Class I Antiarrhythmic Drugs: Na⁺ Channel Blockers

Abstract

Class I antiarrhythmic agents or Na⁺ channel blockers are among the first drugs that have been used for several decades, and are divided into three groups, according to their cellular electrophysiologic effects. The sodium ion currents or I_Na enter the cell very fast during phase-0 of action potential and is responsible for depolarization.

Sodium channel blockers, therefore prolong conduction time, and refractoriness of the atria, ventricle, and the Purkinje system. These agents are effective against many arrhythmias such as atrial fibrillation and flutter.

Their most important side effects are proarrhythmia and inducing torsades de pointes. With introduction of newer antiarrhythmic agents, I_Na blockers are less frequently used.

I_Na currents are controlled and modulated by several genes and the most common being the SCN5A gene. Mutations in SCN5A gene cause several genetic syndromes such as Brugada syndrome, LQT3 syndrome, familial AF, and many others. The novel indications of I_Na blockers such as low dose quinidine in Brugada syndrome, and Mexiletine in LQT3 syndrome, provide new therapeutic options in patients with sodium channelopathies.

Discoveries of ion channels and their respective genes as well as their mutations are discussed in this chapter, including the most recently published guidelines of respective societies.

FormalPara Glossary of Abbreviations

I_Na Sodium current

I_Na-early Early sodium current

I_Na-late Late sodium current

I_Na/K Na/K pump current

I_Na/Ca Na/Ca exchanger current

I_to1 Voltage-activated Ca²⁺ outward current

I_to2 Ca²⁺ activated transient outward current

I_Kr Rapid component of delayed rectifier potassium current

I_Kur Ultra-rapid component of delayed rectifier current

I_Ks Slow component of delayed rectifier current

I_K1 Inward rectifier potassium current

Introduction

For several decades, sodium channel blockers , the so-called “class I antiarrhythmic drugs (AADs)”, have been the frontline of antiarrhythmic therapy for the management of a variety of cardiac arrhythmias [1, 2]. Among many others, quinidine, procainamide, and lidocaine have been in use for several decades. Progress in understanding the mechanisms of arrhythmias on one hand, and understanding the mechanisms of action of AADs from the whole heart to the single ion channels on the other hand, has improved our management of arrhythmias.

In this chapter we review the old and new mechanisms of sodium channel blockers in their broad spectrum from basic to clinical, with focus on the novel indications of theses agents. We use “sodium current” and “I_Na” interchangeably.

There have been several classifications of AADs, based on their direct effect on normal and abnormal cardiac electrical systems as well as different arrhythmia mechanisms. Although each AAD has its own distinct characteristics, classifications are generally appealing for clinicians and teaching purposes.

Vaughan Williams

The Vaughan Williams classification has been used widely for several decades and is based on the effect(s) of AADs or groups of agents on action potential duration (APD) and respective ionic channels [3,4,5].

Class I AADs constitute agents that exclusively or predominantly block the fast sodium current, although many of them may exhibit other ion channel blocking effects such as quinidine’s effect on K⁺ channels. Table 2.1 illustrates the modified Vaughan Williams classification.

Table 2.1 Vaughan Williams classification of antiarrhythmic drugs [5]

Sicilian Gambit

This classification is based on individual agents, which may have multiple effects.

The concept of AAD-specific arrhythmia mechanisms in relation to ion channels are well discussed in the Sicilian Gambit (Table 2.2) [6].

Table 2.2 Sicilian Gambit chart for AADs

The electrophysiological effect of AADs may be investigated at several levels:

• 1. Cell membrane

• 2. Ion currents and ion channels

• 3. Gap junctions

• 4. Receptors

• 5. Pumps

• 6. The whole intact-heart

Action Potential

The registration of a sudden movement of sodium ions from outside the cell membrane (depolarization), into it (inward current), and followed by the slow movement of K⁺ ions from inside the cell membrane (repolarization) to the extracellular space (outward current) [7,8,9]. Fig. 2.1 shows the atrial and ventricular AP with its five phases and respective ion channels.

Figure 2.1

Illustrates atrial and ventricular AP and its respective ion channels involving different phases of APD and respective genes. With permission from Card Electrophysiol Clin 8 (2016) 257–273 [8]

The Cardiac Action Potential: Role of I_Na Current

Figure 2.1 shows the typical atrial and ventricular action potential duration (APD) as well as the respective ion currents and genes that control the ion channels. The atrial and ventricular myocardial APD as well as Purkinje cells APD are somewhat similar and distinctive from those of the sinoatrial and A-V nodal cells.

The sinoatrial node has a fast phase 4 that produces spontaneous depolarization. The depolarizing current of the sinoatrial and A-V node is Ca²⁺ current and L-type Ca²⁺ (I_Ca) channel are discussed elsewhere in this book. Likewise, potassium ions and channels are discussed in another section.

Sodium channels are present in sinoatrial node, but for the most part, are inactivated under physiological (normal) conditions.

Ion Channels

Channels are segments of the cell membrane that allow movement of ions across the cell membrane whether active or passive.

Ion channels are from a group of complex glycoproteins that make pores and permit the transport of cardiac ions, i.e. sodium, potassium, calcium, and chloride across the cell membrane (either inward or outward the cell). This transport takes place when the channel changes from a “closed state” to an “open state”. Opening and closing ion channels are governed by voltage and voltage-operated gates, simplified as “voltage-gated” [10]. Diffusion through these protein channels is called “gating” [11]. These channels have two important features:

• 1. Selective permeability to certain molecules and ions such as selective Na⁺ channel and selective K⁺ channels.

• 2. Many channels can be opened (open state) or closed (closed state) under certain conditions such as chemical or electrical charges, concentrations, etc. [12]

The anatomy and function of these ion channels determine the cardiac APD [13]. The ion transport therefore depends on several factors such as the electrical and concentration gradient of a specific ion across the membrane or other triggers.

These channels further operate at different states such as active transport, inactive transport, open state, and closed state [11, 14].

Cardiac Sodium Current (I_Na) and Channel

Voltage-gated sodium channels made of transmembrane proteins that allow the sodium ion current to travel through these channels are responsible for the rapid upstroke (phase 0) of the cardiac AP (depolarization). Sodium current is an inward current and is the major current that is present in atria, myocardial, and Purkinje cells and is responsible for depolarization, i.e. phase zero of AP (Fig. 2.1). Therefore, the sodium current is responsible for the rapid impulse conduction through atrial, His-Purkinje system, and ventricular myocardium. The sodium channel and current is controlled with multiple genes; however, the most dominant one is SCN5A. Therefore, the sodium channels are the main molecular substrate that are involved in both inherited and acquired disorders of channelopathies. The sodium current in the atria, ventricular, myocardial, and Purkinje cells are voltage dependent activated channels at −75–90 mV [14]. The main voltage-gated sodium channel that is expressed in human cardiac myocytes is Na_v 1.5, which is encoded by the SCN5A gene [15,16,17,18,19]. Transport of I_Na through the channels is determined by α-subunits (i.e. proteins that make the channel). The α-subunits are comprised of four serially linked homologous domains, which make the ion channels pure (Fig. 2.2) [20, 21]. These proteins are encoded and regulated by several genes, the most dominant one being SCN5A. The cardiac sodium channel gene (SCN5A) resides on the short arm of chromosome 3 (3P21) [20]. The most common subunit that controls the sodium current is α-subunit that consists of four homogenous domains as shown in Fig. 2.2 [7, 20, 22]. At the same time, there exist pathways under regulation of ion channel expression, i.e. up or down regulation of certain genes [23, 24].

Figure 2.2

Illustrates the four domains of the sodium channel and SCN5A gene that are involved in various mutations and syndromes. Modified from: Hund T, Mohler PJ. Biophysics of Normal and Abnormal Cardiac Sodium Channel Function. In: Cardiac Electrophysiology: From Cell to Bedside (2014) Elsevier, Philadelphia, USA. With permission [20]

Most of the sodium current transport occurs early during phase zero (phase 0) of AP (I_Na-early or I_Na fast). There remains a small amount of I_Na that causes the channel to remain open during phase 2 and 3 of AP called Late I_Na, I_Na-late or I_Na slow. Although I_Na-late has little contribution under normal (healthy) conditions, it plays an important role under pathological (diseased) conditions (see section under I_Na-late current) [25, 26].

Sodium channels open fast in response to the onset of depolarization phase 0. When the voltage reaches −70 to −60 mV (the threshold of activation), the sodium ions move very rapidly into the cells. At the same time, depolarization triggers fast inactivation and sodium channels close.

The Biology of Cardiac Sodium Channels

• 1. Biophysical properties of the voltage-gated sodium currents [27].

• 2. Biochemical (proteins that make the channel): The effects of different classes of AADs have been investigated using the patch clamp (single channel) technique over the past two decades or more on the Na⁺ channels and its modulators [28]. Channel proteins and their genetic structures have diverse properties that are divided into two main subunits.

  • (a) Alpha (α) subunits: The α-subunit is a dominant one and determines the formation of ion pores and is sufficient to produce a normally functional sodium channel.

    So far, nine sodium channel protein structures that make the α-subunits have been identified; Na V₁.1 to Na V₁.9 [29,30,31]. Relevant to cardiac sodium channels are Na_v I.5 and its gene SCN5A that is involved in some of the cardiac channelopathies and related syndromes such as Brugada syndrome, Long QT 3 (LQT3) syndrome, idiopathic VF, and J-wave syndrome that are discussed later in this chapter (Fig. 2.3).

    Figure 2.3

    

    Shows the SCN5A mutations related to different channelopathy syndromes. Abbreviations: AF atrial fibrillation, DCM dilated cardiomyopathy, LQTS long QT syndrome, MEPPC multifocal ectopic Purkinje-related premature contractions, MI myocardial infarction, SIDS sudden infant death syndrome, SUNDS sudden unexplained nocturnal death syndrome

Voltage-Gated Sodium Channels

• Use-dependence Effect of Sodium Blocking Agents: Most sodium channel blocking agents affect membrane excitability and conduction velocity in a use-dependent fashion.

• Frequency Dependence: Most class I AADs demonstrate frequency-dependence, i.e. the effect is more pronounced at higher rates. However, there exists some differences between the three classes of sodium channel blockers in their frequency-response effect [32].

• Effect of Sodium Blocking Agents: Characterized by increase in refractoriness of the cardiac tissue at fast rates for sodium channel blockers (class I), whereas slower heart rates (lower frequency rates) are mostly observed in class III agents such as Sotalol [33].

Late Na⁺ Current

The sodium current is composed of two components:

• 1. Peak or early sodium current (I_Na-early) occurs during the phase zero of AP and is a rapid inward current that takes approximately 1–2 msec.

• 2. The late sodium current (I_Na-late) takes place in phase 2 and early phase 3 of AP and lasts approximately 100–300 msec. An increase in the I_Na-late prolongs APD, and blockade of the I_Na-late shortens APD. Most I_Na blockers exhibit both early and late I_Na blocking effects, however, at different magnitudes. Ranolazine, a late sodium channel blocker, exhibits 5–9 times higher late than early Na⁺ blocking effects. I_Na-late channel blockers dissociate from the channel faster than I_Na-early, and is probably why they exhibit less proarrhythmic effect compared to I_Na-early blockers [25, 34, 35].

General Electrophysiological and Electropharmacological Effects of Na⁺ Channel Blockers

• 1. All class I agents have direct membrane effects and exhibit local anesthetic effects.

• 2. Slowing of rapid phase zero APD results in decrease in excitability.

• 3. Prolongation of conduction velocity (slowing conduction time).

• 4. Sodium channel blockers suppress both voltage-dependent and time-dependent recovery of excitability. Effects of these agents on voltage-dependent properties (kinetics) are more pronounced in ischemic tissue than normal tissue.

• 5. Suppression of time-dependent property by Na-channel blockers prolongs tissue refractoriness, and if such effect sustains longer than the repolarization phase it will cause post-repolarization refractoriness.

• 6. In cardiac fibers that demonstrate spontaneous automaticity, the sodium channel blockers exhibit increased slowing of the spontaneous diastolic depolarization [36, 37].

• 7. Sodium channel blockers can suppress excitability and prolong conduction and refractoriness. Therefore, may be effective on a variety of arrhythmias with diverse mechanisms and substrates.

• 8. Sodium ion channel blockers also eliminate the triggers, such as PAC and PVCs. It is also important to realize, as it was shown in the CAST trial, that elimination of triggers such as PVCs do not always translate to elimination of mechanisms of arrhythmias nor substrate modifications; risk predictors are not always the same as efficacy predictors. Thus, CAST showed failure of PVC elimination to improve outcome.

Effect of Na ⁺ channel blockers on electrocardiographic and intracardiac intervals (Table 2.3).

Table 2.3 The effect of sodium channel blocking agents on electrocardiogram and intracardiac intervals

Class Ia AAD: Quinidine, Procainamide, Disopyramide, and Ajmaline

As discussed earlier, according to the Vaughan Williams classification, Class I AADs are subdivided into three classes: Ia, Ib and Ic based on their effect on APD (Table 2.1). Class Ia agents mainly affect the phase 0 of APD and thus prolong conduction time, and also prolong repolarization to some degree. The prototypes of this class are quinidine, procainamide, and disopyramide.

Quinidine

• Effects of quinidine on the ECG (Table 2.3).

• Electrophysiologic and antiarrhythmic properties of quinidine (Table 2.4). Pharmacokinetic properties of quinidine (Table 2.5) [38].

  Table 2.4 Effects of sodium channel blockers on electrophysiological variables

  Table 2.5 Dosage and pharmacokinetic properties of sodium channel blockers

• Drug interactions (Table 2.6).

  Table 2.6 Sodium channel blocker drug interactions

• Novel indications of sodium channel blockers of quinidine: Recent reports suggest that low dose quinidine (<600 mg/day) was effective in preventing ventricular arrhythmia recurrences and storm in patients with Brugada syndrome [39,40,41,42,43]. Mizusawa, et al. reported on the effects of low-dose quinidine in VT in patient with Brugada syndrome [44]. High dose quinidine (≥ 1 g/day; needed to block the transient rapid outward potassium current (I_to)) was also found to be effective in ventricular tachyarrhythmias and VT storm in patients with Brugada syndrome [39, 45,46,47]. This effect is only tested in a limited number of patients with Brugada syndrome who have implantable cardioverter-defibrillators (ICDs) [39, 45, 48,49,50].

  Belhassen, et al. reported that quinidine was effective in preventing induction of VF in 22/25 (88%) patients with Brugada syndrome [48].

  The mechanisms of quinidine’s efficacy in patients with Brugada syndrome and ventricular tachyarrhythmias are believed (in part) to be due to blockade of rapid inward I_Na. Quinidine, besides its direct effect on I_Na channel blocker, also exhibits I_to inhibition [44].

  Interestingly, quinidine selectively blocks I_to current more in the epicardial than endocardial region of the right ventricle. This may explain, in part, its efficacy against ventricular arrhythmias in Brugada syndrome [40, 51, 52].

  Quinidine is also effective in patients with short QT (SQT) syndrome by prolonging the QT interval and preventing ventricular arrhythmias [53,54,55]. The SQT interval is due to the gain of function in I_Kr and is related to the mutation in the HERG gene. The SQT syndrome is often seen in combination with familial AF; therefore, quinidine is effective for both conditions. In these cases, quinidine normalizes the QT interval and renders VF as non-inducible [54]. Similarly, quinidine has been shown to be effective in patients with J-wave/early repolarization syndrome [56,57,58,59]. Procainamide, propafenone, flecainide, and disopyramide may induce or unmask ST segment elevation in patients with concealed J-wave syndrome [60,61,62].

• Adverse effects of quinidine:

  • Cardiac: Quinidine has long been known to prolong QT interval and thus induces TdP known as quinidine syncope (1–3%). The mechanism of quinidine-induced TdP is assumed to be due to EAD [63, 64]. The QT prolongation effect of quinidine is more effective at slower heart rates (bradycardia-dependent).

Procainamide

• Effects of procainamide on the ECG (Table 2.3).

• Electrophysiogical properties of procainamide (Table 2.4).

• Phamacokinetic properties of procainamide (Table 2.5).

• Oral dosing (Table 2.5): Due to the short half-life of procainamide, multiple dosages per 24 h are required. Thus, a total dose of 1000–4000 mg per day may be administered. Long acting (slow release of procainamide) is also available and may be administered at twice a day intervals.

• Novel indications of procainamide to unmask “concealed” Brugada ECG patterns in patients suspected of Brugada Syndrome: In Europe, IV ajmaline is used to unmasked concealed or suspected Brugada syndrome (1 mg/kg) [65], whereas in the United States, IV procainamide is used for this purpose [61, 66,67,68].

Disopyramide

• Effects of disopyramide on the ECG (Table 2.3).

• Electrophysiogical properties of disopyramide (Table 2.4).

• Phamacokinetic properties and dosage of Disopyramide (Table 2.5).

• Drug interactions (Table 2.6).

• Indication: Disopyramide is effective against atrial and ventricular arrhythmias as well as effective in patients with paroxysmal and persistent AF. It is also effective against sinus node reentry tachycardia, atrial flutter, atrial tachycardia, AVNRT, and AVRT. Intravenous disopyramide is effective in controlling AF in patients with Wolff-Parkinson-White Syndrome [69]. Disopyramide has been used in the past to control a variety of ventricular arrhythmias such as PVCs, couplets, non-sustained and sustained VT; however, it has been less frequently used in recent years. Effects of disopyramide in post-infarction phase have been investigated and showed that although disopyramide reduced ventricular extrasystoles, it did not show a significant decrease in VT and VF or a reduction in cardiac mortality [70]

• Use of disopyramide in patients with HCM and AF: Disopyramide , due to its negative inotropic effect as well as ventricular relaxation property, is effective in reducing the LV outflow tract gradually. As AF is the most common arrhythmia in patients with HCM, disopyramide is also effective in controlling AF in these patients (300–600 mg daily; others have used 250–750 mg daily [71]) [72]. However, due to its significant cardiac and non-cardiac side effects, long-term use is limited. Sherrid et al., reported on a multicenter study of efficacy and safety of disopyramide in obstructive HCM and reported in this large cohort (118 patients) that disopyramide appeared effective in reducing the symptoms in 78 (66%) of the patients. In the remaining 40 (34%) patients, disopyramide did not adequately reduce their symptoms [73]. Several reports suggest the use of disopyramide for controlling AF in patients with HCM. However, due to its vagolytic effect, disopyramide may increase the ventricular rate in these patients. Therefore, it should be used concomitantly with A-V nodal slowing agents such as beta-blockers or calcium antagonists. Interestingly, disopyramide did not increase the risk of proarrhythmia in these patients [73]. Needless to say, the QT/QTc interval should be monitored during disopyramide therapy in these patients [74]. In summary, disopyramide is effective in selected patients with HCM; however, due to its potential proarrhythmic and torsadogenic effect, careful monitoring is recommended and should generally be used after a beta-blocker trial before considering surgical or alcohol septal ablation [73, 75].

According to the most recently published guidelines, due to disopyramides vagolytic property, should be used in combination with an A-V nodal blocking agent to avoid rapid ventricular response [74].

Ajmaline

Ajmaline is a derivative of the Rauwolfia plant and is not approved in the United States

• Electrophysiogical properties of ajmaline (Table 2.4).

• Phamacokinetic properties and dosage of ajmaline (Table 2.5).

• Novel Indications of Ajmaline : Aside from its usual indication for acute termination of supraventricular or ventricular arrhythmias, ajmaline is used for diagnostic purposes of:

  • 1. Blocking the accessory pathway in patients with Wolff-Parkinson-White syndrome [76,77,78]

  • 2. Unmasking the Brugada ECG signs in individuals suspected of this syndrome [79].

  • 3. Unmasking the latent His-Purkinje system disease.

• Life-threatening ventricular arrhythmias have been reported during ajmaline tests in patients with Brugada syndrome. The incidence is about 1.8% of patients in a large cohort [80, 81]

Class Ib AAD: Lidocaine, Mexiletine

Lidocaine

• Effects of lidocaine on the ECG (Table 2.3).

• Electrophysiologic and antiarrhythmic properties of lidocaine (Table 2.4).

• Pharmacokinetic properties of lidocaine (Table 2.5).

• Drug interactions (Table 2.6).

Mexiletine

• Effects of mexiletine on the ECG (Table 2.3).

• Electrophysiologic and antiarrhythmic properties of mexiletine (Table 2.4). Pharmacokinetic properties of mexiletine (Table 2.5).

• Drug interactions (Table 2.6).

• Novel indication of mexiletine: Since mexiletine does not prolong repolarization, it has been used safely in patients with LQT syndrome; specifically LQT3 in which the SCN5A gene involved that controls the I_Na+ current [82,83,84]. Indeed, mexiletine shortens the QT and QTc interval and therefore reduces indices of malignant arrhythmic events in patients with LQT syndrome. Torsadogenic effects of mexiletine are rare. Another interesting finding is the blockade of mexiletine of the I_Na-late and its potential use in patients with Timothy syndrome [85].

Class Ic AAD: Propafenone and Flecainide

Propafenone (Table 2.1)

• Effects of propafenone on the ECG (Table 2.3).

• Electrophysiologic and antiarrhythmic properties of propafenone (Table 2.4) [43].

• Pharmacokinetic properties of propafenone (Table 2.5).

• Drug interactions (Table 2.6).

• Efficacy of propafenone in patients with AF: Propafenone’s use-dependent property makes it effective against AF and atrial flutter [86, 87]. The recommended dose of propafenone for AF is 150–300 mg three times daily. The average efficacy at 1 year is 40–75% [88]. Propafenone is currently approved for use in patients with paroxysmal and persistent AF [63].

  Propafenone prolongs anterograde and retrograde A-V nodal conduction. Thus, this makes it effective in the prevention and termination of arrhythmias that are A-V node-dependent, i.e. AVNRT and AVRT. Propafenone also reduces excitability, spontaneous automaticity, and triggered activity. It also has mild I_Kr blocking effect as well as a weak beta-blocker effect; however, it is higher than flecainide. Propafenone also prolongs and blocks both anterograde and retrograde conduction of the accessory pathways; thus it is effective against patients with recurrent AVRT [89, 90].

• Efficacy of propafenone in patients with ventricular arrhythmias: Propafenone prolongs ventricular conduction time at a greater degree than refractoriness. This imbalance may be the mechani sm of propafenones proarrhythmia that facilitates (promotes) ventricular tachyarrhythmias [89, 90]. Propafenone is effective in reducing PVCs, couplets, and non-sustained VT. Efficacy for sustained VT in chronic phase of MI is based on electrophysiological testing and is moderate, i.e. 40%.

• Proarrhythmic effects of propafenone: Like flecainide and other class Ic agents, propafenone poses significant ventricular proarrhythmias, especially in patients with CAD, ischemia, presence of myocardial scar, reduced LV systolic function, as well as LVH. Propafenone may increase ventricular response in patients with atrial flutter. This effect is due to propafenone slowing atrial flutter rate and thus allowing more flutter wave conduction to the ventricle [91, 92].

Flecainide

• Effects of flecainide on the ECG (Table 2.3).

• Electrophysiologic and antiarrhythmic properties of flecainide (Table 2.4) [43].

• Pharmacokinetic properties of flecainide (Table 2.5).

• Drug interactions (Table 2.6) [93, 94].

• Dosage (Table 2.7).

  Table 2.7 Available AADs for the treatment of ventricular arrhythmias [95]

• Indication: Flecainide is effective in reducing PVCs, ventricular couples, and non-sustained VT. Initial experience found flecainide effective against sustained monomorphic VT based on Holter and electrophysiological testing; however, due to its proarrhythmic effect, it is less used (see guidelines) [95]. No data supports the reduction of sudden cardiac death (SCD) with flecainide or propafenone. Flecainide for sustained monomorphic VT in patients with CAD based on electrophysiological studies and program stimulation is not very effective: the VT often remains inducible (Fig. 2.4).

  Figure 2.4

  

  Exercise-induced VT in a patient with CAD on 300 mg of flecainide. (a) Baseline sinus rhythm with a narrow QRS morphology. (b) Sinus rhythm with a wider QRS duration under flecainide. (c) Progressive prolongation of the QRS duration and initiation of sustained monomorphic VT during exercise testing

• Ventricular arrhythmias: Flecainide is effective in reducing PVCs, non-sustained, and sustained VT; however, it carries the risk of proarrhythmias. Conceptually, any agent that prolongs conduction time changes the balance between conduction time and refractoriness and hence may cause increased likelihood of facilitating reentry. This was well documented in the case of propafenone, and is similar to flecainide [89, 90]. Fig. 2.4 shows exercise induced VT in a patient with CAD (see Fig. 2.4 legend for explanation). Indication for the use of flecainide in patients with VT is summarized in Table 2.7 from the 2015 ESC Guidelines.

  Almost all class I AADs effects are reversible with isoproterenol [96].

• Novel indication of flecainide : Interesting data is emerging on the use and effectiveness of flecainide in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) [97,98,99,100,101,102,103,104]. Although the treatment of choice for patients with CPVT is beta-blockers and ICDs, only one study has reported flecainide-inhibited ryanodine receptor-mediated calcium release in two patients with CPVT [105]. Van der Werf, et al. reported that flecainide, with a median dose of 150 mg daily, prevented exercise-induced ventricular arrhythmias in 2/3 (76%) of the patients with CPVT [100].

  Flecainide may be used to unmask SCN5A related Brugada syndrome [106]. In a cohort of 22 patients, Wolpert, et al. reported on the intravenous use of flecainide and ajmaline on unmasking Brugada syndrome [107]. Flecainide unmasked 15 of the 22 patients and ajmaline unmasked 100%. Some reports suggest that flecainide may be useful in LQT-related SCN5A mutations. Interestingly, it was found that flecainide normalized the ventricular repolarization [108]. Recent reports suggested that flecainide alone or in combination with digoxin, was highly effective in converting fetal SVT to sinus rhythm [109,110,111,112,113]. The dosage administered was 100 mg 4 times daily for the first 2–3 days and then changed to 300 mg/d. The median time to conversion was 3 days (1–7 days).

• Proarrhythmic effect of flecainide:

  As flecainide exhibits negligible effect on anterograde A-V nodal conduction, when used in patients with atrial flutter, the drugs prolong atrial flutter cycle length [114] and allow a faster conduction via A-V node with 1:1 and 2:1 A-V conduction causing rapid ventricular response; therefore, flecainide should be used concomitantly with slow A-V nodal conduction agents like calcium antagonists or beta blockers [115]. Ventricular proarrhythmic effects of flecainide include sustained monomorphic VT, TdP, and incessant VT. Also, flecainide induces QRS prolongation during exercise and exercise-induced VT as shown in Fig. 2.4. An increase in the QRS duration by 15–20% is a recognized pharmacologic effect of flecainide; however, several cases have reported that as the QRS duration gets longer during exercise, sustained VT emerges, i.e. exercise-induced VT during flecainide therapy [116]. There is an exception that flecainide is effective in patients with CPVT and exercise-induced arrhythmias. Overall, the use of flecainide worldwide is still low. The Euro-Heart survey on AF shows that 17% and 13% of patients with paroxysmal and persistent AF respectively have been treated with class Ic AAD (flecainide and propafenone) [117].

  Contraindications of both propafenone and flecainide include CAD with and without myocardial ischemia, LV systolic dysfunction, and significant evidence of A-V conduction system disease.

Other Drug and Substance Interactions

Grapefruit interacts with many cardiovascular and AADs namely quinidine, disopyramide, and propafenone. Since grapefruit decreases the activity of CYP3A4, any pharmacological agent that metabolizes through this enzyme may cause the blood levels of the drug to rise, resulting in the risk of adverse events [118,119,120,121]. For further detail of other substances, see Table 2.6 [122].

Selective Sodium Channel Blockers

The concept of ion-channel selective agents has emerged as an interesting and appealing notion in avoiding global cardiac effect, potential arrhythmogenesis, and proarrhythmic effects [123, 124]. There exists evidence that atrial channel selectivity is expressed in the atria [125]. Among the selective I_Na channel blockers are vernakalant and ranolazine. Both have significant atrial-selective blocking properties, which are effective against atrial arrhythmias, specifically AF and atrial flutter. Both agents also demonstrate sodium channel blocking effects in experimental models of pulmonary veins [126, 127].

Sodium channels are highly selective for sodium ions to travel across the cell membrane in a voltage-dependent manner [128]. The sodium channel selectivity is significantly higher than the potassium channel selectivity [129]. There are several factors that influence their selectivity such as voltage, pH, and other modulators and modifiers.

In general, sodium channel blockers have high binding affinity to the early (I_Na-early) phase than late (I_Na-late) phase. Ranolazine predominantly blocks the I_Na-late phase and thus has less proarrhythmic effect. Also, late sodium currents exhibit a rapid unbinding to the sodium channel as compared to early sodium current [130]. Interestingly, recent data demonstrates that permanent AF increases the number of late Na⁺ currents in the atria; thus, it is conceivable that ranolazine, a late sodium current blocker, is effective in patients with AF [125, 131,132,133,134].

Sodium channel blocking agents have a direct frequency-dependent effect; therefore, their efficacy will be increased during high-rate arrhythmias such as AF. Furthermore, sodium channels demonstrate higher affinity to AADs in their activated/inactivated states compared to their closed state. Late sodium channel blockers (I_Na-late) dissociate faster from ion channels than early sodium channel blockers (I_Na-early). This may, in part, explain lower proarrhythmic effect of these agents [128].

The limitations of selective ion-channel blockers are as follows:

• 1. At higher concentrations, they lose selectivity properties. This selectivity may work in normal tissue; however, remodeled tissue may be different.

• 2. Some agents like ranolazine exhibit differential effect on the I_Na channels of the atria as compared to the ventricle.

• 3. They still carry the risk of proarrhythmias

• 4. Studies on selective ion-channel blockers are done on healthy tissue preparations in the absence of autonomic, hemodynamic, and structural changes.

Interestingly, both amiodarone and ranolazine are multichannel blockers; however, they exert an atrial selective sodium channel blocking effect [125, 135,136,137].

Genetics of Sodium Channel Dysfunction and Blockers

Molecular Genetics of Arrhythmias and Channelopathies Related to Sodium Channel Blockers and their Mutations

It is quite important to briefly discuss this topic, as more evidence is emerging on the relation of sodium channels and channelopathies to many genetic syndromes related to sodium channels. These concepts are well discussed in the following references [92, 138,139,140,141,142,143].

As discussed earlier, it is now well established that ion channels operate under genetic control and that certain genes encode proteins for healthy sodium channel function. The site of each gene on chromosomes is called the locus, and when genetic information on the DNA sequence is translated to the respective protein(s) via a transcript code with mRNA, it is then passed through the next generation (from the parent). Many of these genes are gender specific and may be dominant or recessive (Mendelian pattern). Several factors affect and determine these mutations including environmental (i.e. radiation, drugs, and chemicals) or other unknown factors. Any errors or modification in their process may cause abnormal mutations, which may lead to the development of specific diseases. Some mutations in the sodium channels are related to Brugada Syndrome, LQT3 Syndrome, dilated cardiomyopathy, AF, and sick sinus syndrome [21, 91, 144].

Sodium Channel Mutations and Related Channelopathies

The term channelopathies refers to a group of genetic abnormalities and mutations of ion channels that produce cardiac arrhythmias [145,146,147]. The most common is the SCN5A mutation related to sodium channels that produce the arrhythmia syndromes listed below and are listed in Table 2.8 and Fig. 2.3 [149, 153].

Table 2.8 Genetic-related sodium channel arrhythmias [140, 148, 149]

These genetic mutations may cause either loss [154] or gain of function or both [17] (Fig. 2.3).

Loss of Function

• 1. Brugada syndrome [154,155,156]

• 2. Sudden unexplained nocturnal death syndrome [157]

• 3. Familial AF.

• 4. Atrial standstill.

• 5. Sick sinus syndrome [158]

• 6. Cardiac conduction disease.

• 7. Progressive cardiac conduction disease [154, 159,160,161,162]

• 8. Congenital A-V block.

• 9. Dilated cardiomyopathy [163,164,165,166]: 16 mutations have been reported.

Gain of Function

• 1. LQT3 syndrome.

• 2. Drug-induced LQTs.

• 3. Familial AF.

• 4. Multifocal ectopic Purkinje-related premature contractions [167]

• 5. Sudden infant death syndrome [24]

• 6. Stillbirth.

• 7. Idiopathic VF/early repolarization [150, 168]

• 8. Arrhythmic storm syndrome during acute myocardial infarction [169]

Sodium Ion Channelopathies and Related Syndromes (Table 2.8 and Fig. 2.3)

Most of these syndromes are related to the SCN5A gene mutation . These are divided into two categories, loss of function, and gain of function [170]. Furthermore, there are a few syndromes that have common genetic mutations such as LQT3 syndrome, Brugada syndrome, and progressive cardiac conduction defect [141, 160, 171,172,173,174]. Laurent G, et al. recently reported a new SCN5A-related cardiac channelopathy that presents as multifocal ectopic Purkinje-related premature contractions [167].

Progressive Cardiac Conduction Disease Syndrome : This syndrome is due to the mutation of SCN5A gene of the Na_V 1.5 channel. It is an inherited arrhythmia disorder and is due to loss of function [175]. Recent studies suggest that autoimmune response may express the sodium channel Na_v 1.5 and produce AV block [176, 177]. So far, 11 forms of mutations have been described. This syndrome overlaps with other sodium channelopathies such as Brugada syndrome, LQT3, and DCM (Fig. 2.3) [160, 178, 179].

Genetic Forms of AF: There is now compelling evidence that a genetic form of AF exists, [180] either as a standalone or part of a broader spectrum of other genetic arrhythmia syndromes such as Brugada syndrome, LQT syndrome, and SQT syndrome [181,182,183,184,185]. Several genes and their mutations are associated with genetic forms of AF such as mutations in sodium channels related to SCN5A, SCN1B-2B and many others [149, 186,187,188].

Aside from ventricular tachyarrhythmias and SCD, AF is the most common arrhythmia associated with Brugada syndrome [189]. The incidence varies from 20–50% according to different geographical regions [190]. Besides Brugada syndromes, AF may also exist in other cardiac channelopathies such as LQT, SQT and CPVT [191].

LQT3 syndrome: LQT3 syndrome is due to an increased function in the late sodium current that prolongs APD [192]. The gene responsible in LQT3 syndrome is related to SCN5A mutation and is either autosomal dominant or a recessive inheritance pattern [179, 193]. Therefore, LQT3-related arrhythmia blockade of the late sodium current by ranolazine is effective against arrhythmias related to LQT3 [194]. Ranolazine, by decreasing I_Na-late, shortens APD and abolishes arrhythmias related to LQT3 [194].

Other genetic-related sodium channel arrhythmias are summarized in Table 2.8.

Management of cardiac sodium channelopathies includes [195]:

• 1. Risk stratification of patients and their relatives. This depends on the severity of the symptoms, phenotypes (ECG findings), and genotypes, i.e. identifying genetic profile and mutations.

• 2. Pharmacological therapy such as beta-blockers, quinidine, ranolazine, and flecainide (see section on novel indication of class I agents).

• 3. ICDs in high-risk patients.

• 4. Surgical left cardiac sympathetic denervation [196, 197].

AAD Drug-Induced Arrhythmias: Proarrhythmia, Arrhythmogenesis, or Arrhythmia Aggravation

Proarrhythmia (Latin) or arrhythmogenesis (Greek) is defined as aggravation of an existing arrhythmia or development of new arrhythmias that were not present before therapy due to a pharmacological agent (cardiac or non-cardiac) or a non-pharmacological intervention [198]. Proarrhythmia has been far recognized [199]; however, this effect has become more obvious since the CAST and other respective trials [200]. In general, cardiac tissue is anisotropic (non-uniform), particularly in myocardial disease, ischemia, and infarction, which increases anisotropic conduction. The most common form and serious proarrhythmia is TdP due to QT prolongation [201]. In general, TdP is usually initiated with a long-short RR interval sequence [202]. AADs exacerbate the occurrence of serious VT in this setting [203]. An important complication of pharmacological agents, whether cardiac or non-cardiac, is their torsadogenic effect. The mechanisms of drug-induced TdP remain controversial. Most studies suggest that ventricular arrhythmias due to TdP are related to EAD-triggered activity, and it may change to reentrant mechanisms. Multiple factors play a role including genetics, gender, and other mechanisms. Focal or reentry mechanisms are contemplated. It is most likely that both are operational [204, 205].

Virtually all class I agents have the risk of proarrhythmia and TdP. The incidence varies significantly depending on the method that is used for evaluation of proarrhythmia, i.e. invasive vs non-invasive methods and interplay of AADs with arrhythmia substrate (Figs. 2.5 and 2.6).

Figure 2.5

Interplay of different ion channel dysfunctions related to channelopathies , ventricular arrhythmias and SCD. With permission from Wagner S, et al. Circ Res 2015;116:1956–1970 [15]. Abbreviations: APD action potential duration, Ca alternans Calcium alternans, DADs delayed afterdepolaizations, EADs early afterdepolarizations, SR sinus rhythm, TdP torsades de pointes, VF ventricular fibrillation, VT ventricular tachycradia

Figure 2.6

Relationship of AADs to Clinical Pathophysiology. Abbreviations: AAD antiarrhythmic drug, ARVD arrhythmogenic right ventricular dysplasia, CAD coronary artery disease, DCM dilated cardiomyopathy, etc. etcetera, HCM hypertrophic cardiomyopathy, HF heart failure, HTN hypertension

Class Ia and Ic AADs are among the pharmacological agents that have a high risk of drug-induced TdP (disopyramide, procainamide, quinidine, propafenone, flecainide). Drug-induced LQT Syndrome is also considered an acquired form of LQT Syndrome [206]. Genetic predisposition is an important factor that promotes drug-induced QT prolongation [207, 208]. A comprehensive review of this subject is published by Camm, et al. [209]

Ventricular proarrhythmic effect of class I agents includes increasing the ventricular response in patients with AF and flutter as well as sustained monomorphic VT, incessant VT, polymorphic VT, VF, TdP, and others.

A recent report has been published by Riad et al. on drug-induced QT prolongation. Patients were divided into four risk profiles: no risk, conditional risk, possible risk and known risk [210].

There are several risk factors for drug-induced proarrhythmias that are determined elsewhere [201, 208, 211,212,213,214,215,216,217,218,219].

Prevention of Sodium Channel Blocker Proarrhythmia [220]:

• 1. Elimination of the predisposing factors such as bradycardia, electrolyte imbalance, cardiac, and non-cardiac agents that promote TdP.

• 2. Modification of underlying heart disease such as HF, impaired renal function, hepatic disease, etc.

• 3. Appropriate monitoring in patients at risk of proarrhythmia and TdP such as ECG monitoring for QT prolongation, etc. [221, 222]

• 4. Appropriate patient teaching and use of digital devices to obtain urgent rhythms.

Sodium Ion Channel Remodeling

There is some evidence, although controversial, about sodium channel remodeling . This mostly occurs in patients with HF, ischemia and infarction, and AF. However, in the remodeled tissue, more than one ion channel is often involved, particularly in patients with persistent and permanent AF [223]. Sodium channel remodeling creates abnormalities that favor occurrence of reentry and EADs. Reverse remodeling hopefully will correct arrhythmias related to sodium channel remodeling [224]. Amiodarone, a multichannel blocker which also blocks the sodium current, has been reported to be effective against AF-induced remodeling [225]. Sodium channels are reduced in remodeled atria during atrial tachycardia in experimental models and in patients with long-standing AF. Under these conditions the sodium channels are down-regulated [226,227,228,229].

The Ideal Antiarrhythmic Agent

A “wish list” of an ideal AAD includes:

• 1. Being effective in prevention of arrhythmias.

• 2. Induce reverse-remodeling.

• 3. Prevent and reverse inflammation and fibrosis.

• 4. Exhibit both ion-channel as well as systemic effect (system pharmacology).

• 5. Minimal to no adverse effect including cardiac and systemic, i.e. no proarrhythmic consequences.

• 6. No drug interaction

• 7. Affordable

At present, such expectations are far from reality.

Nontraditional Sodium Channel Blockers

• 1. Vanoxerine is an oral multichannel blocker that also affects the sodium current and has been reported in a randomized trial that it is effective in converting patients with recent onset of AF and atrial flutter to sinus rhythm. Piccini, et al. reported on using a single oral dose of Vanoxerine (400 mg). In 18 out of 26 patients (69%) who received Vanoxerine for atrial arrhythmias converted to sinus rhythm; however, the trial was prematurely terminated due to increased risk of TdP [230]

• 2. Another agent is Relaxin, which has been tested as an antifibrosis agent and was found to improve the sodium current in a rat model of AF [231]

• 3. WenXin KeLi is a traditional Chinese medicine which has significant multichannel blocking effects, including late and early sodium current [232]

• 4. There is evidence that suggest that fish oil and n-3 PUFA blocks the sodium channels [233, 234]. Furthermore, limited evidence suggests that fatal arrhythmias may be prevented in high-risk subjects by fish oil n-3 fatty acid intake [235, 236]

• 5. Conflicting results exist on the efficacy of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with AF. This is in part due to the complexity on the mechanisms of AF as well as the relation to structural heart disease. For example, it may be effective in patients with hypertension-related AF due to HF and probably not to other etiologies. Previous trials have failed to show significant improvement on the efficacy of these agents in patients with AF. The hypothesis is that these agents may have an anti-fibrotic effect [237, 238]. Two large trials did not show any beneficial effects on reducing AF by valsartan and Irbesartan [239, 240]. Similarly, ACEs and ARBs did not prevent recurrence of AF after catheter ablation [241]. In summary, there is conflicting data regarding the use of ACEs and ARBs. They only work to prevent angiotensin-mediated fibrotic remodeling. Treatment, which has to be given before remodeling, is so advanced that nothing can be done. At the same time, patients have to be at high enough risk for fibrosis that an effect is detectable over the time frame of observation.

Guidelines on the Use of Sodium Channel Blockers (EHRA/ESC; AHA/ACC/HRS; CCS)

Guidelines for the use of sodium channel blockers by EHRA/ESC are summarized in Table 2.7 [242,243,244]. Fig. 2.7 shows the algorithms for using AADs in patients with AF.

Figure 2.7

Algorithm for using AADs in patients with AF. (a) Recent onset AF, (b) Initiation

Summary

• 1. The cardiac sodium channels are voltage-dependent channels that consist of four homologous domains, which are regulated mostly by SCN5A genes.

• 2. AADs that block or modulate the sodium current have a diverse effect on atrial, ventricular, and specialized conduction system. They also exhibit different effects, normal (healthy) and abnormal (pathological substrate) hearts.

• 3. Abnormalities in cardiac sodium channels, respective genes, and their mutations are responsible for a variety of “channelopathies” and related syndromes such as Brugada Syndrome, LQT3, progressive cardiac conduction defect, and many others.

• 4. Precaution should be exercised in patients with systemic disease such as HF, renal, and hepatic failure.

• 5. The concept of AF is constantly evolving; therefore, response to chronic therapy may change over time [245].

• 6. Sodium channel blockers or class I AADs, especially class Ic agents, remain the most common AAD used for the control of a variety of arrhythmias; however, caution must be used to exercise the potential proarrhythmic events, i.e. TdP.

• 7. Recent observations suggest that there are novel indications for several class I agents including quinidine for Brugada syndrome and mexiletine for LQT3 and the like.

• 8. Class I AADs are among the first class of drugs that came into clinical practice and remain among the major indications for cardiac arrhythmias per the current guidelines, and more novel indications related to the sodium current and channels will emerge.

Future Directions

• 1. Development of novel channel selective agents (sodium channel specific targets) [246]. Due to negative impact of large randomized trials on AADs on VAs and sudden death, the pharmaceutical companies were not interested to invest in developing new AADs; however, with the new frontiers in drugs, devices, and pharmacogenetics, new agents may be developed and expedited by the FDA [247, 248]

• 2. Development of screening methods to identify responders, non-responders, and proarrhythmic effects with respect to the channels, substrates, and pharmacological agents [249]

• 3. Gene therapy for channelopathy-related arrhythmias [250]

• 4. Identification of genetic modifiers.

• 5. Correlation with genotype-phenotype and detection of high-risk carriers.

• 6. More detailed insight into the gender/racial, geographic, socioeconomic, circadian variations, and response to medications should be implemented in drug therapy guidelines [251]

• 7. Identification of the level of penetrance of all related genes and mutations and the role of genetics [252]

• 8. Identification of factors that precipitate upregulation or down-regulation of genetic function [24]

• 9. Genomic medicine, pharmacogenomics, and proteomics [253,254,255]

• 10. Role of Receptors.

• 11. Role of MicroRNA [256, 257]

• 12. Development of substrate-based pharmacological agents such as anti-fibrosis and anti-inflammation.

• 13. Pharmacological agents that modulate the gap junction (normalize gap junction conduction) [258].

• 14. Identification of genetic factors related to the risk of drug-induced arrhythmias (the most common one is TdP) [259,260,261].

• 15. Stem cell therapy and regenerative medicine relative to arrhythmias and antiarrhythmics.

• 16. Spinal cord stimulation in the management of drug refractory arrhythmias and storms [262]

• 17. Personalized and precision medicine [263]

• 18. Most importantly, considering the effect of AADs on patients, specifically system biology and pharmacology.

• 19. A gene-specific approach should be implemented more for both risk stratification and selection of AADs [144]

For further information the readers are referred to the following references [176, 264,265,266]