Antihistaminic effect of terfenadine: A new piperidine‐type antihistamine

The antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine-induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7 M, shifted the histamine dose-response curve to the right in a parallel fashion without affecting the dose-response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7 and 1 × 10−6 M) the histamine dose-response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose-response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose-response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose-response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine-induced death in guinea pigs. Terfenadine produced no atropine-like effect against pilocarpine-induced salivation in rabbits, no demonstrable histamine H2 antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.