Antihistamines: a review

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 .