Abstract 17074: Methadone Potently Blocks Cardiac IK1 Leading to Membrane Instability

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael Klein ◽  
Robert Geiger ◽  
Mori J Krantz ◽  
Robert Goldstein ◽  
Thomas P Flagg ◽  
...  
Keyword(s):  
Torsade De Pointes ◽  
Ionic Current ◽  
Delayed Rectifier ◽  
Specific Marker ◽  
Drug Induced ◽  
Cos Cells ◽  
Enzymatic Dissociation ◽  
Significant Prolongation ◽  
Herg Current ◽  
Inwardly Rectifying

Introduction: Methadone is the second most frequently reported cause of drug-induced cardiac arrest in pharmacovigilance databases, yet the mechanism of its pro-arrhythmia is unclear. Methadone-induced QTU wave prolongation has been repeatedly observed and attributed to inhibition of the delayed rectifier hERG current, but QTU fusion suggests the inwardly rectifying K + current (IK1) might also be affected by methadone. Hypothesis: Methadone pro-arrhythmia is associated with potent block of the IK1 current responsible for rapid terminal repolarization of the cardiac action potential (AP). Methods: Human Kir2.2, encoding the IK1 current, was transiently expressed in COS cells. hERG1a was stably expressed in CHO cells. Cardiac myocytes from swine were obtained by ventricular enzymatic dissociation. Ionic current and APs were measured using patch-clamp methods. Methadone HCl (R+S racemates) was dissolved in Tyrode solution. Results: Methadone suppressed IK1 current with an IC 50 of 1.47 uM (Fig 1A). Methadone also suppressed outward IK1 (-60 mV) measured in swine myocytes (Ba 2+ -sensitive current) with an IC 50 of 1.52 μM. Methadone suppressed hERG currents with an IC 50 of 2.1 μM. APs measured in swine myocytes exhibited significant prolongation (13 ± 4 % increase of APD 90 , p<0.029, n=7) as well as slowing of the rate of terminal repolarization (a specific marker of IK1 blockade) in the presence of 1 μM methadone (Fig. 1B). Fluctuations of diastolic voltage increased by 30 ± 12 and 151 ± 27 % (n=3; p<0.04) in 0.1 and 1 μM methadone, respectively, consistent with a reduction in membrane stability. Conclusions: Methadone is an equipotent blocker of IK1 and hERG. The effect of IK1 block coupled with modest hERG block has a synergistic effect on terminal repolarization that may partially explain the pro-arrhythmic impact of methadone. Moreover, this observation may be generalized to other drugs where unsuspected IK1 blockade may contribute to pro-arrhythmia and torsade de pointes.

Terfenadine-Induced Torsade de Pointes: Risk Factors and Mechanisms

1997 ◽  
Vol 13 (3) ◽  
pp. 127-132 ◽  
Author(s):  
Thomas Yk Chan
Keyword(s):  
Risk Factors ◽  
Liver Dysfunction ◽  
Qt Interval ◽  
Torsade De Pointes ◽  
Pharmacokinetic Studies ◽  
Drug Induced ◽  
Significant Prolongation ◽  
Concurrent Use ◽  
Cyp3a4 Inhibitors

Objective: To review the risk factors and mechanisms of terfenadine-induced torsade de pointes and to discuss how this adverse reaction might be avoided. Data Sources: Previous reports of terfenadine-induced torsade de pointes and studies of the underlying mechanisms were identified by a MEDLINE search or from the reference lists of pertinent articles. Study Selection and Data Extraction: All relevant articles were included in the review. Pertinent information was selected for discussion. Data Synthesis: Terfenadine is extensively (99%) metabolized by CYP3A4 to an active acid metabolite (terfenadine carboxylate), and with therapeutic dosages, unchanged terfenadine is usually undetectable in plasma. A review of all the reported cases of torsade de pointes indicated that most patients had one or more factors that would be expected to cause excessively high concentrations of unchanged terfenadine, such as overdose; use of supratherapeutic dosages; concurrent use of CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and troleandomycin; and liver dysfunction. Many patients had one or more factors known to predispose to drug-induced torsade de pointes (e.g., preexisting prolonged QT interval, ischemic heart disease, hypokalemia). Pharmacokinetic studies in healthy volunteers have shown that ketoconazole, itraconazole, erythromycin, and clarithromycin can alter the metabolism of terfenadine and result in the accumulation of unchanged terfenadine, which is associated with significant prolongation of the QT interval. In vitro studies have shown that the proarrhythmic effects of terfenadine are secondary to the blockade of cardiac potassium channels. Terfenadine carboxylate does not have such an effect. Conclusions: Supratherapeutic dosages of terfenadine should never be used. The concurrent use of CYP3A4 inhibitors should be avoided. Terfenadine should be avoided in patients with liver dysfunction or factors known to predispose to drug-induced torsade de pointes.

scholarly journals Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review

2020 ◽  
Author(s):  
Veronique Michaud ◽  
Pamela Dow ◽  
Sweilem B. Al Rihani ◽  
Malavika Deodhar ◽  
Meghan Arwood ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Adverse Event Reporting System ◽  
Torsade De Pointes ◽  
World Health ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Repurposed Drugs ◽  
Qt Syndrome

ABSTRACTBackgroundThe World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored.MethodsA thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds.ResultsEstimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and the 23 torsadogenic compounds.ConclusionThe risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

scholarly journals A web-based tool for the early identification and real time assessment of drug-induced proarrhythmic and torsade de pointes safety risk

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Baretta ◽  
M.A Bisotti ◽  
A Palazzin ◽  
J Cano ◽  
J Gomis-Tena ◽  
...  
Keyword(s):  
Real Time ◽  
Early Identification ◽  
Torsade De Pointes ◽  
Security And Privacy ◽  
Computational Time ◽  
Delayed Rectifier ◽  
Na Channels ◽  
Drug Induced ◽  
Web Based ◽  
The Web

Abstract Introduction It is well recognized that early identification of drug-induced proarrhythmic safety risks is crucial to drug development for ethical, animal sparing and costs reduction considerations. The availability, however, of easily accessible, user-friendly tools for real time assessments of the proarrhythmic potential of chemical compounds has been lacking. The novel Tx index, implemented in the presented web-based tool, was applied to a dataset of 84 compounds. Materials and methods The tool is based on 206,766 cellular simulations of compound-induced effects on Action Potential Duration (APD) in isolated endocardial, midmyocardial, and epicardial cells and on 7,072 tissue simulations on QT prolongation in a virtual tissue. Simulations were performed by blocking the slow and the fast components of the delayed rectifier current (IKs and IKr, respectively) and the L-type calcium current (ICaL) at different levels. Based on these simulations, four Tx indices were defined as the ratio of drug concentration leading to a 10% prolongation of the APDendo, APDmid, APDepi or QT over the maximum Effective Free Therapeutic Plasma Concentration (EFTPC), respectively. A dataset of 44 non-torsadogenic and 40 torsadogenic drug compounds was used to validate the performance of the tool. The workflow of the web-based tool was built on the cloud environment, in compliance with the highest standards of security and privacy. hERG test (positive response: hERG pIC50 &gt;6) was applied to the 84 compounds to compare performances. Results Receiver operating characteristic (ROC) curves were constructed on the four estimated Tx indices for each compound in the dataset to enable the identification of torsadogenic potential cut-off values2. These were identified as 8, 8, and 6.4 for Tx-APDendo, Tx-APDmid, Tx-APDepi and as 9.2 for Tx-QT, respectively. The classification of the 84 compounds resulted in an accuracy ranging between 87% and 88% for the four Tx indices Tx-APDendo, Tx-APDmid, Tx-APDepi and Tx-QT. Discussion and conclusion hERG block exhibits poor performance. When applying the hERG test to the 84 compounds, it exhibited a TPR of 55%, a TNR of 89%, and an A of 73%, in close agreement with previous studies. In comparison, the in silico Tx tests described in this study yield TPRs of 85%, TNRs of 86–89% and As of 86–87%. This method does not include drug effects on Na+ channels, which is related to the misclassification of 3 compounds (quetiapine, ranolazine, and lamotrigine – significant Na+ channels blockers at EFTPC). Future work will include this channel. The presented web-based tool is a highly innovative method for an accurate torsadogenic risk assessment. Each assessment required only a few seconds of computational time. Illustration workflow of the web tool Funding Acknowledgement Type of funding source: None

scholarly journals Dexmedetomidine reduces ventricular arrhythmias in a model of drug-induced QT-prolongation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
G Frommeyer ◽  
J Brandt ◽  
C Ellermann ◽  
J Wolfes ◽  
L Eckardt
Keyword(s):  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Spatial Dispersion ◽  
Torsade De Pointes ◽  
Qt Prolongation ◽  
Recent Experimental Data ◽  
Moderate Increase ◽  
Drug Induced ◽  
Dispersion Of Repolarization ◽  
Significant Prolongation

Abstract Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p&lt;0.05) accompanied by a moderate increase of action potential duration (APD, +5ms, p=ns) after infusion of erythromycin as compared with baseline. Effective refractory period (ERP) was also elevated (+33ms, p&lt;0.05). Erythromycin (+26ms, p&lt;0.05) also significantly increased spatial dispersion of repolarisation. Additional infusion of dexmedetomidine (3μM) resulted in a rather stable QT-interval (+7ms, p=ns) and APD (+7ms, p=ns) as compared with sole erythromycin treatment. Of note, a significant decrease of spatial dispersion (−24ms, p&lt;0.05) was observed while ERP was moderately increased (+13ms, p=ns). Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

K+ Channels of Müller Glial Cells in Retinal Disorders

2018 ◽  
Vol 17 (4) ◽  
pp. 255-260 ◽  
Author(s):  
Feng Gao ◽  
Lin-Jie Xu ◽  
Yuan Zhao ◽  
Xing-Huai Sun ◽  
Zhongfeng Wang
Keyword(s):  
Müller Cells ◽  
Major Type ◽  
Delayed Rectifier ◽  
Muller Cells ◽  
Bkca Channels ◽  
K Channels ◽  
Functional Changes ◽  
Physiological Properties ◽  
Retinal Disorders ◽  
Inwardly Rectifying

Background & Objective: Müller cell is the major type of glial cell in the vertebrate retina. Müller cells express various types of K+ channels, such as inwardly rectifying K+ (Kir) channels, big conductance Ca2+-activated K+ (BKCa) channels, delayed rectifier K+ channels (KDR), and transient A-type K+ channels. These K+ channels play important roles in maintaining physiological functions of Müller cells. Under some retinal pathological conditions, the changed expression and functions of K+ channels may contribute to retinal pathogenesis. Conclusion: In this article, we reviewed the physiological properties of K+ channels in retinal Müller cells and the functional changes of these channels in retinal disorders.

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

2011 ◽  
Vol 300 (5) ◽  
pp. H1806-H1813 ◽  
Author(s):  
Alberto Corrias ◽  
Wayne Giles ◽  
Blanca Rodriguez
Keyword(s):  
Purkinje Cells ◽  
Mechanisms Of Action ◽  
Delayed Rectifier ◽  
Pharmacological Interventions ◽  
Drug Induced ◽  
Current Increase ◽  
Detailed Model ◽  
Purkinje Fibers ◽  
Electrophysiological Properties ◽  
Repolarization Abnormalities

Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K+ current and rapid delayed rectifier K+ current block as well as late Na+ current increase result in significant AP changes. However, enhanced L-type Ca2+ current ( iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics.

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

scholarly journals Drug-induced QT interval prolongation in cancer patients

2011 ◽  
Vol 4 (4) ◽  
pp. 223
Author(s):  
Torben K. Becker ◽  
Sai-Ching J. Yeung
Keyword(s):  
Cancer Patients ◽  
Qt Interval ◽  
Alkylating Agents ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Vascular Disruption ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Multiple Drugs

Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

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