Arrhythmogenic mechanisms of non‐sedating antihistamines

Abstract

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. Recently, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe arrhythmias, namely torsades de pointes, particularly in overdosage, concomitant ingestion of imidazole or macrolide antibiotics and in patients with underlying cardiac or liver diseases. It has now been shown that the molecular target in human ventricle for the potassium channel blockade of antihistamine is HERG gene located in chromosome 7 that expresses the delayed rectifier IKr and appears to be involved in the congenital long QT syndrome. Mechanistic studies showed that blockade of IKr channels by these drugs leads to prolongation of the monophasic action potential (QT interval on surface electrocardiogram) which may then induce the development of early after-depolarization and dispersion of repolarisation leading to torsades de pointes through re-entry mechanism. There are still many questions that need to be answered such as the roles of other potassium channels (IKs, Ito, and Iped) and the relative expression of various potassium channels in different individuals which may be important in the pathogenesis of torsades de pointes with non-sedating antihistamines. There is also a lack of information on the cardiac actions of newer non-sedating antihistamines. It is hoped that with a better understanding of the arrhythmogenic mechanism of non-sedating antihistamines, one will be able to identify those at risk patients and prevent any cardiac toxicity associated with antihistamines and ultimately death.

Clinical outcomes and adverse effect monitoring in allergic rhinitis

“…Factors that increase the risk of H 1 -antihistamine-induced cardiac toxicity are listed in Table III. [128][129][130][131] The chief mechanism underlying the cardiac toxicity of H 1 -antihistamines is blockade of the potassium channels involved in action potential repolarization in the ventricular myocardium-in particular, blockade of the rapidly activating component of the delayed rectifier K 1 current (IKr) component of the cardiac repolarizing current. The slowly activating component of the delayed rectifier K 1 current (IKs) and inward rectifier component of the delayed rectifier K 1 current (IKi) channels, which are expressed to different degrees in different individuals, may also be involved.…”

“…This may then induce the development of early after-depolarizations and dispersion of repolarization, leading to torsade de pointes through re-entry mechanisms. [130][131][132] Clinical evidence of cardiac toxicity of H 1 -antihistamines (torsade de pointes and other ventricular arrhythmias) is extremely rare, 128,133 in contrast with the near-ubiquitous CNS adverse effects of the first-generation H 1 -antihistamines. Astemizole and terfenadine were used for many years in hundreds of thousands of patients before their adverse cardiac effects became apparent.…”

“…134 All new H 1 -antihistamines are now studied in vitro and in animal models for cardiotoxic potential before being administered to human beings. 130,131,[135][136][137] One useful screening test is based on their ability to block the potassium channel encoded by the human ether-a-go-gorelated gene in Xenopus oocytes, which represents the molecular basis of the IKr channel. 132,138 Because there is no correlation between human ether-a-go-go-related gene blockade/cardiotoxic potential and H 1 -antihistamine activity, the cardiotoxic effects of H 1 -antihistamines are not a class effect.…”

“…Measurement of cardiac effects of H 1 -antihistamines in human beings is summarized in Table III. [129][130][131]139,140 Prospective clinical studies involve repetitive escalating doses, potential drug interactions, long-term daily administration, and postmarketing surveillance. In these studies, the second-generation H 1 -antihistamines cetirizine, fexofenadine, and loratadine appear to be free from cardiac toxicity.…”

How to Assess QT Prolongation in Clinical Studies-Implications of the ICH E14 Guidance Document

“…This was the first regulatory document that specifically addressed how to study QT prolongation during development of new drugs and was issued as a response to increasing awareness of proarrhyth mias induced by non-cardiovascular drugs 2-6). For a number of these drugs, QT prolongation and torsades de pointes (TdP) had been observed at standard doses, especially in individuals with impaired drug metabolism with resulting high plasma concentrations [6][7][8]. In the view of some major regulatory agencies, in particular the FDA, the measures proposed in CPMP's 'Points to con sider' document did not provide sufficient protec tion against new drugs with proarrhythmic propen sity.…”