Co-Aleva Mechanism of Action

Antihistamine/Corticosteroid.
Pharmacology: Pharmacodynamics: Pre-Clinical: Ebastine has been shown to produce a rapid and long-lasting inhibition of histamine-induced effect and to have a strong affinity towards H₁-receptors. Following oral administration neither Ebastine nor its metabolites cross the blood-brain barrier. This characteristic is consistent with the low sedative profile seen 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, long-lasting and highly selective histamine H₁-receptor antagonist devoid of untoward CNS actions and anticholinergic effects.
Clinical: Histamine skin wheal studies have shown a statistically and clinically significant antihistamine effect beginning at 1 hour and lasting in excess of 48 hours. After the discontinuation of the administration of a 5-day course treatment with Ebastine, the antihistamine activity remained apparent for more than 72 hours. This activity parallels the plasma levels of the main active acid metabolite, carebastine.
After repeated administration, inhibition of the peripheral receptors remained at a constant level, without tachyphylaxis. These results suggest that Ebastine at a dose of at least 10 mg produces a rapid, intense and long-lasting inhibition of peripheral H₁ histamine receptors, consistent with a once-a-day administration.
Sedation was studied through pharmaco-EEG, cognitive performance, visual-motor coordination tests and subjective estimates. There was no significant increase of sedation at the recommended dose. These results are consistent with those from double blind clinical trials. The incidence of sedation is comparable between placebo and Ebastine.
Pharmacokinetics: Ebastine is rapidly absorbed and undergoes extensive first pass metabolism following oral administration. Ebastine is almost totally converted to the pharmacologically active acid metabolite, carebastine.
After a single 10 mg oral dose, peak plasma levels of the metabolite occur at 2.6 to 4 hours and achieve levels of 80 to 100 ng/mL. The half-life of the acid metabolite is between 15 and 19 hours with 66% of the drug being excreted in the urine mainly as conjugated metabolites. Following the repeated administration of 10 mg once-daily, steady state was achieved in 3 to 5 days with peak plasma levels ranging from 130 to 160 ng/mL.
In vitro studies with human liver microsomes show that Ebastine is metabolized to carebastine predominantly via the CYP3A4 pathway. Concurrent administration of Ebastine with ketoconazole or erythromycin (both CYP3A4 inhibitors) to healthy volunteers was associated with significantly increased plasma concentrations of Ebastine and carebastine, especially with ketoconazole.
Both Ebastine and carebastine are highly protein bound, 95%. In elderly subjects, no statistically significant changes were observed in the pharmacokinetics compared to those of young adult volunteers. In patients with renal insufficiency the elimination half-life of carebastine was increased to 23-26 hours. Similarly, in patients with hepatic insufficiency, the half-life is increased to 27 hours.
Corticosteroids like Betamethasone are readily absorbed from the gastrointestinal tract. It is rapidly distributed to all body tissues. They cross the placenta to varying degrees and may be excreted in small amounts in breast milk. Most corticosteroids in the circulation are extensively bound to plasma proteins, mainly to globulin and less so to albumin. The corticosteroid-binding globulin has high affinity but low binding capacity. The synthetic corticosteroids are less extensively protein bound than hydrocortisone. They also tend to have longer half-lives. Corticosteroids are metabolized mainly in the liver but also in other tissues and are excreted in the urine. The slower metabolism of synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.