Kestine Mechanism of Action

Pharmacotherapeutic group: Antihistamines for systematic use, Other antihistamines for systemic use. ATC code: R06AX22.
Pharmacology: Pharmacodynamics: Mechanism of action: Ebastine causes rapid and prolonged inhibition of the effects induced by histamine, and presents a strong affinity for binding to H₁ receptors.
Neither ebastine nor its metabolites cross the blood-brain barrier after oral administration. This characteristic tallies with the low sedation profile observed in the results of experiments studying the effects of ebastine on the central nervous system.
In vitro and in vivo data demonstrate that ebastine is a potent antagonist with a prolonged effect and highly selective to H₁ histamine receptors. It is free of adverse effects on the CNS and of anticholinergic effects.
Pharmacodynamic effects: Studies carried out on histamine-induced papulae have demonstrated a clinically and statistically significant antihistamine effect, initiating after 1 hour and lasting more than 48 hours. The antihistamine effect was apparent for more than 72 hours after suspending administration in a 5-day treatment with ebastine. This activity was parallel with plasma levels of the main active acid metabolite, carebastine.
The inhibition of the peripheral receptors remained at a constant level after repeated administration, with no tachyphylaxis. These results suggest that a dose of less than 10 mg of ebastine causes rapid, intense and lasting inhibition of the peripheral H₁ histamine receptors, consistent with a single daily administration.
Sedation was studied via the following tests: electroencephalogram, cognitive function, visual-motor coordination, as well as subjective estimations. No significant increase in sedation was observed at the recommended dose. These results tally with those obtained in double blind clinical trials: the incidence of sedation is comparable between placebo and ebastine.
The cardiac effects of ebastine have been investigated in clinical trials. No significant cardiac effects were observed in detailed analyses of doses of up to 100 mg daily (ten times the recommended daily dose).
Pharmacokinetics: Ebastine is rapidly absorbed after administration by the oral route. It undergoes notable first pass hepatic metabolism, giving rise to the appearance of its active acid metabolite, carebastine.
Maximum metabolite plasma levels after a single oral dose of 10 mg are obtained between 2.6 and 4 hours after administration. They reach values of 80 to 100 ng/ml. The half-life of the acid metabolite occurs between 15 and 19 hours, with 66% of the compound excreted in urine, mainly in the form of conjugated metabolites. After repeated administration of 10 mg once daily, steady state was reached after 3 to 5 days with maximum plasma levels between 130 and 160 ng/ml.
In vitro studies with human hepatic microsomes show that ebastine is metabolised to carebastine via enzyme CYP3A4. Concomitant administration of ebastine and ketoconazole or erythromycin (both are CYP3A4 inhibitors) in healthy volunteers was associated with significantly raised ebastine and carebastine plasma concentrations, particularly with ketoconazole (see Interactions).
Both ebastine and carebastine present high protein binding: >97%.
No statistically significant differences were observed in the pharmacokinetic profile of the elderly when compared to young adults.
Ebastine and carebastine plasma concentrations obtained on the first and fifth day of treatment in patients in studies of slight, moderate or severe renal impairment (daily doses of 20 mg), and in those of slight and moderate hepatic impairment (both with doses of 20 mg/day) or severe hepatic impairment (dose of 10 mg/day) were similar to those reached in healthy volunteers, indicating that the pharmacokinetic profile of ebastine and its metabolite do not undergo significant changes in patients with various degrees of hepatic or renal impairment.
Toxicology: Preclinical safety data: The preclinical data do not reveal significant toxic effects based on conventional pharmacological safety studies, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicology.