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.