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2018 - The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Nav1.5

Icon CE   CardioExcyte 96 publication in British Journal of Pharmacology (2018)

Authors:
Meents J.E., Juhasz K., Stölzle-Feix S., Peuckmann-Post V., Rolke R. Lampert A.

Journal:
British Journal of Pharmacology (2018) doi: 10.1111/bph.14348


Abstract:

BACKGROUND AND PURPOSE:
Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long-QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac sodium channel Nav1.5.

EXPERIMENTAL APPROACH:
Heterologously expressed Nav1.5, Nav1.7 or Nav1.8 were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols was used to test the effect of oxycodone on different channel gating modalities. Human stem cell-derived cardiomyocytes were used to measure the effect of oxycodone on cardiomyocyte beating.

KEY RESULTS:
Oxycodone concentration-dependently and use-dependently inhibits Nav1.5 with an IC50 of 483.2 μM. In addition, oxycodone slows recovery of Nav1.5 from fast inactivation and increases slow inactivation. At high concentrations, these effects lead to a reduced beat rate in cardiomyocytes and to arrhythmia. In contrast, no effects could be observed on Nav1.7 or Nav1.8.

CONCLUSION AND IMPLICATIONS:
Oxycodone leads to an accumulation of Nav1.5 in inactivated states with a slow time course. While the concentrations needed to elicit cardiac arrhythmia in vitro are comparably high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slow effects of oxycodone on Nav1.5.


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