Pharmacokinetic overview of oral second-generation H1 antihistamines

Specific H1 antihistamines have become the standard of treatment for relief of symptoms associated with seasonal allergic rhinitis. First-generation antihistamines are small lipophilic molecules that are associated with numerous adverse events largely because of their propensity to cross the blood-brain barrier and their cholinergic activity. Second-generation antihistamines, being more lipophobic, offer the advantages of a lack of CNS and cholinergic effects such as sedation and dry mouth, which are commonly seen in first-generation antihistamines. Their longer duration of action also enables a more patient-friendly dosing regimen which increases patient compliance. This paper reviews the pharmacokinetic properties of these second-generation agents and is intended to provide comparisons that help explain differences in dosing profiles and drug interactions for members of this class of drugs. With the announced withdrawal of terfenadine from the U.S. market in early 1997, 4 second-generation antihistamines are currently widely available: astemizole, loratadine, cetirizine, and fexofenadine. Terfenadine and astemizole both produce significant cardiac QT interval prolongation that may progress to a rare but fatal cardiac ventricular tachycardia known as torsades de pointes. While only terfenadine has been withdrawn due to its adverse effects profile, significant warnings were recently issued for astemizole. The pharmacokinetic profiles of loratadine and cetirizine are reflective of the advantages of these agents as non-cardiotoxic antihistamines. With respect to the newest agent fexofenadine, the major metabolite of terfenadine, published reports are minimal, but its pharmacokinetics differs from that of terfenadine.