Cardiotoxic potential and CNS effects of first-generation antihistamines

The recent discovery of the serious cardiotoxic potential of the second-generation antihistamines terfenadine and astemizole has prompted a re-examination of the possible adverse effects exerted by older compounds belonging to this therapeutic class of drugs. Several clinical and preclinical studies suggest that these first-generation molecules share similar pharmacodynamic properties with newer cardiotoxic histamine H1 receptor antagonists. Both first-generation antihistamines hydroxyzine (HYD) and diphenhydramine (DPH), like astemizole and terfenadine, can act as blockers of the K+ channels encoded by the human ether-á-go-go-related gene (HERG), termed KV(r), which are the molecular determinants of the rapid component of the cardiac repolarizing current IK(Vr), and are involved in the control of neuronal excitability. Experiments performed with DPH derivatives (including the anti-parkinsonian drug orphenadrine) suggest that blockade of KV(r) channels by these compounds is independent of their ability to antagonize H1 receptors. Therefore, caution should be exercised when administering first-generation antihistamines to patients at risk of developing cardiac arrhythmias, epileptic manifestations, or both.