Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine

Treatment with second generation histamine H1 receptor antagonists has been associated with lengthening of the Q-T interval and proarrhythmia. Similar ly, lengthening of the Q-T interval has been reported in patients after ove rdosing with diphenhydramine (DPH), a first generation agent. Therefore, ou r study was designed 1) to assess effects of DPH on cardiac repolarization and 2) to characterize effects of the drug on major voltage-dependent cardi ac K+ currents. First, we noticed that oral administration of DPH at usual dosages to healthy volunteers or to patients (prior to angioplasty) was ass ociated with prolongation of the Q-T-c interval. Although this effect was m odest in most individuals, Q-T-c was increased more than 20 ms in 7 of 20 p atients. Second, we noticed that exposure of isolated guinea pig hearts to DPH 10(-5) M caused a lengthening of monophasic action potential duration. This effect was potentiated by the combined perfusion of other K+ channel b lockers such as indapamide. Finally, experiments performed with the patch-c lamp technique demonstrated unequivocal block of the rapid component of the delayed rectifier (I-Kr) by DPH; however, IC50 determined for block of I-K r (3 . 10(-5) M) is similar to 40-fold greater than plasma concentrations o f the drug measured at usual dosages (7 . 10(-7) M). Consequently, in agree ment with the long-term clinical use of the drug, prolongation of cardiac r epolarization should be minimal in most patients at usual dosages but may b e observed with overdosing. Nevertheless, caution remains since excessive l engthening of cardiac repolarization may occur after administration of DPH with other drugs due to 1) concomitant block of other ionic currents or 2) pharmacokinetic interactions leading to toxic concentrations of DPH.