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
secretion, increases vascular permeability, functions as a neurotrans-
mitter, and plays various roles in immunomodulation, allergy, inflam-
mation, haematopoiesis and cell proliferation. Histamine exerts its
effects through four receptors, designated H1eH4. H1 and H2 recep-
tors are widely distributed, H3 receptors are mainly presynaptic, and
H4 receptors are mainly haematopoietic. H1 antihistamines are classi-
fied 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 vestibular 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; howev-
er, proton pump inhibitors are becoming the drugs of first choice in
some of these disorders. H3 antihistamines are expected to be of po-
tential value in the treatment of some cognitive disorder. H4 antihista-
mines could be of potential therapeutic benefit in the management of
various immune and inflammatory disorders.
Keywords Antihistamines; histamine; histamine receptors
Royal College of Anaesthetists CPD matrix: 1A02
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,
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 --:-
Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
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
antihistamines
histamine is involved in the regulation of sleep and wakefulness,
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 his-
tamine along with tryptase, leukotrienes and prostaglandins as
well as other mediators. Alternatively, histamine can be directly
displaced 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 res-
piratory and gastrointestinal tracts, vasodilatation and sensory
nerve stimulation. 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
decarboxylase (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 stimulation, these cells can rapidly release relatively
large amounts of histamine and thereby efficiently activate
suitable effector mechanisms. 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-methyl-
transferase to N-methylhistamine, which can be further metabo-
lized to N-methyl-imidazole acetic acid by the enzyme
monoamine oxidase. Alternatively, histamine can be metabolized
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 histamine pre-
sent in considerable amounts in certain foods, preventing its
1 Ó 2017 Published by Elsevier Ltd.
 PHARMACOLOGY

uptake into the circulation. However, the DAO pathway is not
active in the central nervous system.
Histamine receptors
Histamine exerts its diverse biologic effects through four types of
receptors; H1, H2, H3 and H4 receptors (Table 1). Additionally,
low-affinity intracellular non-H1, -H2, -H3, or -H4 receptors, have
been recently described in cell nuclei and microsomes, although
biologic functions at these receptors is still somewhat unclear.
The H1 receptor is widely distributed throughout the body,
with well-documented expression in the CNS, smooth muscle,
sensory nerves, heart, adrenal medulla, and immune, endothe-
lial, and epithelial cells. The H1 receptor mediates most of the
postsynaptic effects of histamine within the central nervous
system. Moreover, through its activity at H1 receptors, histamine
stimulates smooth muscle contraction in the respiratory and
gastrointestinal tract, stimulates sensory nerves leading to pru-
ritus and sneezing, and increase vascular permeability leading to
oedema. Simultaneous activation of H1 and H2 receptor can also
result in hypotension, tachycardia, flushing, and headache.
The H2 receptor is also widely expressed and can be found in
gastric mucosal cells, heart, CNS, immune cells, and smooth
muscles of the airway, vasculature, and uterus. H2 receptor
activation stimulates hydrochloric acid secretion from the acid-
secreting parietal cells of the gastric mucosa, leads to smooth
muscle relaxation in the vasculature and airways, increases
cardiac rate and contractility, and mediates some of the immu-
nomodulatory effects of histamine.
The histamine H3 receptor is found mainly in the central
nervous system (basal ganglia, hippocampus and cortical areas),
but can also be found in the peripheral nervous system, airways,
the cardiovascular system, and the gastrointestinal tract. Acting
through presynaptic H3 receptor, histamine regulates its own
release as well as the release of other neurotransmitters such as
noradrenaline, dopamine, serotonin, acetylcholine, and gamma-
amino-butyric acid. In the lower airways, H3 receptors are
located on postganglionic cholinergic nerves and defend against
excess bronchoconstriction and in the upper airways, histamine
may play a role in nasal congestion through its activity at H3
receptors.
The H4 receptor has been detected in bone marrow, periph-
eral blood, spleen, thymus, lung, gastrointestinal tract, liver,
peripheral nerves, and central neurones. Nevertheless, cells that
clearly express functional H4 receptors are mainly haemato-
poietic and include: mast cells, eosinophils, basophils, dendritic
cells, and T cells. H4 receptor activation induces calcium mobi-
lization in mast cells and mediates mast cells migration towards
histamine. Moreover the receptor plays a significant role in
regulating dendritic and T-cell function.
In general terms, the four histamine receptors can be
described as heptahelical G-protein coupled receptors. They
transduce extracellular signals through various G proteins, which
function as mediators between the cell surface receptors and the
intracellular second messenger systems.
Histamine receptors exist in an equilibrium between two
conformational states (Figure 1), active (R*) or inactive (R).

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

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

coupling
Signal C Phospholipase C activation / C Adenylate cyclase activa- C Adenylate cyclase inhibi- C Adenylate cyclase inhibi-
transduction [ IP3 and DAG / tion / tion / tion /
[ Intracellular Ca and protein kinase [ cAMP / Y cAMP Y cAMP
C activation Protein kinase A activation C MAPK pathway activation C MAPK pathway activation
C Phospholipase A2 activation / C Phospholipase A2 activa-
[ Arachidonic acid tion /
C NOS activation [ Arachidonic acid
C Phospholipase D activation C Inhibition of Na/H exchanger

C Y Intracellular Ca
Selective Histaprodifen Amthamine Alpha-Methyl-histamine Clobenopropit (partial
agonists Dimaprit Imetit agonist)
Impromidine Immepip Imetit
Immepip
4-Methylhistamine
Antagonists/ Chlorphenamine Cimetidine Thioperamide JNJ-7777120
inverse Promethazine Ranitidine Pitolisant (ABT-288) VUF-6002
agonists Loratidine Famotidine MK-0249
(examples) Fexofenidine Nizatidine JNJ-17216498

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

Table 1

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 2 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
 PHARMACOLOGY

The two-state model of histamine receptors

a b Agonist
Resting state

R R* R R*

c d Agonist
Inverse agonist
True antagonist

R R* R R*

(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.

Figure 1

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. Clini-
cally useful H1 antihistamines such as phenbenzamine, pyril-
amine, 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 (prom-
ethazine), 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-glycoprotein efflux pump, first-generation
H1 antihistamines readily penetrate the non-fenestrated capil-
laries of the central nervous system (CNS; bloodebrain barrier)

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 3 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
 PHARMACOLOGY
Comparison between first- and second-generation H1 antihistamines
First generation
Receptor selectivity Inverse agonists at H1 receptors
Weak antimuscarinic
a-Anti-adrenergic (promethazine)
Anti-serotonergic (cyproheptadine)
Central H1 occupation High occupancy
Examples Alimemazine
Chlorphenamine
Clemastine
Cyproheptadine
Hydroxyzine
Promethazine
Cyclizine
Cinnarizine
Clinical uses Allergic rhinitis
Atopic dermatitis
Acute and chronic urticaria
Insect bites and stings
Anaphylaxis (intravenous chlorphenamine)
URT infection (no evidence)
Insomnia
Sedative premedication (promethazine)
Vertigo and motion sickness (cinnarizine)
Treatment/prevention of PONV (cyclizine)
Side-effects CNS depression (somnolence, impaired
cognitive and psychomotor performance);
other CNS effects (seizures, dyskinesia,
dystonia, hallucinations)
Anticholinergic effects (dry mouth, blurred
vision, urine retention)
Drugs of abuse
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 bind to central H1 receptors, 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
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.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 4 Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
Second generation
Highly selective for H1 receptors
0e30% occupancy
Acrivastine
Bilastine
Cetirizine
Levocetirizine (isomer of cetirizine)
Loratadine
Desloratadine (metabolite of loratadine)
Mizolastine
Fexofenadine (metabolite of terfenadine)
Allergic rhinitis
Atopic dermatitis
Acute and chronic urticaria
Insect bites and stings
Seasonal asthma with allergic rhinitis
URT infection (no evidence)
Minimal or no CNS depression
Minimal or no anticholinergic effects
Polymorphic ventricular tachycardias with
torsade de pointes and ventricular fibrillation
(astemizole and terfenadine; both not in
clinical use)
All H1 antihistamines are of potential value in the management
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 evi-
dence is derived from large randomized, controlled trials using
second-generation drugs. Moreover, first-generation H1 antihis-
tamines have an unsatisfactory benefit-to-risk ratio owing to their
sedating effects, and although 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 antimuscarinic anticholinergic adverse effects.
 PHARMACOLOGY
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 re-
actions 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 pub-
lished 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 blood
ebrain 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.
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
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
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 ven-
tricular tachycardias with torsade de pointes and ventricular
fibrillation. New second-generation H1 antihistamines such as
cetirizine, desloratadine, 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 poten-
tial of second-generation H1 antihistamines 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
receptors. This hypothesis became generally accepted and the
search for H2-specific antihistamines soon began. In 1969, bur-
imamide, the first H2 antihistamine was discovered; however it
was insufficiently potent for oral administration. Further modi-
fication 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 neph-
rotoxicity. 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 ago-
nists 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 pop-
ular in relieving the symptoms of gastro-oesophageal reflux disease
(heart burn). As prescription medications, H2 antihistamines alone
are not generally effective for more severe grades of gastro-
oesophageal reflux disease; however, they are still recommended
and used widely for patients with mild or infrequent 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 reg-
ular use of these medications in uninvestigated dyspepsia can mask
the symptoms of gastric malignancy in elderly patients.
5 Ó 2017 Published by Elsevier Ltd.
 PHARMACOLOGY
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; how-
ever, 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 in-
hibitors, 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, to reduce the frequency
of bleeding from gastroduodenal erosions in hepatic coma, 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 cimetidine should be avoided in this group of patients.
H3 antihistamines
The successful cloning and functional expression of the histamine
H3 receptor in the late 1990s facilitated the efforts of several
pharmaceutical companies in developing a host of potential drugs
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,
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Please cite this article in press as: Mahdy AM, Webster NR, Histamine and antihistamines, Anaesthesia and intensive care medicine (2017), http://
dx.doi.org/10.1016/j.mpaic.2017.01.007
serotonin, norepinephrine and gamma-amino-butyric acid. These
effects could be of potential benefit in the treatment of sleep
disorders, attention-deficit hyperactivity disorder, dementias,
schizophrenia, and Alzheimer’s disease. Moreover, the periph-
eral actions of H3 antihistamine might prove to be of value in
relieving nasal congestion in patients with allergic rhinitis. One
of the most advanced H3 antihistamines in clinical development
is the nonimidazole-based inverse agonist pitolisant (formerly
known as tripolisant; BF2.649). Pitolisant has been granted
orphan drug status by the European Medicine agency for the
treatment of excessive diurnal sleepiness in patients with nar-
colepsy, Parkinson’s disease, and obstructive sleep apnoea/
hypopnoea. Several H3 antihistamine compounds are still un-
dergoing phase I and phase II clinical trials.
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.
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.
Alcaftadine is a new antihistamine with combined antagonist
activity at histamine H1, H2, and H4 receptors. It significantly
reduces itching, eosinophil recruitment and redness after expo-
sure to an allergen. Alcaftadine was recently approved by the
FDA for the prevention of itching associated with allergic
conjunctivitis. A
FURTHER READING
Bernstein JA. Antihistamines. In: Grammer Leslie C, Greenberger Paul
A, eds. Patterson’s allergic diseases. 7th edn. Lippincott Williams
and Wilkins, 2009; 561e73.
British Medical Association and the Royal Pharmaceutical Society of
Great Britain. British national formulary. London: BMJ Publishing
Group & RPS Publishing, 2014.
Golightly LK, Greos LS. Second-generation antihistamines: actions
and efficacy in the management of allergic disorders. Drugs 2005;
65: 341e84.
Schwartz JC. The histamine H3 receptor: from discovery to clinical
trials with pitolisant. Br J Pharmacol 2011; 163: 713e21.
Simons FER. Advances in H1-antihistamines. N Engl J Med 2004; 351:
2203e18.
Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and
inflammatory disorders. Br J Pharmacol 2009; 157: 24e33.
6 Ó 2017 Published by Elsevier Ltd.