The current cardiac safety situation with antihistamines.

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. The clinical interest of classical 'first generation' antihistamines is currently rather limited by their anticholinergic and sedative properties. The second generation of antihistamines, so-called non-sedating antihistamines, are free of these side-effects. However, since the 1990s, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe dysrhythmias. These drugs prolong the monophasic action potential and surface electrocardiographic QT interval and may lead to the development of early after-depolarization and possibly torsades de pointes through an inhibition of potassium channel repolarization. Concomitant administration with drugs that inhibit the hepatic cytochrome P-450 (imidazole antifungals, macrolide antibiotics) or those that prolong the QT interval by the same or other mechanism (e.g. antiarrhythmics, antipsychotics, tricyclic antidepressants) increases their effect on the cardiac repolarization. The cardiac safety profile of newer non-sedating antihistamines requires confirmation. Drugs with low or no potential to block the K + rectification channel (e.g. IKr channels) are likely to possess cardiac safety advantages. Other drug-related factors such as the physico-chemical properties of the antihistamines and its metabolic profile may also contribute to the cardiac response. Mizolastine is a new non-sedating antihistamine with antiallergic properties. It has a good bioavailability and a metabolism via the cytochrome P-450 oxidation accounting for only 35% of its hepatic clearance. In addition, mizolastine displays low lipophilicity and consequently low cardiac tissue fixation. In clinical studies, mizolastine has not shown any dose-related increase in QT intervals. Its clinical use has not been associated with ventricular dysrhythmias. Thus, although the post-marketing experience with mizolastine is still limited, mizolastine offers a safe alternative for the therapeutic management of allergic rhinitis and urticaria. However, more data are still needed on the cardiac safety of this and other non-sedating antihistamines.