Selective inhibition of peripheral histamine responses by loratadine and terfenadine

To determine the selectivity of the non-sedating antihistamines loratadine and terfenadine and the sedating antihistamine diphenhydramine for peripheral and central histamine H1-receptors, these compounds were examined against intravenous (i.v.) and intracerebroventricular (i.c.v.) histamine-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs. Animals were prepared with i.c.v. or i.v. cannulas and instrumented for the measurement of airway resistance (RAW) and dynamic lung compliance (CDyN). Loratadine, terfenadine or diphenhydramine were administered orally 2 h before either i.v. or i.c.v. injection of histamine. Each antihistamine blocked the i.v. histamine bronchospasm with the order of potency loratadine (ED40 = 0.08 mg/kg) greater than terfenadine (ED40 = 0.44 mg/kg) greater than diphenhydramine (ED40 = 5 mg/kg). These drugs also blocked i.c.v. histamine-induced bronchoconstrictions, but loratadine and terfenadine were approximately 10 times less potent against i.c.v. histamine bronchoconstriction than they were against i.v. histamine. In contrast, diphenhydramine was equipotent against i.c.v. and i.v. histamine bronchoconstriction. These results demonstrate that the non-sedating antihistamines loratadine and terfenadine, unlike diphenhydramine, are more effective against peripheral than central H1-receptors, probably because of poor penetration of the blood-brain barrier.