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Related Concept Videos

Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers01:22

Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers

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Class I antiarrhythmic drugs are used to treat various types of arrhythmias or irregular heart rhythms. These drugs block the sodium (Na+) channels in the cardiac cells, thereby affecting the movement of electrical impulses across the heart. Class I antiarrhythmic drugs are divided into three subgroups: Class IA, Class IB, and Class IC, each with distinct mechanisms of action and effects on the heart.
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
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Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers01:12

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Class III antiarrhythmic drugs are a group of medications that can prolong action potentials in the heart. They achieve this by blocking potassium channels or enhancing inward currents from sodium channels. However, these drugs have a unique property of "reverse use-dependence," which is most pronounced at slower heart rates and can lead to torsades de pointes—a specific type of arrhythmia. However, it is essential to note that excessive QT interval prolongation—a measure of...
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Heart Failure Drugs: Inotropic Agents01:26

Heart Failure Drugs: Inotropic Agents

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Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...
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Dysrhythmias VI: Management of Dysrhythmias01:25

Dysrhythmias VI: Management of Dysrhythmias

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Dysrhythmia management involves a multifaceted approach, incorporating pharmacological treatments, medical procedures, surgical interventions, lifestyle modifications, and patient education.Pharmacological ManagementAntiarrhythmic Drugs:Class I (Sodium Channel Blockers): This class includes quinidine and procainamide, which reduce the speed of impulse conduction in the heart, stabilize the cardiac membrane, and control arrhythmias. Quinidine and procainamide are Class IA agents that prolong the...
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Dysrhythmias I: Introduction01:15

Dysrhythmias I: Introduction

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Dysrhythmias refers to abnormalities in the heart's rhythm. They result from disruptions in the heart's electrical conduction system, which includes the sinoatrial(SA)node, atrioventricular(AV) node, the bundle of His, bundle branches, and Purkinje fibers.Definition and PathophysiologyDysrhythmias result from disorders of impulse formation, impulse conduction, or both. The heart contains specialized cells in the sinoatrial node, atrioventricular node, and the bundle of His and Purkinje fibers...
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Mechanism of Cardiac Arrhythmias01:28

Mechanism of Cardiac Arrhythmias

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Arrhythmias are irregular heart rhythms occurring when the heart's electrical impulses become abnormal. These disturbances can lead to various symptoms, depending on their severity and the underlying cause. Some common factors contributing to arrhythmias include hypoxia, ischemia, electrolyte imbalances, excessive catecholamine exposure, drug toxicity, and muscle overstretching. Arrhythmias can be classified into two main types based on the rate and site of origin of abnormal heart rhythms.
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Updated: Sep 1, 2025

Laser-Induced Action Potential-Like Measurements of Cardiomyocytes on Microelectrode Arrays for Increased Predictivity of Safety Pharmacology
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MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Muhammad Erfan Uddin1, Eric D Eisenmann1, Yang Li1

  • 1Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

International Journal of Molecular Sciences
|August 12, 2022
PubMed
Summary
This summary is machine-generated.

The multidrug and toxin extrusion 1 (MATE1) transporter restricts dofetilide accumulation in heart cells, preventing QTc prolongation. MATE1 inhibition increases dofetilide retention, highlighting its cardioprotective role.

Keywords:
PBPK modelingarrhythmiadofetilideorganic cation transporters

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Area of Science:

  • Pharmacology
  • Cardiology
  • Molecular Biology

Background:

  • Dofetilide is a critical antiarrhythmic drug for atrial fibrillation.
  • Clinical use of dofetilide can prolong the QTc interval, increasing arrhythmia risk.
  • Mechanisms governing dofetilide's cellular transport and disposition are not fully understood.

Purpose of the Study:

  • To identify the transporter responsible for dofetilide disposition.
  • To elucidate the role of identified transporters in dofetilide-induced QTc prolongation.
  • To investigate the clinical implications of dofetilide transport mechanisms for drug-drug interactions.

Main Methods:

  • Conducted a xenobiotic transporter screen to identify dofetilide transporters.
  • Utilized MATE1 knockout and pharmacologically inhibited mice models.
  • Employed a physiologically-based pharmacokinetic (PBPK) model for translational analysis.

Main Results:

  • Identified Multidrug and Toxin Extrusion 1 (MATE1) as a key dofetilide transporter.
  • MATE1 deficiency in mice led to increased dofetilide retention in cardiomyocytes and enhanced QTc prolongation.
  • Urinary excretion of dofetilide was dependent on MATE1 genotype, explaining drug-drug interactions.

Conclusions:

  • MATE1 plays a conserved cardioprotective role by limiting excessive dofetilide accumulation in cardiomyocytes.
  • MATE1-mediated transport provides a mechanistic basis for dofetilide drug-drug interactions.
  • Concurrent administration of MATE1 inhibitors with dofetilide warrants caution due to potential cardiotoxicity.