Loratadine blockade of K+ channels in human heart: Comparison with terfenadine under physiological conditions

Recently, there has been considerable attention focused on drugs that prolo ng the QT interval of the electrocardiogram, with the H-1-receptor antagoni st class of drugs figuring prominently. Albeit rare, incidences of QT prolo ngation 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 rep olarization. Several studies have demonstrated block of multiple cardiac K channels by terfenadine, including I-to, I-sus, I-K1, and I-Kr or human et her-a-go-go-related gene (HERG). In contrast to terfenadine, previous studi es 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 c ardiac K+ channel-blocking profile for loratadine and terfenadine under phy siological conditions [37 degrees C, holding potential (V-hold) = -75 mV] w ith 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 stu died in stably transfected HEK cells. In contrast to previous studies in no nhuman systems and/or under nonphysiological conditions, terfenadine (1 mu M) had no effect on I-to, I-sus,or I-K1 at pacing rates up to 3 Hz. Similar results were found for 1 mM loratadine. However, both drugs potently block ed HERG current amplitude, with a mean IC50 of 173 nM for loratadine and 20 4 nM for terfenadine (pacing rate, 0.1 Hz). Neither drug exhibited any sign ificant use-dependent blockage of HERG (pacing rates = 0.1- 3 Hz). These re sults point to a similarity in the human cardiac K+ channel-blocking effect s of loratadine and terfenadine and provide a possible mechanism for the ar rhythmias associated with the use of either drug.