ARRHYTHMOGENIC ACTIONS OF ANTIHISTAMINES

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Only in recent years has it become accepted that antihistamines have the potential to adversely effect cardiac rhythm. The ability of terfenadine and astemizole to prolong cardiac repolarization and induce the syndrome of torsades de pointes, demonstrated the need for careful evaluation of the cardiovascular actions of other antihistamines. The Food and Drug Administration now requires complete evaluation of the cardiac actions and arrhythmogenic potential of newly developed antihistamines. However, the older antihistamines still in widespread clinical use, such as diphenhydramine, also require testing. In this application, we propose to systematically evaluate in vitro the arrhythmogenic potential of selected first generation antihistamines (cyproheptadine, hydroxyzine, promethazine, chlorpheniramine, phenindamine and clemastine) alone and combined with drugs likely to interact. We will also seek confirmation of the clinical relevance of results obtained in in vitro models which indicate that drugs or combinations should have effects on myocardial repolarization in man. We will apply a three-stage approach in this work. Antihistamines will be examined for their ability to block potassium channels in feline cardiac myocytes using the whole cell patch technique. Those found to block potassium channels will be evaluated in isolated perfused feline hearts (Langendorff) and cardiac muscle (microelectrode recordings) for their effects on repolarization. Those agent found to prolong repolarization at concentrations likely to occur in clinical use or after overdose will be selected for evaluation in man. In the first year, diphenhydramine will be studied clinically because of our recent finding that it prolongs cardiac repolarization in vitro. The effects of diphenhydramine on the surface electrocardiogram (PR, QRS, and QT intervals) will be evaluated in healthy normal volunteers at doses used clinically. When appropriate, the effects of concomitant drugs, e.g. decongestants (alpha agonists) and specific inhibitors of cytochrome P450, will be evaluated for their potential to produce clinically relevant drug interactions in vitro and in man. Clinical protocols will make comparisons at steady state for all treatments and utilize a placebo controlled randomized crossover design. These studies should provide information that will lead to the safer use of antihistamines by detection of their ancillary actions on cardiac ion channels and human cardiac repolarization. This information will enable physicians to identify patients at risk for adverse response to these actions. Also, the appropriate treatment of patients with intentional or accidental overdose of antihistamines can be determined.