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Comparative effects of loratadine and terfenadine on cardiac K+ channels.
J Cardiovasc Pharmacol. 1997 Jul; 30(1):42-54.JC

Abstract

Nonsedating H1-receptor antagonists appear to have wide and variable effects on the QT interval, mediated through modulation of cardiac K+ channels. By using the whole-cell patch-clamp technique, we examined the effects of terfenadine, loratadine, and descarboethoxyloratadine on a large family of K+ channels in ventricular myocytes and in Xenopus oocytes expressing the HERG delayed rectifier. The channels studied included the inward rectifier (I(Kl)) of rat and guinea pig, the transient outward K+ current (I(to)) of rat, the maintained K+ current (I(ped)) of rat, and the delayed rectifier K+ channels (I(Ks) and I(Kr)) of guinea pig myocytes. Loratadine and descarboethoxyloratadine, at therapeutic concentrations (30 to 100 nM), had no measurable effect on any one of the five types of K+ channels studied. At higher concentrations, 0.3 to 1.0 microM, only terfenadine had a significant suppressive effect on I(Kl) and delayed rectifier K+ channels, I(Kr) and I(Ks). At higher concentrations (1 to 2.5 microM), there were marked differences in the ability of the three drugs to suppress the five K+ channels. Generally, terfenadine was the most and loratadine, the least effective blocker of all K+ channels examined. The most susceptible K+ channels were the delayed rectifier channels (I(Ks) and I(Kr)) in guinea pig and I(ped) in rat myocytes. Comparative effects of loratadine and terfenadine examined on the I(Kr) channel (HERG) expressed in Xenopus oocytes suggest much higher affinity of this channel to terfenadine, such that 1 microM terfenadine completely suppressed the current, whereas loratadine had little or no effect. The preferential suppressive effect of terfenadine on the expressed HERG channel was consistent with data obtained on I(Kr) in isolated guinea pig ventricular myocytes. The strong suppressive effect of terfenadine, noted particularly on the I(Kr) and to a lesser extent on I(to), I(Kl), and I(Ks), may be the cause of the reported incidence of QT prolongation and arrhythmogenesis. The absence of significant effect of loratadine and descarboethoxyloratadine, especially on I(Kr), I(to), I(ped), and I(Kl), even at 100 x highest plasma concentrations achieved, may explain the absence of significant reports of QT prolongation and arrhythmogenesis by the latter drugs.

Authors+Show Affiliations

Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, U.S.A.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9268220

Citation

Ducic, I, et al. "Comparative Effects of Loratadine and Terfenadine On Cardiac K+ Channels." Journal of Cardiovascular Pharmacology, vol. 30, no. 1, 1997, pp. 42-54.
Ducic I, Ko CM, Shuba Y, et al. Comparative effects of loratadine and terfenadine on cardiac K+ channels. J Cardiovasc Pharmacol. 1997;30(1):42-54.
Ducic, I., Ko, C. M., Shuba, Y., & Morad, M. (1997). Comparative effects of loratadine and terfenadine on cardiac K+ channels. Journal of Cardiovascular Pharmacology, 30(1), 42-54.
Ducic I, et al. Comparative Effects of Loratadine and Terfenadine On Cardiac K+ Channels. J Cardiovasc Pharmacol. 1997;30(1):42-54. PubMed PMID: 9268220.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative effects of loratadine and terfenadine on cardiac K+ channels. AU - Ducic,I, AU - Ko,C M, AU - Shuba,Y, AU - Morad,M, PY - 1997/7/1/pubmed PY - 1997/7/1/medline PY - 1997/7/1/entrez SP - 42 EP - 54 JF - Journal of cardiovascular pharmacology JO - J Cardiovasc Pharmacol VL - 30 IS - 1 N2 - Nonsedating H1-receptor antagonists appear to have wide and variable effects on the QT interval, mediated through modulation of cardiac K+ channels. By using the whole-cell patch-clamp technique, we examined the effects of terfenadine, loratadine, and descarboethoxyloratadine on a large family of K+ channels in ventricular myocytes and in Xenopus oocytes expressing the HERG delayed rectifier. The channels studied included the inward rectifier (I(Kl)) of rat and guinea pig, the transient outward K+ current (I(to)) of rat, the maintained K+ current (I(ped)) of rat, and the delayed rectifier K+ channels (I(Ks) and I(Kr)) of guinea pig myocytes. Loratadine and descarboethoxyloratadine, at therapeutic concentrations (30 to 100 nM), had no measurable effect on any one of the five types of K+ channels studied. At higher concentrations, 0.3 to 1.0 microM, only terfenadine had a significant suppressive effect on I(Kl) and delayed rectifier K+ channels, I(Kr) and I(Ks). At higher concentrations (1 to 2.5 microM), there were marked differences in the ability of the three drugs to suppress the five K+ channels. Generally, terfenadine was the most and loratadine, the least effective blocker of all K+ channels examined. The most susceptible K+ channels were the delayed rectifier channels (I(Ks) and I(Kr)) in guinea pig and I(ped) in rat myocytes. Comparative effects of loratadine and terfenadine examined on the I(Kr) channel (HERG) expressed in Xenopus oocytes suggest much higher affinity of this channel to terfenadine, such that 1 microM terfenadine completely suppressed the current, whereas loratadine had little or no effect. The preferential suppressive effect of terfenadine on the expressed HERG channel was consistent with data obtained on I(Kr) in isolated guinea pig ventricular myocytes. The strong suppressive effect of terfenadine, noted particularly on the I(Kr) and to a lesser extent on I(to), I(Kl), and I(Ks), may be the cause of the reported incidence of QT prolongation and arrhythmogenesis. The absence of significant effect of loratadine and descarboethoxyloratadine, especially on I(Kr), I(to), I(ped), and I(Kl), even at 100 x highest plasma concentrations achieved, may explain the absence of significant reports of QT prolongation and arrhythmogenesis by the latter drugs. SN - 0160-2446 UR - https://www.unboundmedicine.com/medline/citation/9268220/Comparative_effects_of_loratadine_and_terfenadine_on_cardiac_K+_channels_ L2 - https://doi.org/10.1097/00005344-199707000-00007 DB - PRIME DP - Unbound Medicine ER -