Antihistamines: a review

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