Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole

@article{Zhou1999BlockOH,
  title={Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole},
  author={Z Zhou and Vicken R. Vorperian and Qiuming Gong and S Zhang and Craig T. January},
  journal={Journal of Cardiovascular Electrophysiology},
  year={1999},
  volume={10}
}
Electrophysiologic Effects of Astemizole Metabolites. Introduction: The selective H1‐receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current IKr and the human ether‐a go‐go‐related gene (HKRG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1‐receptor antagonist properties, has a long elimination time of 9 to 13 days, and… 
The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.
TLDR
Although N-desbutylhal ofantrine has been suggested to be a safer antimalarial agent compared to halofantrine, the results suggest that the gain in the safety margin for QT interval prolongation-related cardiotoxicity is minimal.
Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG.
TLDR
Inhibition by mefloquine of KvLQT1/minK in the human heart may in part explain the synergistic prolongation of QT interval observed when this drug is coadministered with the HERG antagonist halofantrine.
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TLDR
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TLDR
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TLDR
Investigation of the influence of lumefantrine and its major metabolite desbutyl-lumefanrine on wild type hERG K+ channels in stably transfected human embryonic kidney cells suggests that lumefants have a weaker proarrhythmic potential than their comparator compounds.
Cardiac hERG K+ Channel as Safety and Pharmacological Target.
  • S. Su, Jinglei Sun, Yi Wang, Yanfang Xu
  • Medicine
    Handbook of experimental pharmacology
  • 2021
TLDR
A reduction of the hERG/IKr current has been recognized as a predominant mechanism responsible for the drug-induced delayed repolarization known as acquired long QT syndromes (LQTS), which is linked to an increased risk for "torsades de pointes" ventricular arrhythmias and sudden cardiac death.
Blockade of the Human Ether A-Go-Go–Related Gene (hERG) Potassium Channel by Fentanyl
TLDR
Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death of individuals with high-concentration overdose or compromised cardiac repolarization.
Flunarizine is a Highly Potent Inhibitor of Cardiac hERG Potassium Current
TLDR
The effects of flunarizine on potassium currents through cardiac channels encoded by the human ether-a-go-go related gene (hERG) stably expressed in CHO cells are examined with standard whole-cell voltage-clamp techniques.
Effect of trazodone on hERG channel current and QT-interval.
TLDR
It is suggested that trazodone prolongs the QT-interval through inhibition of hERG channel current through a reverse frequency-dependent manner at clinically relevant concentrations.
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References

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TLDR
The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.
Antiallergic effects of major metabolites of astemizole in rats and guinea pigs.
TLDR
In the studies of histamine release from rat peritoneal mast cells induced by compound 48/80 or from lung fragments in actively sensitized guinea pigs, desmethylastemizole, 6-hydroxydesmethylast emizole and norastemIZole were much less potent than was astemizole.
Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole
TLDR
Results suggest that blockade of HERG channels by terfenadine and astemizole might contribute to the cardiac side effects of these compounds.
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TLDR
Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.
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TLDR
Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of a stemizole including the lengthening of repolarization.
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TLDR
Block of repolarizing K+ currents, particularly IK1, by astemizole and terfenadine produces reverse rate-dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.
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TLDR
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TLDR
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TLDR
It is suggested that terfenadine blocks the hKvl.5 channel after it opens by entering into the internal mouth of the channel and is about 6 times more potent than quinidine.
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TLDR
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