Implications of Antiarrhythmic Pharmacology

Antiarrhythmic pharmacology is often categorized according to the Vaughan Williams classification system. This system classifies 4 groups of medications according to their mechanism of action, with 3 of the 4 groups impacting the cardiac action potential. The fourth group in this classification system exerts its antiarrhythmic effect by blocking the β1-adrenergic receptors of the sympathetic nervous system. One limitation of this classification system is that most medications impacting the cardiac action potential affect more than 1 ion channel. Although calcium channel blockers impact the slow calcium channel of the cardiac action potential, they are considered safer medications than those that block the fast sodium channel and the potassium channel.1This column focuses on the cardiovascular and electrophysiological effects of sodium and potassium channel blockers and other important clinical considerations in the care of patients receiving these class I and class III agents. If a medication is temporarily placed on hold for a clinical reason, the clinician must plan for return of the arrhythmia for which the patient is being treated. Because of the high-risk features of sodium and potassium channel blockers, nursing knowledge is vital to ensure optimal assessment, counseling, and evaluation of medication effect.Most sodium and potassium channel blockers can be used to treat atrial and ventricular arrhythmias.2,3 Sodium channel blockers, however, have a limited role in treating ventricular arrhythmias and preventing sudden cardiac death because of a lack of evidence of survival benefit and evidence for increased mortality with long-term use in patients with ischemic heart disease.4,5 Specific situations in which oral sodium channel blockers are used to treat ventricular arrhythmias include quinidine in the treatment of Brugada syndrome,6 mexiletine to treat congenital long QT syndrome,7 and flecainide to treat catecholaminergic ventricular tachycardia.8 The sodium channel blockers flecainide and propafenone are used to convert and maintain sinus rhythm in structurally normal hearts.2All class I antiarrhythmics (Table 1) by definition block the fast sodium channel in phase 0 of the action potential, but drugs in the 3 subsets (classes IA, IB, and IC) do so to varying degrees. Class IC agents exert the most sodium blocking effect, followed by class IA agents, with class IB agents exerting the least effect.9 Blocking of the fast sodium channel interferes with rapid depolarization and decreases conduction velocity, resulting in increased duration of the cardiac action potential of the Purkinje fibers. These agents also decrease conduction velocity (negative dromotropy) in nonnodal tissue. Some class I agents also block 1 or more of the potassium currents in phase 3 of the action potential. Potassium channel blockade has a direct effect on the cardiac action potential duration and the effective refractory period. Although impacting the effective refractory period is beneficial in the treatment of reentrant tachycardias, the potential downside is an increased risk of torsades de pointes. Individual class I medications impact the effective refractory period to different degrees. Class IA agents increase the refractory period, class IB agents decrease the refractory period, and class IC agents have no effect.9Unrelated to sodium-blocking effects, class I medications can suppress abnormal automaticity. They also are strong inhibitors of vagal activity, resulting in increased sinoatrial rate and increased conduction through the atrioventricular node, which may offset some of their benefit by allowing an increased ventricular rate during the treatment of atrial arrhythmias.9 The cardiovascular and electrophysiological effects of specific class I agents are discussed below. Table 1 describes additional physiological and care considerations with the use of these medications.Quinidine, disopyramide, and procainamide are the 3 class IA agents. These agents block both phase 0 (sodium channel) and phase 3 (rapid component of the delayed rectifier potassium current) of the cardiac action potential. Sodium channel blockade also results in slowing of conduction velocity, including over accessory pathways.10 Potassium channel involvement increases the recovery period after repolarization and prolongs the effective refractory period. Of all the class I medications, class IA agents have the greatest impact on the QT interval, producing a slightly prolonged QT interval. Class IA agents decrease automaticity and excitability and have an anticholinergic and peripheral vasoconstrictive effect. The anticholinergic effect may increase the ventricular rate in atrial arrhythmias.2,3,9 The mechanism producing anticholinergic effects may vary among these 3 medications and thus there may be drug-to-drug variability.11 Electrophysiology effects of class IA agents include prolongation of QRS and QT intervals, increased risk for torsades de pointes, increased defibrillation threshold, and increased risk for atrioventricular block.3Quinidine blocks the sodium channel at higher heart rates and the potassium channel at lower heart rates2; quinidine also impacts other ion channels.3 Quinidine may unmask an underlying sick sinus syndrome, and its initiation requires electrocardiographic monitoring.2Disopyramide has significant anticholinergic effects that limit its use; it is most effective in atrial fibrillation in the presence of high vagal tone, such as during sleep.2 With the exception of quinidine, class IA agents exert a negative inotropic effect. Disopyramide has the most significant negative inotropic effect and thus is avoided in patients with heart failure.2Lidocaine and its oral analogue mexiletine are the 2 class IB agents. These agents inhibit influx of sodium into the fast channel of the cardiac cell membrane during phase 0 of the cardiac action potential. However, they suppress the sodium channel the least of the 3 groups of class I medications.9 Likewise, they slow conduction velocity the least of the class I agents. They do not block the potassium channel during phase 3 of the cardiac action potential; they actually decrease the refractory period and may shorten the QT interval.3 They suppress automaticity, most specifically in the ventricles. These medications act preferentially in ischemic tissue.3 They do not exhibit any anticholinergic properties. Potential cardiac effects include bradycardia, atrioventricular block, sinus node depression, and hemodynamic collapse.3Flecainide and propafenone, the 2 class IC agents, exhibit potent inhibition of the fast sodium channel and decrease the maximal rate of phase 0 depolarization. QRS widening occurs because of slowing of His-Purkinje conduction. The QT interval is usually prolonged, but there is no effect on the refractory period.2,9 However, QRS prolongation is associated with a proarrhythmic risk, including the risk for monomorphic ventricular tachycardia in the presence of a myocardial scar.3 These medications require great caution in patients with conduction system disease in whom a pacemaker is not in place. The PR interval may increase in patients in sinus rhythm. Class IC agents also have a negative inotropic effect and can result in an exacerbation of heart failure.2 Propafenone has small β-blocking actions and calcium channel–blocking effects that can worsen heart failure.11 Class IC agents also increase the defibrillation threshold.3Flecainide and propafenone can slow the atrial rate in atrial flutter, leading to 1:1 atrioventricular conduction and increasing the ventricular rate.2 Therefore, β-blocking agents or nondihydropyridine should be given at least 30 minutes prior to administration of these medications to prevent a rapid ventricular response caused by 1:1 conduction during atrial flutter. These agents are not indicated in patients with structural heart disease because of the finding in the Cardiac Arrhythmia Suppression Trial of a propensity for fatal proarrhythmic effects.5 In addition, these medications should be avoided in patients with sinus or atrioventricular node dysfunction, infranodal conduction disease, ischemic heart disease, atrial flutter, or Brugada syndrome (drug-induced Brugada syndrome can occur).2,3Most class III antiarrhythmic agents inhibit potassium ion efflux during phases 2 and 3 of the cardiac action potential by blocking the rapid component of the delayed rectifier potassium current. They delay repolarization, prolong the QT interval, and prolong the effective refractory period in all cardiac tissue.3,9 Because of delayed repolarization, such agents are associated with a risk of proarrhythmias. A true class III agent by definition acts only on the repolarization phase and does not impact conduction. The following medications are classified as predominant class III agents: amiodarone, dronedarone, ibutilide, dofetilide (the purest class III agent), and sotalol. There is diversity among the class III agents. Indications and electrophysiological effects for each agent are outlined in Table 2.In addition to blocking the potassium channel, amiodarone is a weak sodium channel blocker and has effects similar to those of class II and IV agents. This complex medication blocks 7 different ion channels, has anticholinergic properties, and is a vasodilator.3,9,12 It relaxes smooth and cardiac muscle and reduces preload and afterload. The vasodilator property of amiodarone makes it one of the antiarrhythmics that may be used in patients with heart failure. Amiodarone also may predispose patients to hypotension.2The antiarrhythmic effect and associated QT prolongation can be delayed for days to weeks after initiation of amiodarone. Loading of the medication accelerates the time to antiarrhythmic effect.2 Although amiodarone impacts the QT interval, proarrhythmia is less frequent than with other class III agents; torsades de pointes is uncommon.13 However, in high-risk patients such as those with advanced heart failure, the risk for proarrhythmias may be greater.14 Amiodarone increases the defibrillation threshold and can slow ventricular tachycardia below an implantable defibrillator detection rate.3 Because amiodarone has β-adrenergic blockade and calcium channel blockade properties, patients without permanent pacemakers require careful monitoring for bradycardia and atrioventricular block. Amiodarone should be avoided in patients without a permanent pacemaker who have baseline conduction system disease and in patients with a prolonged QT interval.2Intravenous amiodarone should not be used in patients with preexcitation. Although amiodarone may slow conduction over an accessory pathway, it may cause a greater slowing across the atrioventricular node and thus precipitate accelerated conduction over the accessory pathway, increasing the risk for ventricular fibrillation. Some researchers report lethal outcomes with the administration of intravenous amiodarone in the presence of atrial fibrillation in patients with preexcitation.15 Amiodarone is known for its multiple medication interactions and its numerous extracardiac effects.2,3,9,16Table 2 describes additional physiological effects and care considerations for amiodarone. Table 3 lists the extracardiac effects often seen with long-term amiodarone use.Dronedarone is similar to amiodarone in that it is a predominant class III antiarrhythmic while exhibiting effects of all 4 classes. Dronedarone does not contain the iodine components found in amiodarone and thus is considered to have fewer toxic effects on extracardiac organs. Compared with amiodarone, dronedarone is also considered less efficacious.2,17 Bradycardia and QT prolongation are the 2 most common cardiac effects seen with this medication. Dronedarone should not be used in patients considered to have a contraindication to amiodarone because of conduction system disease or QT prolongation.2 Although amiodarone is considered to be tolerated in patients with structural heart disease and heart failure, dronedarone should be avoided in patients with class III or IV heart failure or in those who have had an episode of decompensated heart failure in the past 4 weeks, especially if they have depressed left ventricular function (left ventricular ejection fraction [LVEF] of 35% or less).18This medication is for intravenous use only for either pharmacological cardioversion of an atrial arrhythmia or to facilitate a direct current cardioversion. All mechanisms of action of ibutilide are not clear. Ibutilide prolongs the duration of the cardiac action potential by blocking the delayed rectifier potassium current. It may also promote the influx of sodium through the late slow inward sodium channel.19 Before administration of ibutilide, the serum potassium level should be assessed to ensure it is at the high end of the reference range. Ibutilide administration predisposes a patient with a low serum potassium level to torsades de pointes. Any hypomagnesemia should also be corrected, and intravenous magnesium may be administered prophylactically to prevent torsades de pointes.19 This medication should be avoided in patients with LVEF of less than 30% or with any baseline QT prolongation.2 All patients receiving ibutilide must be monitored during and for 4 hours after administration or until the QTc has returned to baseline.19Dofetilide is considered a purer class III agent. It cannot be used if the baseline QTcis greater than 440 milliseconds (or greater than 500 milliseconds in patients with existing bundle branch block). The major adverse cardiac effect of dofetilide is torsades de pointes. To prevent this adverse event, all QT-prolonging medications and hypokalemia must be avoided. Potassium levels should be assessed carefully in patients receiving diuretic therapy when using dofetilide. Hospitalization for 3 days of QT interval monitoring is required for initiation and with any dose increase. In a studyof dofetilide in patients with atrial fibrillation and heart failure with reduced LVEF, dofetilide did not cause an increase in mortality.20 It is one of the few agents that can be used for rhythm control in patients with heart failure.2,21 Prescribing is limited by a US Food and Drug Administration Risk Evaluation and Mitigation Strategy program.Sotalol is a nonselective β-blocking agent with class III properties. Significant class III effects are seen only at doses greater than 160 mg.22 Sotalol has proarrhythmic potential and should not be used if there is QT prolongation (baseline greater than 450 milliseconds).2,3 Because of the risk of QT prolongation, a 3-day hospitalization for QT-interval monitoring22 is recommended for patients who are beginning sotalol treatment and have no implantable cardioverter defibrillator or are experiencing atrial fibrillation. Additional contraindications include bradycardia (heart rate < 50 beats/min), sick sinus syndrome or second-or third-degree atrioventricular block (unless a pacemaker is in place), hypokalemia (diuretic therapy), uncontrolled heart failure, and LVEF less than 20% (which may lead to heart failure decompensation).2,3 Unlike most antiarrhythmic agents, sotalol appears to decrease the defibrillation threshold.3Class I and class III antiarrhythmic agents are used to treat symptomatic cardiac arrhythmias, have complex mechanisms of action, and create cardiovascular and electrophysiological effects requiring diligent assessment and evaluation for safety and optimal outcomes. These medications may have drug interactions and potential noncardiac adverse effects. In addition, patients taking these medications may have impaired metabolism because of comorbid disease. Nursing knowledge of the mechanisms of action, contraindications, monitoring requirements, and potential adverse effects is important for effective patient counseling and for safe and effective medication practices.