Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity

Abstract

Despite the enormous success of second generation antihistamines, in the mid-1980s, about 10 years after their introduction in the market, several reports appeared in the literature indicating the rare occurrence of a form of polymorphic ventricular dysrhythmia, the 'torsade de pointes', after the administration of astemizole or terfenadine. This cardiac side-effect has been interpreted as a consequence of the interference of these drugs with cardiac K+ channels involved in action potential repolarization, and in particular with the IKr component of the cardiac repolarizing current. As the K+ channels encoded by the human ether-a-gogo-related gene (HERG) seem to represent the molecular basis of IKr, this cardiac K+ channel was soon recognized as a primary target for second generation antihistamine-induced proarrhythmic effects. In fact, both terfenadine and astemizole have been shown to block HERG K+ channels in a concentration range similar to that found in the plasma of subjects with cardiotoxic manifestations. However, no correlation can be found between the ability to prolong the cardiac action potential duration and the H1-antagonistic activity by several antihistamines, suggesting that HERG blockade and cardiotoxic potential are not class properties of second generation antihistamines. In fact, other molecules such as cetirizine, loratadine, acrivastine, and fexofenadine seem to lack both cardiotoxic potential and HERG-blocking ability at therapeutically relevant concentrations. The marked heterogeneity displayed by second generation antihistamines in their ability to prolong the cardiac action potential duration and to block HERG K+ channels might be of considerable therapeutical significance for those patients at risk of developing cardiac dysrhythmias and in need of therapy with H1-receptor blockers; it also emphasizes the importance of an evaluation of the possible blockade of HERG K+ channels during the early developmental phases of novel compounds belonging to this therapeutical class.

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

“…Over the past 30 years, second-generation antihistamines have been developed, which have less central activity and therefore do not cause the drowsiness. Overdose of both first-and second-generation antihistamines can cause severe cardiac arrhythmia (Hestand and Teske, 1977;Craft, 1986;Taglialatela et al, 2000) by directly inhibiting cardiac K ＋ currents (Taglialatela et al, 1999). These findings led us to hypothesize that chlorpheniramine, one of first-generation antihistamines, may exert arrhythmic effects by affecting K ＋ currents.…”

Antimuscarinic actions of antihistamines on the heart

“…The cardiovascular effects of antihistamines have been studied more intensely in recent years due to the untoward effect of terfenadine and astemizole to cause cardiac arrhythmias [4]. The arrhythmias, in the case of terfenadine, were caused by the altered pharmacokinetics of the antihistamine in patients when concurrent administration of an antibiotic or antifungal (e.g., erythromycin, ketoconazole) caused elevated plasma levels of the antihistamine [9].…”

“…The arrhythmias, in the case of terfenadine, were caused by the altered pharmacokinetics of the antihistamine in patients when concurrent administration of an antibiotic or antifungal (e.g., erythromycin, ketoconazole) caused elevated plasma levels of the antihistamine [9]. The high levels of antihistamine inhibited HERG potassium channels in the heart and resulted in Torsades de pointe, a serious arrhythmia [4]. All of the second generation compounds are now tested for effects on the HERG channel and none interact significantly.…”

“…The newer agents also cause less drowsiness than first generation antihistamines (e.g., diphenhydramine) [2]. In addition, the newest compounds do not interact with HERG channels in the heart to cause a prolonged QT syndrome as did terfenadine, the parent compound of fexofenadine [3,4].Another potential interaction of antihistamines with cardiac function is at receptors involved in modifying heart rate and contraction. The first generation compounds were known to be competitive inhibitors of muscarinic receptors [5] and caused tachycardia by impairing vagal tone on the heart and xerostomia by inhibiting muscarinic stimulation of salivary function.…”

“…The newer agents also cause less drowsiness than first generation antihistamines (e.g., diphenhydramine) [2]. In addition, the newest compounds do not interact with HERG channels in the heart to cause a prolonged QT syndrome as did terfenadine, the parent compound of fexofenadine [3,4].…”