, some first-
generation H1 antihistamines are drugs of abuse leading to
euphoria and hallucinations. First-generation H1 antihistamines
commonly cause antimuscarinic anticholinergic effects such as
dry mouth, blurred vision and dysfunctional urine voiding.
Gastrointestinal upset, jaundice and pancytopenias have also
been reported. Cyproheptadine causes appetite stimulation and
inappropriate weight gain secondary to anti-serotonin effects.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:7
Second-generation H1 antihistamines are considerably less
likely than first-generation drugs to cause adverse effects. In
manufacturers’ recommended doses, the second-generation H1
antihistamines impair CNS function significantly less than the
first-generation H1 antihistamines. Moreover, they lack any
anticholinergic antimuscarinic effects. There are occasional
reports of fixed-drug eruptions, exacerbations of existing urti-
caria and hepatitis after cetirizine or loratadine ingestion.
Two early second-generation H1 antihistamines, astemizole
and terfenadine, which are no longer approved, block the rapid
component of delayed rectifier potassium current (IKr). As a result,
these two agents potentially prolong the QT interval and may lead
to cardiac arrhythmias, including polymorphic ventricular tachy-
cardias with torsade de pointes and ventricular fibrillation. New
second-generation H1 antihistamines such as cetirizine, deslor-
atadine, fexofenadine and loratadine have 1:1000 of the potency in
blocking the IKr current and are free of potential cardiac toxicity in
therapeutic and supra-therapeutic doses. The weight of evidence to
date suggests that the potential of second-generation H1 antihis-
tamines to cause ventricular arrhythmias is not a class effect.
H2 antihistamines
In the 1960s, it became clear that ‘traditional antihistamines’ do not
antagonize the stimulatory effect of histamine on gastric acid
secretion, which lead to the assumption that histamine mediates its
effect through two receptor subtypes designated H1 and H2 recep-
tors. This hypothesis became generally accepted and the search for
H2-specific antihistamines soon began. In 1969, burimamide, the
first H2 antihistamine was discovered; however it was insufficiently
potent for oral administration. Further modification of burimamide
led to the development of metiamide, which was an effective agent;
however, it was not suitable for clinical practice because of its bone
marrow toxicity and nephrotoxicity. Further investigations into the
activity and toxicity of similar compounds led to the discovery of
cimetidine, which was the first clinically useful H2 antihistamine.
This was followed by ranitidine, famotidine and nizatidine.
Like H1 antihistamines, H2 antihistamines are inverse
agonists and not true H2 antagonists, as was previously thought.
They exert their antihistaminic effects by binding to, and stabi-
lizing, the inactive state of the H2 receptor. Moreover, in the
absence of histamine, these drugs can inhibit the constitutive
activity of H2 receptors.
H2 antihistamines inhibit the chronotropic, inotropic and
delayed vasodilatory effects of histamine, and, of particular
therapeutic importance, suppress basal and stimulated acid
secretion by parietal cells. They accomplish the latter effect
through their inverse agonist activity at the H2 receptors of the
parietal cells, thus opposing the effects of histamine released by
the enterochromaffin-like cells of the stomach. Moreover, these
compounds attenuate the stimulatory effects of gastrin and
acetylcholine on gastric acid production.
The four H2 antihistamines are currently available over the
counter in relatively low doses, and have become extremely
popular in relieving the symptoms of gastro-oesophageal reflux
disease (heart burn). As prescription medications, H2 antihista-
mines alone are not generally effective for more severe grades of
gastro-oesophageal reflux disease; however, they are still rec-
ommended and used widely for patients with mild or infrequent
328 Ó 2011 Elsevier Ltd. All rights reserved.
 PHARMACOLOGY
symptoms, and also, in combination with proton pump inhibitors
for patients with persistent nocturnal symptoms. They are also
used in the treatment of functional dyspepsia, but caution should
be exerted as the regular use of these medications in unin-
vestigated dyspepsia can mask the symptoms of gastric malig-
nancy in elderly patients.
H2 antihistamines can also be used to promote healing of non-
steroidal anti-inflammatory drug-associated ulcers, and have
been used in high doses in ZollingereEllison syndrome;
however, proton pump inhibitors are currently the first option in
treating such conditions.
In Helicobacter pylori-induced ulcers, maintenance treatment
with low-dose H2 antihistamines has largely been replaced by
eradication regimens involving the use of proton pump inhibi-
tors, clarithromycin and either amoxicillin or metronidazole.
These eradication regimens are usually effective in healing ulcers
caused by H. pylori and treatment is seldom required for more
than 4 weeks. However, in high-risk patients (e.g. those with
a history of complications, frequent recurrences, ulcers testing
negative for H. pylori, refractory giant ulcers, or severely fibrosed
ulcers), maintenance therapy with H2 blockers or proton pump
inhibitors is still indicated.
H2 antihistamines are also used prophylactically to reduce the
incidence of stress-related gastrointestinal bleeding (stress-
induced ulcers) in intensive care patients and to reduce the risk
of acid aspiration in obstetric patients. They are also sometimes
administered as a premedication before elective surgery to
reduce the risk of acid aspiration; however, there is currently no
evidence to support the latter practice.
H2 antihistamines can also be used, off label, in combination
with an H1 antihistamine in patients with acute and chronic
urticaria that is refractory to treatment with an H1 antihistamine
alone. Moreover, they can also be administered concomitantly
with an H1 antihistamine in patients with anaphylaxis whose
hypotension is unresponsive to epinephrine. In the latter case,
H1 antihistamine should be given first, as rapid intravenous
administration of cimetidine or ranitidine alone may exacerbate
the hypotension and induce cardiac dysrhythmias.
H2 antihistamines have a good safety record and are generally
well tolerated. Side-effects include diarrhoea and gastrointestinal
disturbances, altered liver function tests, headache, dizziness,
rash and tiredness. Rare side-effects include acute pancreatitis,
bradycardia, AV block, confusion, depression and hallucinations,
particularly in the elderly. Hypersensitivity reactions, including
fever, arthralgia, myalgia and anaphylaxis, and blood disorders,
including agranulocytosis, leucopenia, pancytopenia and throm-
bocytopenia, have also been reported. Additionally, gynaeco-
mastia, loss of libido and impotence have been reported in patients
receiving cimetidine. Cimetidine is also a well-known inhibitor of
the cytochrome P450 enzymes and therefore has the capacity to
reduce the metabolism of drugs that are metabolized by these
enzymes if given concomitantly. This is particularly relevant in
patients receiving warfarin, phenytoin and theophylline, and
hence cimitidine should be avoided in this group of patients.
H3 antihistamines
The successful cloning and functional expression of the hista-
mine H3 receptor in the late 1990s facilitated the efforts of several
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:7
pharmaceutical companies in developing a host of potential dugs
that can therapeutically modulate the function of this receptor.
In animal models, H3 antihistamines counteract the effects of
histamine on presynaptic H3 receptors, and enhance the release
of several neurotransmitters including histamine, dopamine,
serotonin, norepinephrine and gamma-amino-butyric acid. These
effects could be of potential benefit in the treatment of several
disorders, including narcolepsy, obesity, Parkinson’s disease,
depression, Alzheimer’s disease and attention-deficit hyperac-
tivity disorder. Moreover, the peripheral actions of H3 antihis-
tamine might prove to be of value in relieving nasal congestion in
patients with allergic rhinitis.
Compounds with an agonist activity at the H3 receptor are
also being developed. These compounds can increase histamine
and dopamine release and might be useful in the management of
insomnia, migraine and schizophrenia.
H3 antihistamine and H3 agonists are not yet approved in
clinical practice; however, some compounds are currently
undergoing phase I and phase II clinical trials.
H4 antihistamines
The H4 receptor is the newest member of the histamine receptor
family and, in contrast to other histamine receptors, it has
a distinct expression profile on mast cells, eosinophils, dendritic
cells and T lymphocytes.
The H4 receptor plays a significant role in modulating a range
of physiological functions of immune cells, including chemo-
taxis, cytokine release and adhesion molecule expression.
Moreover, the use of H4 antihistamines in animal models of
colitis, asthma and pruritus has already produced some prom-
ising results. It is therefore hoped that H4 antihistamines will be
of therapeutic benefit in the management of various immune and
inflammatory disorders in the future. Moreover, some recent
evidence supports a novel role of the histamine H4 receptor in
cancer progression representing a promising molecular target
and avenue for cancer drug development. A
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329 Ó 2011 Elsevier Ltd. All rights reserved.