ArticleBritish journal of pharmacology2011
On the relationship between block of the cardiac Na⁺ channel and drug-induced prolongation of the QRS complex.
Article in British journal of pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed.
- Predicting QRS and PR interval prolongations in humans using nonclinical data.British journal of pharmacology · 2017Trial
- The Cardiac Sodium Channel Safety Profile of Cenobamate at Therapeutic Concentrations: In Vitro Analyses.Clinical and translational science · 2025Article
- Risk of Ventricular Arrhythmia and Sudden Cardiac Arrest Among Older Patients Using Lamotrigine for Epilepsy.Neurology · 2025Article
- Antiseizure medications and their differing effects on cardiovascular risk.Epilepsy & behavior reports · 2025Review
- Association of atrial fibrillation with lamotrigine: An observational cohort study.Pharmacotherapy · 2025Observational
- An overview of drug-induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety.Clinical and translational science · 2024Review
- The state of the art in secondary pharmacology and its impact on the safety of new medicines.Nature reviews. Drug discovery · 2024Review
- The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose.Biomolecules · 2023Article
- The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- The Anti-Epileptic Drugs Lamotrigine and Valproic Acid Reduce the Cardiac Sodium Current.Biomedicines · 2023Article
- The Antidepressant Paroxetine Reduces the Cardiac Sodium Current.International journal of molecular sciences · 2023Article
- Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner.International journal of molecular sciences · 2022Article
- Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications.Clinical and translational science · 2022Article
- The grapefruit polyphenol naringenin inhibits multiple cardiac ion channels.Naunyn-Schmiedeberg's archives of pharmacology · 2022Article
- Highly Parallelized, Multicolor Optogenetic Recordings of Cellular Activity for Therapeutic Discovery Applications in Ion Channels and Disease-Associated Excitable Cells.Frontiers in molecular neuroscience · 2022Article
- The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Article
- Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current.Frontiers in cell and developmental biology · 2022Article
- Unmasking of Brugada syndrome by lamotrigine in a patient with pre-existing epilepsy: A case report with review of the literature.Frontiers in cardiovascular medicine · 2022Article
- Local Anesthetic Like Inhibition of the Cardiac NaJournal of experimental pharmacology · 2022Article
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3 authors.
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Abstract
background and purposeInhibition of the human cardiac Na(+) channel (hNa(v) 1.5) can prolong the QRS complex and has been associated with increased mortality in patients with underlying cardiovascular disease. The safety implications of blocking hNa(v) 1.5 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. However, interpretation of hNa(v) 1.5 blocking potency requires knowledge of how hNa(v) 1.5 block translates into prolongation of the QRS complex. EXPERIMENTAL APPROACH: We tested Class I anti-arrhythmics, other known QRS prolonging drugs and drugs not reported to prolong the QRS complex. Their block of hNa(v) 1.5 channels (as IC(50) values) was measured in an automated electrophysiology-based assay. These IC(50) values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fC(max)) to provide an IC(50) : fC(max) ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC(50) : fC(max) ratios <30. For 55 non-QRS prolonging drugs tested, 72% had ratios >100. Finally, we determined the relationship between the IC(50) value and the free drug concentration associated with prolongation of the QRS complex in humans. For 37 drugs, QRS complex prolongation was observed at free plasma concentrations that were about 15-fold lower than the corresponding IC(50) at hNa(v) 1.5 channels. CONCLUSIONS AND IMPLICATIONS: A margin of 30- to 100-fold between hNa(v) 1.5 IC(50) and fC(max) appears to confer an acceptable degree of safety from QRS prolongation. QRS prolongation occurs on average at free plasma levels 15-fold below the IC(50) at hNa(v) 1.5 channels. LINKED ARTICLE: This article is commented on by Gintant et al., pp. 254-259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01433.x.
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