Pharmacology of Antihistamines

Diana S Church1, 2 and

Martin K Church1, 2Email author

World Allergy Organization Journal20114(Suppl 3):S22

DOI: 10.1186/1939-4551-4-S3-S22
World Allergy Organization; licensee BioMed Central Ltd. 2011
Published: 15 March 2011

Abstract
This article reviews the molecular biology of the interaction of histamine with its H 1receptor and describes the concept that H1-antihistamines are not receptor
antagonists but are inverse agonists i.e. they produce the opposite effect on the
receptor to histamine. It then discourages the use of first-generation H 1antihistamines in clinical practice today for two main reasons. First, they are less
effective than second generation H1-antihistamines. Second, they have unwanted
side effects, particularly central nervous system and anti-cholinergic effects, and
have the potential for causing severe toxic reactions which are not shared by secondgeneration H1-antihistamines. There are many efficacious and safe secondgeneration H1-antihistamines on the market for the treatment of allergic disease. Of
the three drugs highlighted in this review, levocetirizine and fexofenadine are the
most efficacious in humans in vivo. However, levocetirizine may cause somnolence
in susceptible individuals while fexofenadine has a relatively short duration of action
requiring twice daily administration for full all round daily protection. While
desloratadine is less efficacious, it has the advantages of rarely causing somnolence
and having a long duration of action. Lastly, all H 1-antihistamines have antiinflammatory effects but it requires regular daily dosing rather than dosing 'ondemand' for this effect to be clinically demonstrable.

Keywords
H1-antihistamines cetirizine levocetirizine fexofenadine loratadine desloratadine
It is now more than a century since the discovery of histamine,[1] more than 70 years
since the pioneering studies of Anne Marie Staub and Daniel Bovet led to the
discovery of the first antihistamine[2] and more than 60 years since the introduction
into the clinic of antergan in 1942,[3] followed by diphenhydramine in 1945[4] and

chlorpheniramine, brompheniramine, and promethazine later the same decade.

Medicinal chemistry was very different in those days compared with the present day
as elegantly described by Emanuel in his review entitled "Histamine and the
antiallergic antihistamines: a history of their discoveries."[5] The usual way of testing
novel compounds was to measure histamine-induced contractions of pieces of
muscle from experimental animals, usually guinea-pig intestine, suspended in an
organ bath. Candidate antihistaminic compounds were primarily modifications of
those synthesized as cholinergic antagonists and are from diverse chemical entities,
ethanolamines, ethylene diamines, alkylamines, piperazines, piperidines, and
phenothiazines. It is hardly surprising, therefore, that these first-generation
antihistamines had poor receptor selectivity and significant unwanted side effects.
During this time, knowledge of the nature and diversity of receptors was rudimentary
to say the least and it was only several decades later that the existence of more than
one species of histamine receptor was discovered. This review will concentrate on
the histamine H1-receptor. Further details on the biology and clinical functions of
histamine H2-, H3-, and H4-receptors are the subject of a separate review[6].

The Histamine H1-Receptor

The human histamine H1-receptor is a member of the superfamily of G-protein
coupled receptors. This superfamily represents at least 500 individual membrane
proteins that share a common structural motif of 7 transmembrane -helical
segments[7, 8] (Figure 1A). The histamine H1-receptor gene encodes a 487 amino
acid protein with a molecular mass of 55.8 kDa[9, 10]. The absence of introns in the
H1-receptor gene indicates that only a single receptor protein is transcribed with no
splice variants[10].

Figure 1
A, Diagram of a histamine H1-receptor in a membrane showing the 7 transmembrane
domains. Histamine stimulates the receptor after its penetration into the central core of the
receptor. B, A surface view of an activated receptor with histamine linking domains III and V. C, A
surface view of an inactive receptor with cetirizine linking domains IV and VI.

The histamine H1-receptor, like other G-protein coupled receptors, may be viewed as
"cellular switches," which exist as an equilibrium between the inactive or "off" state
and the active or "on" state[11]. In the case of the histamine H1-receptor, histamine
cross-links sites on transmembrane domains III and V to stabilize the receptor in its
active conformation, thus causing the equilibrium to swing to the on position[12]
(Figure 1B). H1-antihistamines, which are not structurally related to histamine, do not
antagonize the binding of histamine but bind to different sites on the receptor to
produce the opposite effect. For example, cetirizine cross-links sites on
transmembrane domains IV and VI to stabilize the receptor in the inactive state and
swing the equilibrium to the off position[13] (Figure 1C). Thus, H1-antihistamines are
not receptor antagonists but are inverse agonists in that they produce the opposite
effect on the receptor to histamine[14]. Consequently, the preferred term to define
these drugs is "H1-antihistamines" rather than "histamine antagonists."

First-Generation H1-Antihistamines

Because first-generation H1-antihistamines derive from the same chemical stem from
which cholinergic muscarinic antagonists, tranquilizers, antipsychotics, and
antihypertensive agents were also developed, they have poor receptor selectivity and
often interact with receptors of other biologically active amines causing
antimuscarinic, anti--adrenergic, and antiserotonin effects. But perhaps their
greatest drawback is their ability to cross the blood-brain barrier and interfere with
histaminergic transmission. Histamine is an important neuromediator in the human
brain which contains approximately 64,000 histamine-producing neurones, located in
the tuberomamillary nucleus. When activated, these neurones stimulate H 1-receptors
in all of the major parts of the cerebrum, cerebellum, posterior pituitary, and spinal
cord[15] where they increase arousal in the circadian sleep/wake cycle, reinforce
learning and memory, and have roles in fluid balance, suppression of feeding, control
of body temperature, control of the cardiovascular system, and mediation of stresstriggered release of adrenocorticotrophic hormone and -endorphin from the pituitary
gland[16]. It is not surprising then that antihistamines crossing the blood-brain barrier
interfere with all of these processes.
Physiologically, the release of histamine during the day causes arousal whereas its
decreased production at night results in a passive reduction of the arousal response.
When taken during the day, first-generation H 1-antihistamines, even in the
manufacturers' recommended doses, frequently cause daytime somnolence,
sedation, drowsiness, fatigue, and impaired concentration and memory[17, 18].
When taken at night, first-generation H1-antihistamines increase the latency to the
onset of rapid eye movement sleep and reduce the duration of rapid eye movement
sleep[1921]. The residual effects of poor sleep, including impairment of attention,
vigilance, working memory, and sensory-motor performance, are still present the
next morning[20, 22]. The detrimental central nervous system effects of firstgeneration H1-antihistamines on learning and examination performance in children
and on impairment of the ability of adults to work, drive, and fly aircraft have been
reviewed in detail in a recent review[23].
The use of first-generation H1-antihistamines in young children has recently been
brought into question. In the United States, reports of serious and often lifethreatening adverse events of promethazine in children led to a "boxed warning"
being added in 2004 to the labeling of promethazine. The warning included a
contraindication for use in children younger than 2 years and a strengthened warning
with regard to use in children 2 years of age or older[24]. In February 2009, the
Medicines and Healthcare products Regulatory Agency (MHRA) in the United
Kingdom[25] advised that cough and cold remedies containing certain ingredients,
including first-generation H1-antihistamines, should no longer be used in children

younger than 6 years because the balance of benefit and risks has not been shown
to be favorable. Reports submitted to regulators stated that more than 3000 people
have reported adverse reactions to these drugs and that diphenhydramine and
chlorpheniramine were mentioned in reports of 27 and 11 deaths, respectively[25].

Second-Generation H1-Antihistamines
A major advance in antihistamine development occurred in the 1980s with the
introduction of second-generation H1-antihistamines,[26] which are minimally
sedating or nonsedating because of their limited penetration of the blood-brain
barrier. In addition, these drugs are highly selective for the histamine H 1-receptor and
have no anticholinergic effects.
When choosing an H1-antihistamine, patients seek attributes that include good
efficacy, a rapid onset of action, a long duration of action, and freedom from
unwanted effects. Although some of these attributes may be predicted from
preclinical and pharmacokinetic studies, it is only in the clinical environment that they
may be definitively established.

Efficacy
The efficacy of an H1-antihistamine is determined by 2 factors: the affinity of the drug
for H1-receptors (absolute potency) and the concentration of the drug at the sites of
the H1-receptors.
The affinity of an H1-antihistamine for H1-receptors is determined in preclinical
studies. Desloratadine is the most potent antihistamine (Ki 0.4 nM) followed by
levocetirizine (Ki 3 nM) and fexofenadine (Ki 10 nM) (the lower the concentration, the
higher potency). Although these are often considered to be fixed values, they may be
influenced by temperature and pH, and therefore, they can differ in physiologic and
pathologic conditions. For example, in inflammation the pH of the tissues is
reduced[27] from 7.4 to 5.8, leading to a 2-to 5-fold increase in the affinity of
fexofenadine and levocetirizine for H1-receptors but no change in the affinity of
desloratadine[28].
As shown in Figure 2, histamine receptors are situated on the cellular membranes of
cells, including vascular and airways smooth muscle, mucous glands, and sensory
nerves, all of which are surrounded by the extracellular fluid. Many factors affect
concentration of free drug in this compartment. First, it must be absorbed into the
systemic circulation after oral dosage with a tablet or capsule. Most H 1-

antihistamines are well absorbed, the exception being fexofenadine, which has a
very variable absorption because of the influence of active transporting proteins as
described later[29, 30]. Second is the extent of plasma binding which, with H 1antihistamines, is high, varying from ~65% with desloratadine to ~90% for
levocetirizine[31]. Third, and probably most influential, is the apparent volume of
distribution which determines the plasma concentration of a drug after complete body
distribution. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg),
larger for fexofenadine (5.4-5.8 L/kg), and particularly large for desloratadine (~49
L/kg)[32]. The large apparent volume of distribution of desloratadine is largely due to
its extensive intracellular uptake. In the study of Gillard and colleagues,[31] the 4hour plasma concentrations of levocetirizine, desloratadine, and fexofenadine are 28,
1, and 174 nM, respectively.

Figure 2
Diagrammatic representation of the absorption of an H 1 -antihistamine. Histamine H1receptors are indicated by stars on the surface of cells and a sensory nerve in the extravascular
space.

Because data on the concentrations of H1-antihistamines in relevant extracellular

fluids is generally lacking, the best indirect estimate of efficacy is obtained by
calculating receptor occupancy from knowledge of absolute potency and peak drug
concentrations in the plasma, usually at ~4 hours after a single oral dose using the
following equation[31].
Receptor occupancy ( % ) = B max L L + Ki

where Bmax is the maximal number of binding sites (set to 100%), L the concentration
of free drug in the plasma, and Ki the equilibrium inhibition constant ( absolute
potency).
Thus, the calculation of receptor occupancy after single oral doses of drug shows
values of 95%, 90%, and 71% for fexofenadine, levocetirizine, and desloratadine,
respectively, indicating that they are all very effective H 1-antihistamines. Although
receptor occupancy for these drugs appears to correlate with pharmacodynamic
activity in skin wheal and flare studies and with efficacy in allergen challenge
chamber studies,[33, 34] are the differences relevant in clinical practice? Studies in
allergic rhinitis suggest that the above 3 drugs are of similar effectiveness[35, 36].
However, in chronic urticaria in which local histamine concentrations are high, the
differences do seem to be important. For example, in head to head studies in this
condition levocetirizine appears significantly more effective than desloratadine[37,
38].

Speed of Onset of Action

The speed of onset of action of a drug is often equated to the rate of its oral
absorption. However, this is not strictly correct as seen from Figure 3, which shows
the inhibition of the histamine-induced flare response (indicative of the prevention by
levocetirizine of sensory neurone stimulation in the extravascular space) plotted
against the concentration of free drug in the plasma. In this study in children,[39]
plasma concentrations of drug are near maximum by 30 minutes and yet it takes an
additional 1.5 hours for the drug to diffuse into the extravascular space to produce a
maximal clinical effect. In adults, the maximal inhibition of the flare response is
usually ~4 hours for levocetirizine, fexofenadine, and desloratadine[4042] but may
be longer for drugs, such as loratadine and ebastine, which require metabolism to
produce their active moiety[40].

Figure 3
Hysteresis loop of the inhibition of the histamine-induced flare response plotted against
the plasma concentration of unbound levocetirizine after administration of a single 5-mg
dose to children. Redrawn from Ref. 39.

Duration of Action
Figure 3 also shows that the duration of action of levocetirizine in inhibiting the
histamine-induced flare response is also much longer than would be predicted from a
knowledge of its plasma concentration[39]. This is presumably due to "trapping" of
the drug by its strong and long-lasting binding to histamine H 1-receptors[13].
Although less active in the wheal and flare test, desloratadine has a similarly long
duration of action[41]. However, the duration of action of fexofenadine, calculated in
the study of Purohit et al[43] as the time for the wheal to be inhibited by at least 70%,
is less prolonged, being 8.5 hours for 120 mg fexofenadine compared with 19 hours
for cetirizine. The primary reason for the shorter duration of action of fexofenadine is
that it is actively secreted into the intestine and urine[44].

Anti-Inflammatory Effects
Although the majority of research into H1-antihistamines has focused on the
histamine-dependent early phase symptoms of the allergic response, it is now
becoming clear that these drugs have anti-inflammatory effects. This follows the

observation by Bakker and colleagues[45] that histamine can activate NF-B, a

transcription factor involved in the synthesis of many pro-inflammatory cytokines and
adhesion molecules involved in the initiation and maintenance of allergic
inflammation. The anti-inflammatory effects of H1-antihistamines, which is a class
effect mediated through the H1-receptor, are summarized in Ref[14]. The clinical
implications of this lie in the ability of H 1-antihistamines to reduce nasal congestion
and hyper-reactivity,[36] which result from the sensitization of sensory neurones in
the nose by allergic inflammation[46]. However, as nasal congestion is more slowly
relieved than other nasal symptoms,[47] continuous rather than on demand therapy
with antihistamines is required for its treatment[48].

Elimination
The metabolism and elimination of H1-antihistamines have been extensively reviewed
elsewhere[32, 49] and will be only briefly summarized here. Cetirizine and
levocetirizine are not metabolized and are excreted primarily unchanged in the
urine[32]. Desloratadine undergoes extensive metabolism in the liver. Although this
gives the potential for drug-drug interactions, no significant interactions have been
reported[49]. Fexofenadine, which is also minimally metabolized, is excreted primarily
in the feces after its active secretion into the intestine under the influence of active
drug-transporting molecules[49]. This gives the potential for interactions with agents
such as grapefruit juice and St Johns Wort, which inhibit these transporters.
Although plasma concentrations of fexofenadine may be increased by these agents,
no significant resulting adverse reactions have been reported[49].

Unwanted Effects
Somnolence
A major reason for the reduced penetration of second-generation H 1-antihistamines
into the brain is because their translocation across the blood-brain barrier is under
the control of active transporter proteins, of which the ATP-dependent efflux pump, Pglycoprotein, is the best known[50, 51]. It also became apparent that antihistamines
differ in their substrate specificity for P-glycoprotein, fexofenadine being a particularly
good substrate[52]. In the brain, the H1-receptor occupancy of fexofenadine
assessed using positron emission tomography scanning is negligible, <0.1%, and, in
psychomotor tests, fexofenadine is not significantly different from placebo[53].
Furthermore, fexofenadine has been shown to be devoid of central nervous effects
even at supraclinical doses, up to 360 mg[54].

Although fexofenadine is devoid of CNS effects, other second-generation H 1antihistamines many still penetrate the brain to a small extent where they have the
potential to cause some degree of drowsiness or somnolence, particularly when
used in higher doses. For example, positron emission tomography scanning of the
human brain has shown that single oral doses of 10 and 20 mg of cetirizine caused
12.5 and 25.2% occupancy of the H1-receptors in prefrontal and cingulate cortices,
respectively[55]. These results would explain the repeated clinical findings that the
incidence of drowsiness or fatigue is greater with cetirizine than with placebo[5659].
Recent publications have suggested that, at manufacturer's recommended doses,
levocetirizine is less sedating than cetirizine[60] and desloratadine causes negligible
somnolence[49, 61]. However, it should be pointed out that "mean results" do not
reveal everything as some patients may show considerable somnolence whereas
others are unaffected.
Cardiotoxicity
The propensity of astemizole and terfenadine to block the I Kr current, to prolong the
QT interval, and to potentially cause serious polymorphic ventricular arrhythmias
such as torsades de pointes is well documented[14, 62]. These 2 drugs are no
longer approved by regulatory agencies in most countries. In addition, some firstgeneration H1-antihistamines, such as promethazine,[63] brompheniramine,[64] and
diphenhydramine,[65] may also be associated with a prolonged QTc and cardiac
arrhythmias when taken in large doses or overdoses. No clinically significant cardiac
effects have been reported for the second-generation H 1-antihistamines loratadine,
fexofenadine, mizolastine, ebastine, azelastine, cetirizine, desloratadine, and
levocetirizine[6669].

Conclusions
In conclusion, the use of first-generation H1-antihistamines should be discouraged in
clinical practice today for 2 main reasons. First, they are less effective than secondgeneration H1-antihistamines[17, 70, 71]. Second, they have unwanted side effects
and the potential for causing severe toxic reactions which are not shared by secondgeneration H1-antihistamines. With regard to second-generation H1-antihistamines,
there are many efficacious and safe drugs on the market for the treatment of allergic
disease. Of the 3 drugs highlighted in this review, levocetirizine and fexofenadine are
the most potent in humans in vivo. However, levocetirizine may cause somnolence in
susceptible individuals whereas fexofenadine has a relatively short duration of action
and may be required to be given twice daily for all-round daily protection. Although
desloratadine is less potent, it has the advantages of rarely causing somnolence and

having a long duration of action. Lastly, all H1-antihistamines have anti-inflammatory

effects but it requires regular daily dosing rather than dosing "on demand" for this
action to be clinically demonstrable.