Antihistamines: a review

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