Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity

Despite the enormous success of second generation antihistamines, in the mi d-1980s, about 10 years after their introduction in the market, several rep orts appeared in the literature indicating the rare occurrence of a form of polymorphic ventricular dysrhythmia, the 'torsade de pointes', after the a dministration of astemizole or terfenadine. This cardiac side-effect has be en interpreted as a consequence of the interference of these drugs with car diac K+ channels involved in action potential repolarization, and in partic ular with the IKr component of the cardiac repolarizing current. As the Kchannels encoded by the human ether-a-gogo-related gene (HERG) seem to repr esent the molecular basis of IKr, this cardiac K+ channel was soon recogniz ed as a primary target for second generation antihistamine-induced proarrhy thmic effects. In fact, bath terfenadine and astemizole have been shown to block HERG K+ channels in a concentration range similar to that found in th e plasma of subjects with cardiotoxic manifestations. However, no correlati on can be found between the ability to prolong the cardiac action potential duration and the H-1-antagonistic activity by several antihistamines, sugg esting that HERG blockade and cardiotoxic potential are not class propertie s of second generation antihistamines. In fact, other molecules such as cet irizine, loratadine, acrivastine, and fexofenadine seem to lack both cardio toxic potential and HERG-blocking ability at therapeutically relevant conce ntrations. The marked heterogeneity displayed by second generation antihist amines in their ability to prolong the cardiac action potential duration an d to block HERG K+ channels might be of considerable therapeutical signific ance for those patients at risk of developing cardiac dysrhythmias and in n eed of therapy with H-1-receptor blockers: it also emphasizes the importanc e of an evaluation of the possible blockade of HERG K+ channels during the early developmental phases of novel compounds belonging to this therapeutic al class.