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. 2020 Nov 9;11:581837. doi: 10.3389/fphar.2020.581837

TABLE 6.

Emergent antiarrhythmic drugs for AF rhythm control: mechanisms and clinical effects.

Drugs Targets Mechanisms Clinical effects
Ranolazine
Vaughan Williams ID
Nav1.5
Kv11.1 (hERG; IKr)
Therapeutic mechanisms
Frequency-dependent block of atrial peak and late INa → ↓dV/dtmax, ↑ diastolic excitation threshold, ↓ Ca2+ overload
Reverse frequency-dependent block of atrial IKr → counteracts Ach-induced ↓atrial APD
Therapeutic benefits for AF
Atrial-selective effects of INa block
↓ EAD-induced triggered activity
↑ atrial ERP
↑ atrial postrepolarization refractoriness
Frequency-dependent ↑ atrial conduction time
↓ phase-3 EADs, DADs, triggered activity
↓ AF duration
↓ AF dominant frequency → ↑ likelihood of defibrillation success
↓ Ach-mediated AF
↑ atrial APD
Proarrhythmic mechanisms
↓ ventricular IKr (mitigated by ↓ ventricular late INa)
Proarrhythmic risks
Slight ↑ QT (without causing torsades de pointes or ↑transmural dispersion of repolarization)
Vernakalant
(RSD1235)
Vaughan Williams III
Nav1.5
Atrial K+ channels
Kv1.5 (IKur), IKACh, Ito
Other K+ channels
Kv11.1 (hERG; IKr)
Therapeutic mechanisms
Atrial-predominant INa block: Open-state, voltage- and frequency-dependent
→ ↓ atrial dV/dtmax
Rapid onset/offset kinetics
↓ late INa (HEK cells)
Open-state ↓IKur (HEK cells)
↓ IKACh
Therapeutic benefits for AF
Atrial-selective effects
↓ atrial impulse conduction (at rapid heart rates)
↓ atrial excitability
Frequency-dependent ↑ atrial ERP
↑ AVN refractoriness
↑ atrial APD
Rapid conversion of recent-onset AF
Proarrhythmic mechanisms
↓ INa (SAN)
↓ ventricular IKr (mitigated by ↓ ventricular late INa)
Proarrhythmic risks
Sinus bradycardia
Slight ↑ QT (without causing torsades de pointes or ↑transmural dispersion of repolarization)
Niferidil (RG-2)
Vaughan Williams III
Kv1.5 (atrial-specific)
Nav1.5
Therapeutic mechanisms
↓ IKur, ↓IKACh, ↓atrial IKr
Open-state, voltage- and frequency-dependent INa block
Rapid kinetics
Therapeutic benefits for AF
↑ atrial APD
↑ atrial ERP
↓ recent-onset AF and ↓ persistent AF
Proarrhythmic mechanisms
↓IKss and ↓IKur (murine ventricles)
Proarrhythmic risks
↑ ventricular APD (mice)
Vanoxerine (GBR-12909)
DRI
Kv11.1 (hERG; IKr)
Cav1.2
Nav1.5
Therapeutic mechanisms
Strongly frequency-dependent IKr block > ICaL block > frequency-dependent INa block
Therapeutic benefits for AF
High conversion rate for recent-onset AF
Proarrhythmic mechanisms
↓ventricular IKr
Proarrhythmic risks
↑ QT → VT/torsades de pointes? (Conflicting studies)
Antazoline
First-generation antihistamine (H1-receptor blocker)
Nav1.5?
K+ channels?
Therapeutic mechanisms
↓ INa?
↓ IK?
Therapeutic benefits for AF
High conversion rate for PAF
↑ atrial APD
↑↑ atrial ERP
↑ atrial postrepolarization refractoriness
↑ interatrial conduction time
Proarrhythmic mechanisms Proarrhythmic risks
Bradycardia
Non-sustained sinus tachycardia
XEN-D0103 (S66913) Kv1.5 (atrial-specific) Therapeutic mechanisms
↓ atrial-specific IKur
Therapeutic benefits for AF: none
Atrial-selective ion channel blockade
↑ atrial APD
No effect on AF burden
Proarrhythmic mechanisms Proarrhythmic risks: None
A293
Doxapram
I K2P inhibitors blockers
Atrial-specific K2P channels (TASK-1, TASK-3) Therapeutic mechanisms
↓ atrial-specific leak current IK2P
Therapeutic benefits for AF
Atrial-selective ion channel blockade
↑ atrial APD
↑ atrial ERP
Prevents atrial electrical remodeling
Proarrhythmic mechanisms Proarrhythmic risks: None

ACS, acute coronary syndrome; AF, atrial fibrillation; AP, action potential; APD, action potential duration; DRI, Dopamine reuptake inhibitor; dV/dtmax, maximum action-potential upstroke velocity; EAD/DAD, early/delayed afterdepolarizations ERP, effective refractory period; PAF, paroxysmal atrial fibrillation; SAN, sinoatrial node; VT, ventricular tachycardia.