Flecainide mechanism of action

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Flecainide Mechanism of Action: Sodium Channel Blockade and Ryanodine Receptor Inhibition

Sodium Channel Blockade in Cardiac Myocytes

Flecainide is a class Ic antiarrhythmic drug that primarily works by blocking fast inward sodium (Na+) channels in the heart. This action slows the rapid upstroke of the cardiac action potential, prolongs depolarization, and reduces conduction velocity in atrial and ventricular myocytes, as well as in the atrioventricular node and His-Purkinje system. The sodium channel blockade is use-dependent, meaning its effects are more pronounced at higher heart rates, which is important for suppressing tachyarrhythmias such as atrial fibrillation and supraventricular tachycardia 149.

Effects on Atrial Fibrillation: Action Potential Duration and Refractory Period

In experimental models of atrial fibrillation, flecainide increases the atrial effective refractory period (ERP) and action potential duration (APD) in a tachycardia-dependent manner. This leads to a reduction in conduction velocity and an increase in the minimum path length required for reentrant circuits, making it harder for atrial fibrillation to sustain itself. Flecainide also reduces regional differences in ERP, which helps stabilize the atrial rhythm .

Ryanodine Receptor (RyR2) Inhibition in CPVT

Flecainide has been shown to inhibit the cardiac ryanodine receptor (RyR2), which is responsible for releasing calcium (Ca2+) from the sarcoplasmic reticulum during each heartbeat. In catecholaminergic polymorphic ventricular tachycardia (CPVT), a condition caused by abnormal RyR2-mediated Ca2+ release, flecainide’s ability to suppress spontaneous Ca2+ release is critical for its antiarrhythmic effect. Studies using mouse models of CPVT demonstrate that flecainide can prevent arrhythmias even when sodium channels are blocked, indicating that direct RyR2 inhibition is a principal mechanism in this context 23456.

Multiple Modes of RyR2 Inhibition

Flecainide inhibits RyR2 through at least two distinct mechanisms: a fast block that affects the open state of the channel and a slow block that affects the closed state. Both modes of inhibition reduce arrhythmogenic Ca2+ release, and their effectiveness can be influenced by factors such as cytoplasmic pH and the activation state of the channel .

Ongoing Debate: Direct vs. Indirect RyR2 Effects

There is ongoing debate about whether flecainide’s antiarrhythmic action in CPVT is due to direct RyR2 inhibition or secondary to its effects on sodium channels. Some studies argue that flecainide does not directly block physiologically relevant RyR2 Ca2+ flux, and that its benefits in CPVT may result from Na+-dependent modulation of intracellular Ca2+ handling rather than direct RyR2 inhibition 7810. However, other research supports a direct inhibitory effect on RyR2, especially in permeabilized cells or under certain experimental conditions 2356.

Clinical Implications and Monitoring

Because flecainide slows conduction and can prolong the QRS complex, electrocardiogram (ECG) monitoring is recommended to detect excessive conduction slowing, especially after starting therapy or increasing the dose .

Conclusion

Flecainide’s antiarrhythmic action is primarily due to its blockade of cardiac sodium channels, which slows conduction and stabilizes cardiac rhythm. In specific conditions like CPVT, direct inhibition of the RyR2 calcium release channel also plays a significant role, though the extent and clinical relevance of this mechanism remain debated. Both actions contribute to flecainide’s effectiveness in treating a range of cardiac arrhythmias 12345678+2 MORE.

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Most relevant research papers on this topic

Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation.

Flecainide effectively terminates atrial fibrillation in an experimental model by causing tachycardia-dependent increases in atrial action potential duration, increasing the wavelength to a point where the arrhythmia can no longer sustain itself.

RCTAnimal StudyHighly Cited

1992·

235citations

·Zhiguo Wang et al.

Abstract 15420: Resolving a Controversy: Inhibition of Cardiac Ryanodine Receptors is the Principal Mechanism of Antiarrhythmic Action of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Flecainide's antiarrhythmic action in CPVT is primarily due to its ability to inhibit cardiac ryanodine receptors, not just sodium channel block.

In Vitro StudyRigorous Journal

2020·

0citations

·D. O. Kryshtal et al.

RYR2 Channel Inhibition Is the Principal Mechanism 0f Flecainide Action in CPVT.

Flecainide's antiarrhythmic action in CPVT is primarily due to its ability to inhibit ryR2-mediated calcium release, rather than solely relying on sodium channel block.

In Vitro StudyRigorous Journal

2020·

64citations

·D. O. Kryshtal et al.

Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Flecainide suppresses various cardiac arrhythmias and can also cause pro-arrhythmic effects, with its diverse actions resulting from multiple cellular levels and interactions.

Non-RCTAnimal StudyRigorous Journal

2018·

56citations

·S. Salvage et al.

Multiple Modes of Ryanodine Receptor 2 Inhibition by Flecainide

Flecainide inhibits cardiac ryanodine receptors (RyR2) through two distinct modes, both involving a cytoplasmic site of action, and has an additional inhibitory mechanism reducing burst duration at diastolic cytoplasmic calcium concentrations.

In Vitro Study

2014·

39citations

·D. Mehra et al.

Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia

Flecainide's efficacy in CPVT is not solely based on its block of ryanodine receptor 2, but also on its effects on Na+ channels and the combined block of INa and RyR2.

2016·

4citations

·Alan J. Williams et al.

The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT.

Flecainide's antiarrhythmic effect in CPVT may not be solely due to inhibition of cardiac ryanodine receptor activity, but may also involve depressed Na+ influx through INa and cytoplasmic reticulum effects.

Rigorous Journal

2015·

23citations

·Godfrey L. Smith et al.

Flecainide induces a sustained countercurrent dependent effect on RyR2 in permeabilized WT ventricular myocytes but not in intact cells

Flecainide has a sustained countercurrent-dependent effect on RyR2 in permeabilized ventricular myocytes, but not in intact cells, suggesting its insufficient concentration to influence RyR2.

In Vitro Study

2023·

2citations

·E. Steer et al.

Impact of flecainide on left bundle branch capture criteria

Flecainide effectively treats supraventricular and ventricular arrhythmias, but requires 12-lead ECG monitoring for QRS prolongation at rest and during exercise.

2023·

1citation

·I. Shadrin et al.

The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2.

Flecainide's principal action in CPVT is not through direct interaction with RyR2, but rather through Na(+)-dependent modulation of intracellular Ca(2+) handling.

In Vitro StudyRigorous JournalHighly Cited

2015·

98citations

·M. Bannister et al.

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