Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Abstract

Aim: To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods: hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results: Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD 90 ) in both concentration-and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC 50 for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold. Conclusion:The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

Cardiovascular safety of antihistamines

“…An increased repolarization time and T wave disturbances were also reported in the case of another first-generation antihistamine – hydroxyzine [3, 17, 18]. …”

“…Some of the most important representatives of antihistamines are noteworthy:

Diphenhydramine – the proarrhythmic effect, due to the influence on potassium channels, was reported while administering medically overdosed diphenhydramine [3, 16]. An increased repolarization time and T wave disturbances were also reported in the case of another first-generation antihistamine – hydroxyzine [3, 17, 18].

Fexofenadine – this terfenadine metabolite is minimally metabolized.

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The Conventional Antihistamine Drug Cyproheptadine Lacks QT-interval–Prolonging Action in Halothane-Anesthetized Guinea Pigs: Comparison With Hydroxyzine

“…Interestingly, spontaneous Ca 2+ release from the sarcoplasmic reticulum is shown to contribute to increased beat-to-beat variability of repolarization by interspersed prolongation of action potential duration, which is exacerbated by blockade of slowly activating delayed-rectifier K + current (I Ks ) (19). In this study, the QT-interval-prolonging effects of 1 mg/kg of hydroxyzine were comparable to that of 10 mg/kg of diphenhydramine, reflecting that hydroxyzine and diphenhydramine inhibited the hERG K + currents with an IC 50 value of 0.16 and 2.7 mM, respectively (8,20). Although it is reported that syncope was induced while taking hydroxyzine in a patient with hERG mutation (10), there is no direct evidence that the drug clinically induced torsade de pointes at present.…”

Risk of QT prolongation and torsade de pointes associated with exposure to hydroxyzine: re‐evaluation of an established drug

“…; Lee et al. ) we report an estimated IC 50 of 0.39 μ mol/L for hydroxyzine at near‐physiological temperature, when tested over a clinically‐relevant concentration range. This IC 50 value generated a CSI value of 39 for a 50 mg dose of hydroxyzine (ratio between hERG IC 50 and C max,free of hydroxyzine [0.01 μ mol/L]), assuming no other risk factors.…”

“…; Lee et al. ). Inhibition of hERG channels can delay action potential repolarization (due to a reduction in the outward potassium current peak) and potentially cause QT interval prolongation and the associated cardiac risks, although there are limitations to linking this data to real‐world safety concerns (Letsas et al.…”