Loratadine Blockade of K⁺ Channels in Human Heart: Comparison with Terfenadine under Physiological Conditions

Abstract

Recently, there has been considerable attention focused on drugs that prolong the QT interval of the electrocardiogram, with the H₁-receptor antagonist class of drugs figuring prominently. Albeit rare, incidences of QT prolongation and ventricular arrhythmias, in particular torsade de pointes, have been reported with the antihistamines astemizole and terfenadine and more recently with loratadine. The most likely mechanism for these drug-related arrhythmias is blockage of one or more ion channels involved in cardiac repolarization. Several studies have demonstrated block of multiple cardiac K⁺ channels by terfenadine, includingI_to, I_sus,I_K1, and I_Kr or human ether-a-go-go-related gene (HERG). In contrast to terfenadine, previous studies have shown the antihistamine loratadine to be virtually free of cardiac ion channel-blocking effects. This disparity in the lack of any significant cardiac ion channel-blocking effect and the existence of numerous adverse cardiac event reports for loratadine prompted the comparison of the human cardiac K⁺channel-blocking profile for loratadine and terfenadine under physiological conditions [37°C, holding potential (V_hold) = −75 mV] with the whole-cell patch-clamp method. Isolated human atrial myocytes were used to examine drug effects on I_to,I_sus, and I_K1, whereas HERG was studied in stably transfected HEK cells. In contrast to previous studies in nonhuman systems and/or under nonphysiological conditions, terfenadine (1 μM) had no effect onI_to, I_sus, orI_K1 at pacing rates up to 3 Hz. Similar results were found for 1 μM loratadine. However, both drugs potently blocked HERG current amplitude, with a mean IC₅₀ of 173 nM for loratadine and 204 nM for terfenadine (pacing rate, 0.1 Hz). Neither drug exhibited any significant use-dependent blockage of HERG (pacing rates = 0.1–3 Hz). These results point to a similarity in the human cardiac K⁺ channel-blocking effects of loratadine and terfenadine and provide a possible mechanism for the arrhythmias associated with the use of either drug.