Terfenadine, the first non-sedating antihistamine

Alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) is a potent antagonist of histamine H1-receptor-mediated responses both in vitro and in vivo; no anticholinergic, antiserotonergic or antiadrenergic effects can be demonstrated with terfenadine. In vitro mechanism studies suggest that terfenadine antagonizes histamine in a dualistic manner: competitive at concentrations of 3.16 X 10(-8)-1 X 10(-7) mol/l and unsurmountable at concentrations of 3.16 X 10(-7)-1 X 10(-6) mol/l. In vitro and ex vivo experiments have shown terfenadine to associate/dissociate with histamine H1-receptors much more slowly than a classical competitive antihistamine, chlorpheniramine. Ex vivo experiments as well as radioactive disposition/autoradiographic studies have demonstrated that terfenadine or its metabolites do not readily penetrate into the brain, a finding which suggests an explanation for the lack of CNS effects in both animal and human studies. Clinically, terfenadine is effective against perennial allergic rhinitis, acute seasonal allergic rhinitis and allergic skin conditions while being devoid of CNS effects including sedation, psychomotor impairment or interaction with diazepam or alcohol. Thus, terfenadine is a new antihistamine with a completely different and novel profile from the "classical antihistamines" and as such should prove to have significant clinical advantages for the symptomatic treatment of histamine-associated disorders.