An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety
Abstract The human voltage‐gated sodium channel Nav1.5 (hNav1.5/SCN5A) plays a critical role in the initiation and propagation of action potentials in cardiac myocytes, and its modulation by various drugs has significant implications for cardiac safety. Drug‐dependent block of Nav1.5 current (INa) c...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.70098 |
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| author | Khuram W. Chaudhary Colleen E. Clancy Pei‐Chi Yang Jennifer B. Pierson Alan L. Goldin John E. Koerner Todd A. Wisialowski Jean‐Pierre Valentin John P. Imredy Armando Lagrutta Simon Authier Robert Kleiman Philip T. Sager Peter Hoffmann Michael K. Pugsley |
| author_facet | Khuram W. Chaudhary Colleen E. Clancy Pei‐Chi Yang Jennifer B. Pierson Alan L. Goldin John E. Koerner Todd A. Wisialowski Jean‐Pierre Valentin John P. Imredy Armando Lagrutta Simon Authier Robert Kleiman Philip T. Sager Peter Hoffmann Michael K. Pugsley |
| author_sort | Khuram W. Chaudhary |
| collection | DOAJ |
| description | Abstract The human voltage‐gated sodium channel Nav1.5 (hNav1.5/SCN5A) plays a critical role in the initiation and propagation of action potentials in cardiac myocytes, and its modulation by various drugs has significant implications for cardiac safety. Drug‐dependent block of Nav1.5 current (INa) can lead to significant alterations in cardiac electrophysiology, potentially resulting in conduction slowing and an increased risk of proarrhythmic events. This review aims to provide a comprehensive overview of the mechanisms by which various pharmacological agents interact with Nav1.5, focusing on the molecular determinants of drug binding and the resultant electrophysiological effects. We discuss the structural features of Nav1.5 that influence drug affinity and specificity. Special attention is given to the concept of state‐dependent block, where drug binding is influenced by the conformational state of the channel, and its relevance to therapeutic efficacy and safety. The review also examines the clinical implications of INa block, highlighting case studies of drugs that have been associated with adverse cardiac events, and how the Vaughan‐Williams Classification system has been employed to qualify “unsafe” sodium channel block. Furthermore, we explore the methodologies currently used to assess INa block in nonclinical and clinical settings, with the hope of providing a weight of evidence approach including in silico modeling, in vitro electrophysiological assays and in vivo cardiac safety studies for mitigating proarrhythmic risk early in drug discovery. This review underscores the importance of understanding Nav1.5 pharmacology in the context of drug development and cardiac risk assessment. |
| format | Article |
| id | doaj-art-59970e5aa66e4ba7a9f9b5b4dfcef406 |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj-art-59970e5aa66e4ba7a9f9b5b4dfcef4062024-12-24T15:26:30ZengWileyClinical and Translational Science1752-80541752-80622024-12-011712n/an/a10.1111/cts.70098An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safetyKhuram W. Chaudhary0Colleen E. Clancy1Pei‐Chi Yang2Jennifer B. Pierson3Alan L. Goldin4John E. Koerner5Todd A. Wisialowski6Jean‐Pierre Valentin7John P. Imredy8Armando Lagrutta9Simon Authier10Robert Kleiman11Philip T. Sager12Peter Hoffmann13Michael K. Pugsley14Bristol Myers Squibb New Brunswick New Jersey USADepartment of Physiology and Membrane Biology University of California Davis Davis California USADepartment of Physiology and Membrane Biology University of California Davis Davis California USAHESI Washington DC USAUniversity of California, Irvine Irvine California USAIndependent San Diego California USAPfizer Groton Connecticut USAUCB Biopharma SRL Braine‐l'Alleud BelgiumMerck & Co., Inc. Rahway New Jersey USAMerck & Co., Inc. Rahway New Jersey USACharles River Laboratories Laval Quebec CanadaClario Philadelphia Pennsylvania USAStanford University Palo Alto California USAIndependent Beaufort South Carolina USACytokinetics South San Francisco California USAAbstract The human voltage‐gated sodium channel Nav1.5 (hNav1.5/SCN5A) plays a critical role in the initiation and propagation of action potentials in cardiac myocytes, and its modulation by various drugs has significant implications for cardiac safety. Drug‐dependent block of Nav1.5 current (INa) can lead to significant alterations in cardiac electrophysiology, potentially resulting in conduction slowing and an increased risk of proarrhythmic events. This review aims to provide a comprehensive overview of the mechanisms by which various pharmacological agents interact with Nav1.5, focusing on the molecular determinants of drug binding and the resultant electrophysiological effects. We discuss the structural features of Nav1.5 that influence drug affinity and specificity. Special attention is given to the concept of state‐dependent block, where drug binding is influenced by the conformational state of the channel, and its relevance to therapeutic efficacy and safety. The review also examines the clinical implications of INa block, highlighting case studies of drugs that have been associated with adverse cardiac events, and how the Vaughan‐Williams Classification system has been employed to qualify “unsafe” sodium channel block. Furthermore, we explore the methodologies currently used to assess INa block in nonclinical and clinical settings, with the hope of providing a weight of evidence approach including in silico modeling, in vitro electrophysiological assays and in vivo cardiac safety studies for mitigating proarrhythmic risk early in drug discovery. This review underscores the importance of understanding Nav1.5 pharmacology in the context of drug development and cardiac risk assessment.https://doi.org/10.1111/cts.70098 |
| spellingShingle | Khuram W. Chaudhary Colleen E. Clancy Pei‐Chi Yang Jennifer B. Pierson Alan L. Goldin John E. Koerner Todd A. Wisialowski Jean‐Pierre Valentin John P. Imredy Armando Lagrutta Simon Authier Robert Kleiman Philip T. Sager Peter Hoffmann Michael K. Pugsley An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety Clinical and Translational Science |
| title | An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety |
| title_full | An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety |
| title_fullStr | An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety |
| title_full_unstemmed | An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety |
| title_short | An overview of drug‐induced sodium channel blockade and changes in cardiac conduction: Implications for drug safety |
| title_sort | overview of drug induced sodium channel blockade and changes in cardiac conduction implications for drug safety |
| url | https://doi.org/10.1111/cts.70098 |
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