Antihistamines: a review

300
REVIEW ARTICLE
The chemical compound §-imidazole-ethylamine
was first synthesised in 1907. It was later given
the name "histamine" (meaning "an amine present
in all tissues") 1 , and its role in allergy and inflammation
was discovered shortly thereafter. The first
antihistamines to be used in medical therapy (fenbenzamine
and pirylamine) were developed
during the '30s at the Pasteur Institute. In 1946,
two further drugs were independently discovered
in the U.S.A.: diphenhydramine and tripelennamine
2 . Since that time, literally hundreds of molecules
with antihistamine properties have been
developed, and their use in clinical therapy has
incessantly grown throughout the past 50 years.
The classical antihistamines have always been
associated with sedation and anticholinergic
effects. Since the '80s research has attempted to
avoid or prevent these unwanted side effects
through the investigation and development of new
active principles. Over the last decade, some of
these new compounds have been shown to be
associated to important drug interactions and
potential toxicity.
The aim of the present review is to provide a
bibliographic summary on the clinical pharmacology
of the main antihistamines, their safety profiles
and their place in the therapeutic armamentarium
for the management of allergic diseases.
HISTAMINE AND ITS RECEPTORS
Histamine is a chemical mediator participating
in many cell physiology processes, among them
H1 Antihistamines: a review
I. J‡uregui Presa
Allergy Unit, Basurto Hospital, Bilbao, Spain
allergic reactions, inflammation gastric acid secretion
and -probably- central and peripheral neurotransmission
3 . It exerts its effects through three
distinct types of postsynaptic receptors.
H1 receptors. These receptors may be identified
in the bronchial and gastrointestinal smooth muscle
and in the brain. They are responsible for the
constriction of the bronchial and vascular smooth
muscle, for the activation of the afferent vagal
nerves of the airways and of the cough receptors,
for the increase in vascular permeability, for the
local irritative manifestations such as pruritus and
pain, and for the release of inflammatory mediators
and the recruitment of inflammatory cells 4 .
H2 receptors. These are present in the gastric
mucosa, in the uterus and in the brain. They also
increase vascular permeability, and they stimulate
the gastric acid secretion 4 .
H3 receptors. These may be found in the brain
and in the bronchial smooth muscle. They are responsible
for cerebral vasodilation and might be
involved in the negative feedback system through
which histamine inhibits its own synthesis and
release from the nerve endings 3 . The main efforts
in the investigation of antihistamine have been
directed at the specific inhibitors of the H1 and H2
receptors. The H3 antagonists, currently in the
phase of animal experimentation, might find their
use in the therapy of various processes affecting
the central nervous system (CNS) 5 . The present
review will be centred exclusively on the antagonists
of the H1 receptors, which in pharmacological
usage receive the generic denomination of
antihistamines.
Alergol Inmunol Clin, October 1999 Vol. 14, No. 5, pp. 300-312

No. 5 H1 Antihistamines: a review 301
CHEMISTRY OF THE ANTIHISTAMINES
The typical antihistamines have an ethylamine
side chain (similar to that of histamine itself)
which is united to one or more cyclic groups. The
structural characteristics of the H1 receptor antagonists
have been historically used for classifying
them into six broad chemical families: ethanolamines,
ethylenediamines, alkylamines, phenothiazines,
piperazines and piperidines (Table I) 6 .
Several of the new H1 receptor antagonists are
chemically speaking piperidines, or at least they
possess piperidine rings (Fig. 1). Many of them
are direct derivatives of the parent compound or
active metabolites of the primary molecules (such
as cetirizine from hydroxyzine, or fexofenadine
from terfenadine) 6 .
Generally, the molecular nucleus of the H1 receptor
antagonists is necessary for their H1 affinity and
selectivity, while the side chains or radicals influence
other properties of the molecules. As an example,
the first-generation antihistamines contain aromatic
rings and alkyl substituents which render them
lipophyllic, thus explaining their ability to cross the
haemato-encephalic barrier (HEB) 7 . Efforts have
been directed at suppressing or preventing this property
by adding or eliminating radicals in the molecular
structure; thus, terfenadine requires its phenylbutanol
structure in order not to cross the HEB 4,8 ,
and loratadine has a carboxyethyl ester radical which
limits its distribution in the CNS 9 .
The ethylamine group, which is common to all
typical antihistamines, is also shared by many anticholinergic
and adrenergic blocking compounds.
For this reason, these compounds have antidopaminergic,
antiserotoninergic and antimuscarinic
effects, which in many patients become undesirable
side effects. They have, however, also been taken
advantage of for therapeutic purposes: the antiemetic
and antikinetotic actions of many antihistamines
(diphenhydramine, dimenhydrinate, phenothiazines)
are predominantly due to their central sedative
and anticholinergic properties 9 . Some antihistamines,
such as cyproheptadine, ketotifen, astemizole
and cetirizine also induce increased appetite, which
has been ascribed to an antiserotoninergic action 9 .
This undesired side effect, which is well documented
particularly in the case of cyproheptadine, has
been often taken advantage of in "reconstituents"
and preparations for the treatment of hypo-orexia 10 .
Table I. Chemical classification of the H1 antihistamines
Chemical group Typical compounds Second-generation
(first generation) compounds
Alkylamines Bromphenyramine Acrivastine
Chlorphenyramine
Triprolidine
Ethanolamines Diphenhydramine
Dimenhydrinate
Doxylamine
Carbinoxamine
Clemastine
Ethylenediamines Pirylamine
Tripelennamine
Antazoline
Phenothiazines Promethazine Mequitazine
Piperazines Buclyzine, Ciclyzine
Cinarizine, Flunarizine Oxatomide
Hydroxyzine Cetirizine
Piperidines Azatadine Loratadine
Cyproheptadine Astemizole
Ketotifen Levocabastine
Mizolastine
Ebastine
Terfenadine
Fexofenadine
Miscellany Azelastine
(ftalazinone
derivative)
MECHANISMS OF ACTION
The antihistamines behave as competitive antagonists
of histamine: they bind to the H1 receptor
without activating it, and thus prevent histamine
from binding to and activating this receptor. The
binding of many antihistamines is readily reversible
but some of them, such as terfenadine and
astemizole, are not easily dissociated from their
binding to the receptors 11 . Even though there are
some specific molecules for which such effects
have been documented, antihistamines as a group
do not chemically inactivate histamine, nor do
they antagonise it in a physiological sense, nor do
they in any manner prevent its release 9 .
Many recent studies suggest that some H1
receptor antagonists might also have antiinflammatory
or antiallergic properties in the broadest
sense of those concepts. Although the first publication
in this context referred to azatadine 12 , this
type of additional actions has been later attributed
to many second-generation antihistamines.

302 I. J‡uregui Presa Volume 14
Cetirizine 13,14 reduces the attraction of inflammatory
cells to the inflammatory focus after antigen
challenge and inhibits the expression of the intercellular
adhesion molecule 1 (ICAM-1) on the surface
of epithelial cells. It also might be able to block the
antigen-induced production of leukotrienes (LTC 4) 15 .
Loratadine and its metabolite decarboethoxyloratadine
inhibit the release of tryptase and amacroglobulin
16 , of interleukins (IL) 6 and 8 17 and
of leukotrienes and prostaglandin D2 (PGD2) 18 , and
also the expression of ICAM-1 and of HLA-II
antigens on the surface of epithelial cells 19 .
Terfenadine inhibits the inflammatory cellular
infiltrate and the eosinophil activation products in
nasal lavage fluid and also the expression of surface
ICAM-1 20 . It may also inhibit the release of leukotrienes
from basophils and eosinophils and of
histamine from basophils, as well as inhibiting skin
reactivity to the platelet activation factor (PAF) 15 .
Topical azelastine, which was initially studied as
a "dual action" antihistamine with a clinical profile
similar to that of ketotifen or oxatomide 2 , also seems
to inhibit the eosinophyllic infiltrate and the expression
of surface ICAM-1 in nasal epithelial cells 21 .
Ebastine might have an antagonist action on the
IgE-induced release of PGD2 and LTC 4/D 4 22 .
A recent study in a rat model ascribes to mizolastine
an antiinflammatory effect on the skin
reaction induced by arachidonic acid 23 .
Finally, fexofenadine inhibits the spontaneous
release of IL-6 in fibroblast cultures 24 and the
eosinophil-induced release of IL-8 and GM-CSF,
as well as the expression of surface ICAM-1 in
cultures of nasal epithelial cells.
These antiinflammatory effects of antihistamines
are not considered to be linked to H 1 receptor blockage.
As they have mostly been demonstrated in
vitro and with experimental concentrations of the
drugs that are much higher than those achieved in
vivo with the usual pharmacological dosages, their
relative importance within the overall spectrum of
the clinical efficacy of these drugs is still unknown 15 .
PHARMACOKINETICS AND
PHARMACODYNAMICS
Almost all the H1 receptor antagonists have
adequate oral absorption and can achieve maximal
plasma concentrations within the 24 hours follo-
Cl
HN
N
HISTAMINA
HISTAMINE
CH 2 CH 2 NH 2
CHLORPHENYRAMINE
CLORFENIRAMINA
N
PRIMERA FIRST-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS
DE RECEPTORES H1
Cl
CH CH 2 CH 2
CH O CH 2
CH 2
DIPHENHYDRAMINE
DIFENHIDRAMINA
Fig. 1a. Primary structure of histamine and of various H1
antihistamines.
wing administration. Most of the second-generation
antihistamines, with the exception of acrivastine,
cetirizine, levocabastine, fexofenadine and
perhaps some other active metabolites experience
hepatic first-pass metabolism, so that the plasma
concentrations of the parent drugs are usually
indetectable a few hours after administration 26 .
Nevertheless, the effects of the antihistamines, as
documented in studies of inhibition of histamineinduced
skin reactions, persist over a time that is
variable for each compound (Table II). This might
be due to a greater tissue concentration, or to active
metabolites maintaining the effect 27 .
Because all the H1 receptor antagonists inhibit
the skin reactions induced by histamine, this test
has become a standardised biologic test for the
action of antihistamines 15 . However, as several
authors have pointed out 28 , there is not always a
N
OH N N CH2CH2 O CH2CH2 O
H
N
CH 3
CH 3
CH 3
CH 3
HIDROXICINA
HYDROXYZINE

No. 5 H1 Antihistamines: a review 303
HO N
CH 3
N
CH CH
N
C CH CH 2
ACRIVASTINE
ACRIVASTINA
CH 2 CH 2 CH 2 CH C
TERFENADINA
TERFENADINE
O
LORATADINA
LORATADINE
SEGUNDA SECOND-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS
DE RECEPTORES H1 Fig. 1b. Primary structure of histamine and of various H1 antihistamines.
correlation between the degree of inhibition of the
skin response and the clinical efficacy of the
various drugs.
All the "classical" antihistamines and also many
of the second-generation ones (terfenadine 29 , ebastine
30 , astemizole 31 , loratadine 26 , mizolastine 32 ) are
metabolised to a greater or lesser extent by the
hepatic cytochrome p-450 system (CYP), a fact of
utmost importance in the development of drug interactions
and drug toxicity. The CYP is an enzymatic
system responsible for drug metabolism and
detoxification present in the liver and in other tissues,
and its constituent isoenzymes are classified
into "families" according to the similarity of their
aminoacid sequences 33 . As a result of genetic variability,
the number of p-450 isoenzymes varies, and
each drug is metabolised in a different manner 15 .
Astemizole or terfenadine are metabolised by the
3A4 family (CYP3A4). Within this same family,
some substances can behave as enzymatic inhibitors
while others act as enzyme substrates, and this
OH
N C O CH2CH2 O
C OH
HO N CH 2 CH 2 CH 2 C
Q
Q HCl
N
OH
FEXOFENADINE
FEXOFENADINA
CH 3
C
CH 3
CH 3
CH 3
CH 3
COOH
CH 2
O
AZELASTINE
AZELASTINA
N
N
N
Cl
CH N N CH2 CH2 O CH2 C OH
CH 3
ASTEMIZOLE
ASTEMIZOL
LEVOCABASTINE
LEVOCABASTINA
HC O
N CH2 CH2 CH2 C C
HC O
EBASTINE
EBASTINA
N CH 2 CH 2 CH 2 C C
CAREBASTINE
CAREBASTINA
F
NC
gives rise to multiple interactions 33 . Table III summarises
some inhibitors and substrates of the
CYP3A4. It should be noted that natural flavonoids
present in grape juice may also inhibit the 3A4
family 33,34 and that erythromycin is at the same time
inhibitor and substrate for the CYP3A4 33 .
On the other hand, erythromycin is by itself
able to block some potassium channels in the
myocardium 35 . This might be fundamental, as will
be explained later, in its interactions with some
antihistamines.
SIDE EFFECTS ON THE
CARDIOVASCULAR SYSTEM
The potential cardiotoxicity of antihistamines
was first reported in relation with astemizole 36 and
later with terfenadine 37 . Considerable attention was
focused on the latter drug, however, possibly because
it was the most widely used one in the USA 38 .
O
N
H
O
H
CH 3
CH 3
CH 3
CH 3
CH 3
O
O
C OH
CH 3
COOH

304 I. J‡uregui Presa Volume 14
Table II. Chemical classification of the H1 antihistamines 15,24,26
Drug Dose Plasma elimination Skin test Protein binding Clearance
(mg/day) half-life suppression (%) (ml á min -1 á kg -1 )
Acrivastine 16 - 24 ~2 hours 8 hours 50 4.41
Astemizole 10 - 20 12 - 20 days 6 - 8 weeks 97 11.0
Azelastine (oral) 4 - 8 22 - 42 hours 1 week 77 - 88 8.45
Bromphenyramine 9 - 18 24.9 hours 3 - 9 hours
Chlorphenyramine 6 - 12 24.2 hours 24 hours
Clemastine 2 - 3 7 - 12 hours 10 - 24 hours
Cetirizine 10 7 - 10 hours 24 - 72 hours 93 - 98 0.8
Hydroxyzine 75 20 hours 2 - 36 hours
Ebastine 10 15 hours 28 hours 97.7 1.3 - 2.0
Levocabastine
Nasal spray 0.6 35 - 40 hours 10 - 12 hours 55 0.43
Eye drops 0.2 35 - 40 hours 4 hours
Loratadine 10 8 - 24 hours 12 - 14 hours 97 - 99 ?
Mizolastine 10 14.5 hours 24 hours 1.15
Noberastine 10 15 hours 32 - 72 hours
Terfenadine 120 17 hours 24 - 72 hours 97 8.8
Fexofenadine 120 - 180 14.4 hours 24 - 72 hours
The reported arrhythmia associated to astemizole
and terfenadine is a polymorphic ventricular tachycardia
known by the name of torsades de pointes
because of its changing electrical axis in the ECG,
with waves of alternating amplitudes and directions
(Figure 2). Torsades de pointes may appear as acute
episodes with haemodynamic compromise and
even sudden cardiac death 39 and are associated to a
lengthening of the QT interval in the sinus rhythm
ECG. The QT interval itself depends on the duration
of the cardiac action potential, which is in its
turn dependent on the ionic currents and fluxes in
the myocardium and most particularly on the socalled
potassium rectifier channel 40 .
As already pointed out, terfenadine is a prodrug
acting through its acid metabolite (terfenadine
carboxylate, or fexofenadine), and this conversion
occurs through a CYP3A4-dependent hepatic
first-pass metabolism. Terfenadine is a potent
blocker of the potassium rectifier channel 41 . Its
accumulation in the organism because of overdosage
or of the concomitant administration of other
substrate drugs or CYP3A4 inhibitors may lengthen
the heart rate-corrected QT interval (QTc). If
the concomitant drug is erythromycin, which is at
the same time a CYP3A4 substrate and a
CYP3A4 inhibitor 33 and also a potassium rectifier
channel blocker 35 , the heart repolarisation derangements
will be even more marked.
This effect might perhaps be shared by all the
piperidine antihistamines 42 , but it has been
demonstrated mainly with astemizole, terfenadine
and ebastine 43 at a dosage one- to fourfold the respective
peripheral antihistamine one although not
with the active metabolites fexofenadine and carebastine,
in experimental models 44,45 . Nevertheless,
an isolated clinical observation has been published
of torsades de pointes and lengthened QT
interval in a patient with indetectable levels of
astemizole and "therapeutic" concentrations of its
major metabolite demethyl-astemizole 46 .
Cetirizine, an active metabolite of hydroxyzine,
does not prolong the QTc interval at dosages up to
sixfold the indicated therapeutic ones 47 . Loratadine
has the same interactions with macrolides and
imidazoles as the other piperidines, yet this does
not induce clinically significant changes in the
QTc interval 48,49 . It has been reported that loratadine,
contrary to astemizole, terfenadine and ebastine,
does not block the potassium channels even at
concentrations 100-fold its normal plasma level 50 .
Even so, and according to WHO drug surveillance
data, loratadine and cetirizine have also been
associated, though much less frequently than terfenadine
or astemizole, to reports of sudden or
cardiac death 51 . There are also recent experimental
studies suggesting that loratadine might be able to
block certain potassium channels 52 .

No. 5 H1 Antihistamines: a review 305
Table III. Inhibitors of the 3A4 family of cytochrome P-450
(CYP3A4)
Enzymatic inhibitors
Cimetidine, Ranitidine
Clarythromycine, Erythromycine, Troleandomycine (TAO)
Ketoconazole, Itraconazole
Fluvoxamine, Norfluoxetine (a metabolite of fluoxetine)
Natural flavonoids in grape juice
Enzymatic substrates
Astemizole, Terfenadine, Ebastine, Loratadine, Mizolastine
Cisapride
Erythromycin
A number of added risk factors for the development
of torsades de pointes in patients under treatment
with antihistamines have been considered,
such as previous hepatic dysfunction, hypokaliaemia,
hypomagnesaemia, bradycardia situations and
the congenital long QT syndrome (Table IV) 33,40 .
Even though these side effects have not been as
intensively investigated for other H1 antagonists, a
quinidine-like effect on myocardial conduction has
been described for antihistamines as a group 9. A
cohort study actually demonstrated a greater incidence
of ventricular arrhythmias and cardiac arrest
in the group of patients receiving O.T.C. antihistamines
as compared to the groups receiving terfenadine
or clemastine 53 . However, other studies have
not evidenced actions on cardiac electrophysiology
for chlorphenyramine or pirylamine, suggesting
that this may be a piperidine effect or a specific one
of astemizole, terfenadine and ebastine 54 .
The initial worry that cardiotoxicity might
represent a class effect of the antihistamines,
however, appears to be unfounded 38 considering
that fexofenadine (with negligible hepatic metabolism
24 ) and probably further active metabolites
with potent H 1-antagonist action 45 are devoid of
this adverse effect. Whatever the case may be, it
appears to be important to keep in mind all the
factors already pointed out (Table IV) when prescribing
antihistamines in clinical practise.
ANTIHISTAMINES IN BRONCHIAL ASTHMA
There is a long-standing belief that antihistamines
may be harmful in asthmatic patients because
Table IV. Risk factors for ventricular arrhythmias in patients
receiving antihistamines 33,40
1. Coadministration of other drugs
a. Agents which prolong the QT interval, such as quinidine
or erythromycin
b. Enzymatic substrates/inhibitors of CYP3A4 (Table III)
2. Preexistent liver disease
3. Electrolyte balance derangements
a. Hypokaliemia
b. Hypomagnesemia
4. Congenital long QT syndrome
5. Bradycardia situations
of the mucosal dryness effect of the anticholinergic
action of the initial preparations to which the
induction of bronchial asthma in children was
ascribed 55 . However, and considering that histamine
causes bronchial constriction and oedema, it
appears to be logical to think that antihistamines
might revert some of its effects on the bronchial
tree, and that they are not contraindicated in asthmatic
patients 56 . In this context, there is ample
experience in Spain with ketotifen, and a number
of studies suggest that azelastine, cetirizine, loratadine,
terfenadine and astemizole might at least
block the bronchospasm induced by histamine 57 .
In any case, the effects of histamine in the latephase
reaction have not been fully clarified and
further studies are warranted for defining the
effects of H1 antagonism in this late phase, particularly
in the case of the antihistamines with additional
antiinflammatory properties 15 .
As the aim of the present review is to try to
define the place of the principal antihistamines in
the therapeutic armamentarium, a brief chemical
and therapeutic discussion of the main H1 antihistamines
currently used in Spain follows as a conclusion.
"CLASSICAL" H1 ANTIHISTAMINES
Chlorphenyramine and dextrochlorphenyramine.
The prototypes of the alkylamines (propylamines),
chlorphenyramine and its isomer dextrochlorphenyramine
are used in a host of O.T.C.
"anticatarrhal" preparations, usually in associations
with vasoconstrictors, expectorants and analgesics.
Dexchlorphenyramine is furthermore the
only antihistamine available for parenteral use in

306 I. J‡uregui Presa Volume 14
Fig. 2. Ventricular tachycardia of the "torsades de pointes" variety. Simultaneous recording of leads I, II, III and V1.
our country 10 . Their plasma half-life is about 24
hours, the same as the duration of the suppression
of the skin test with histamine 57 (Table II). The
rationale for their retarded-release formulations
("Repetabs") is mainly to delay the plasma concentration
peak in order to reduce the adverse
CNS 4 effects representing the main problem of
these drugs: at therapeutic dosages they cause
somnolence, abatement of the reflexes and electroencephalographic
(EEG) changes 58 .
Diphenhydramine. In Spain, this drug is at present
only available in some anticatarrhal associations
and as an hypnotic 10 because of the intensity
of its CNS effects 58 . Its derivative dimenhydrinate
is widely used in our country as an antikinetotic.
Clemastine. This is the prototype of the ethanolamines,
the same chemical family as diphenhydramine,
in Spain. It is currently available only
for oral administration 10 . Its plasma half-life is 7-
12 hours, with a skin test suppression period of
12-24 hours. Its anticholinergic, antidopaminergic
and antiserotoninergic affects are similar to those
of the other "classical" antihistamines 9 .
Cyproheptadine and azatadine. With a very
close structural correlation between them, the two
classical piperidines are characterised by their
potent antiserotoninergic, anticholinergic and
sedative effects. The first one of these effects has
been taken advantage of for indications such as
Cushing's syndrome, the carcinoid syndrome or
vascular migraine 9 , and also in the management of
hypo-orexia 10 . Azatadine is the parent compound
of loratadine.
Hydroxyzine. This drug has an elimination halflife
of 14-20 hours in the adult and concentrates
rapidly in the skin, so that sustained high skin
concentrations can be observed after both single
and multiple dosing; it can inhibit the response to
histamine during at least 36 hours after a single
dose in healthy adult subjects 4 . It is classically
considered to be the most effective antihistamine
for the management of pruritus 59 , an effect that is
in part attributable to its potent sedative action
(which has been taken advantage of for therapeutic
purposes).
Cinarizine and flunarizine. These classical
piperazines, which are structurally different from
hydroxyzine and cetirizine, have been mostly
used for their antikinetotic activity. Flunarizine is
the bi-fluorinated derivative of cinarizine and also
has a calcium channel-blocking action 6 ; it is used
for prophylaxis of migraine and vertigo and in the
management of cerebral and peripheral vascular
conditions.
Promethazine. An ethylamine derivative of
phenothiazine, this compound has the same sedative
characteristics of other phenothiazine drugs,
together with potent antihistamine and antikineto-

No. 5 H1 Antihistamines: a review 307
tic actions 9 . During the '70s and '80s it was one of
the most widely used antihistamines in our
country despite its potential toxicity: it can cause
blood dyscrasias, neuro- and hepatotoxicity and
diverse skin reactions such as contact urticaria,
systemic contact dermatitides and phototoxic and
photoallergic reactions 60 .
SECOND-GENERATION H 1
ANTIHISTAMINES
Mequitazine. A phenothiazine derivative similar
to prometazine but without sedative effects at
the recommended dosages; this characteristic has
been attributed in principle to a greater affinity of
the drug for the peripheral than for the central H1
receptors 2 . Similar to other antihistamines, mequitazine
has evidenced bronchodilator activity
which was in this case ascribed to the calmodulininhibiting
ability of phenothiazines, which would
thus interfere the action of phospholipase A 2 61 .
With the exception of the absence of sedation at
low dosages, its adverse effects are those of phenothiazines
as a group 9 .
Ketotifen. A derivative of the tricyclic compound
benzo-cyclo-heptathiofene, this drug has
been marketed as a membrane stabiliser for the
effector cells of the allergic reactions. Its pharmacologic
profile is similar to that of the cromones,
and it is orally active 62 . Its main action, however,
is a double competitive and non-competitive inhibition
of the H1 receptor 2 . It shares with other
older antihistamines the sedative and antiserotoninergic
effects 2,6,9 .
Oxatomide. This is a piperazine and structurally
and chemically very similar to the antikinetotic
cinarizine. Also oxatomide was marketed as a
mastocyte degranulation inhibitor 63 ; however,
and similar to ketotifen, its main effects are H1
antihistaminic, anticholinergic and antiserotoninergic
2,64 . Recent publications from Japan stress its
various antiinflammatory and antiallergic
actions 65,66 .
Astemizole. This molecule is metabolised by
the hepatic cytochrome p-450 to demethyl-astemizole
(DMA), which has significant antihistamine
activity. Once oral administration is begun, stable
plasma concentrations of astemizole are achieved
after one week, and the plasma concentrations of
astemizole plus its metabolites persist for over
four weeks 31 . Astemizole has a half-life of 1.1
days, and its metabolite DMA 9.5 days 4 . The suppressive
effects on the skin response to histamine
and the histamine-induced bronchoconstriction
may persist for four to six weeks (Table II). As
pointed out earlier, it is subject to the drug interactions
of other antihistamines metabolised by
the hepatic cytochrome p-450 and together with
DMA is potentially cardiotoxic 36,46 . Astemizole
has not been associated to drowsiness, but it has
been associated to weight gain4.
Terfenadine. This is chemically a butyrofenone
derivative 29 and it is the most representative one
among the non-sedative antihistamines, as it does
not cross the haemato-encephalic barrier due to its
phenylbutanol structure 8 . Its half-life is 16 to 24
hours and, as already stated, it is a prodrug acting
through its acid metabolite, terfenadine carboxylate
or fexofenadine, after first-pass hepatic metabolism.
Terfenadine rapidly inhibits the skin response
to histamine, and this effect persists for
seven days more after the withdrawal of the
drug 4,29 . Its drug interactions and its cardiotoxic
potential have already been discussed. In a number
of studies, the side effects of terfenadine on
the CNS and on the gastrointestinal tract, as well
as its anticholinergic effects, have been similar to
those of placebo 9 .
Azelastine. This is a ftalazinone derivative and
structurally unrelated to other antihistamines. It
was initially investigated for oral use as an inhibitor
of the mastocitary release of inflammatory
mediators 67 . It is metabolised through hepatic oxidation;
although it has a 22-hour half-life, its
pharmacologically active major metabolite,
demethyl-azelastine, has a half-life of 54 hours 68 .
It is available in Spain for topical use as nasal
spray and eye drops, and has demonstrated significant
inhibition of the intranasal response to histamine
69 and effectiveness in the control of the
symptoms of rhinitis similar to that of a number
of systemic antihistamines 70 . Dysgeusia, or changes
in taste perception, is the most frequently
reported adverse effect 4,70 .
Levocabastine. This cyclohexyl-piperidine was
developed for topical ocular and nasal administration.
It has a 35 - 40 hour half-life and little or no
systemic absorption 71 . In controlled studies it has
been less effective that topical steroids 4 but at

308 I. J‡uregui Presa Volume 14
least as effective as disodium cromoglycate 4 , topical
azelastine 72 , terfenadine 73 or loratadine 74 in the
control of the symptoms of allergic rhinoconjunctivitis.
It is available as nasal sprays and eye
drops.
Cetirizine. This is the acid metabolite of
hydroxyzine. Forty to sixty per cent of the amount
administered is excreted unchanged in the urine
and its elimination is reduced in renal failure 14 .
Like hydroxyzine, it is rapidly concentrated in the
skin. It is considered to be the most effective
antihistamine, with the exception of astemizole,
for the suppression of the skin response to histamine
4,28 . The beginning of its action occurs one
hour after administration and its peak effect is
seen 4 to 8 hours after administration 14 . As previously
stated, it has been attributed antiinflammatory
13 and antiasthmatic 15 effects. As it is not
metabolised by the CYP, it lacks the drug interactions
of other compounds 26 . Cetirizine does not
prolong the QTc interval at doses up to sixfold the
therapeutic ones 47 . Even though in more objective
studies cetirizine has no effect on the psychomotor
performance at dosages up to 10 mg/day 4 , the
clinical experience shows that it causes subjective
drowsiness, which may be its major drawback.
Loratadine. This is a piperidine with a structure
similar to that of azatadine, from which it differs
in the presence of a carboxyethyl radical that
limits its distribution in the CNS 9 . Loratadine is a
prodrug that is metabolised to a large extent by
the CYP3A4 system to its active metabolite
decarboethoxy-loratadine (DCL) 75 . Its half-life is
8 to 11 hours, and that of DCL 17 to 23 hours. At
the recommended dosages it does not cause sedation
and does not have cardiovascular effects 76 .
Loratadine is less effective than other piperidines
in the suppression of the skin response to histamine,
but this does not appear to hamper its clinical
efficacy 28 . Because of its hepatic first pass metabolism,
loratadine has the same drug interactions
with macrolides and imidazoles as other piperidines
but, as already stated, this does not cause significant
changes in the QTc interval 48,49 , as it is not
a potent potassium channel blocker 50 .
Ebastine. Chemically this is a piperidino-butyrofenone
6 , and it is structurally very similar to the
terfenadine molecule (Fig. 1 b). It is also a prodrug
and is metabolised by the hepatic CYP3A4
system in first-pass metabolism, after which it
acts through its carboxylated metabolite carebastine
(or LAS-X-113), with a half-life of 10.6
hours 77 . As already stated, and because they share
chemical structure and metabolic pathways, ebastine
has the same drug interactions as terfenadine
30 . At least in theory, might also share a similar
cardiotoxicity risk as it blocks the myocardial
potassium rectifier channel 43 , though to a lesser
degree than terfenadine 44 and its therapeutic dosage
is also six times lower. Its acid metabolite carebastine
is devoid of these effects and interactions
44,45 . On the other hand, ebastine has been
demonstrated not to have anticholinergic actions,
nor does it impair the psychomotor performance
at therapeutic dosages 78 .
Mizolastine. Its structure is that of a piperidinebenzoimidazole
derivative; it acts as a specific
ligand for the H1 receptors with peak antihistamine
activity four hours after administration, which
is maintained for approximately 24 hours 32 . Its
effectiveness in the suppression of the skin reaction
to histamine is similar to that of cetirizine and
terfenadine, and greater than that of loratadine 79 . It
is metabolised in the liver, predominantly through
glucuronisation of the original molecule and to a
much lesser degree through oxidation through the
CYP3A4 and CYP2A6 systems 32 , although it evidences
the same interactions with imidazoles and
macrolides as other piperidines 32 . As no active
metabolites have been detected 80 , its pharmacologic
activity appears to depend on the original
compound. Mizolastine does not cause sedation at
a dosage of 10 mg/day but it does so at 20
mg/day 81 ; it does not appear to interact significantly
with alcohol 82 , or to have anticholinergic
effects 83 .
Fexofenadine. This is the acid metabolite of terfenadine.
As already stated, 99% of the administered
dose of terfenadine undergoes first-pass
hepatic metabolism to its carboxylic acid metabolite,
and acts through it. Fexofenadine has a distribution
phase of 2 to 4 hours and an elimination
phase of 17 hours 24 , and shares the antihistamine
properties and the lack of sedative and anticholinergic
effects of the parent compound. However,
as it undergoes practically no metabolisation in
the liver 24 , it does not interact with the imidazoles
or the macrolides nor, foreseeably, with other
inhibitors or substrates of the cytochrome p-450.
As it does not inhibit the myocardial K + chan-

No. 5 H1 Antihistamines: a review 309
nels 45 , it has no effects on the QTc interval of the
ECG 24,33,38 . Fexofenadine has been investigated in
multiple clinical studies in allergic rhinitis and
chronic urticaria at dosages of 60 mg/12 hours
and at single daily doses of 120 mg, 180 mg and
240 mg 24,84,85 . It has evidenced optimal efficacy
and tolerability although in a number of studies
there does not appear to exist a linear dose-response
relationship between a given dosage and
the reduction of symptoms 15 . On the basis of these
clinical studies, the dosage recommended as
the optimal one for adults and children over 12
years is 120 mg once a day for allergic rhinitis,
and 180 mg once a day for chronic urticaria 86 . On
the other hand, fexofenadine does not interact
with alcohol nor does it affect psychomotor performance,
and preliminary studies suggest that no
dose adjustment is required in the elderly nor in
patients with hepatic or renal failure 24,86 .
Others. There are many new H1 receptor antagonists
which have not yet been marketed in Spain,
such as acrivastine (a triprolidine metabolite with a
very short duration of action requiring four times
daily dosage 4 ), noberastine (an astemizole derivative
with a faster beginning of action than the parent
compound 87 ) or epinastine (an antihistamine with
antiinflammatory actions studied fundamentally in
Japan for use in bronchial asthma 88 ). A number of
new molecules are currently under study for oral or
topical administration, but it is still too early to
define their eventual role.
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