M. Rizwan Sardar, MD, Wajeeha Saeed, MD, Kar-Lai Wong, MD, FACC
The patient is a 52-year-old white man who presented with recurrent atrial fibrillation (AF). He first suffered AF 5 years ago. The episode lasted for 4 hours and spontaneously terminated shortly after presentation to the emergency department. He had been maintained on β-blockers. In the past 5 years he had 3 episodes of AF; all of them converted spontaneously within 1 to 3 hours. The frequency of AF has increased, and this was the third episode that he had suffered in the past 6 months. The duration of AF also lasted longer, and one episode required cardioversion. During AF, the patient complained of palpitations and fatigue but no lightheadedness or chest pain.
The patient is otherwise healthy and without other medical problems, specifically denying hypertension, diabetes, or peripheral vascular disease. He exercises by running three miles daily. He is not taking any medication besides a β-blocker. His previous workup, including echocardiogram, stress test, and thyroid function test, was normal. He was placed on flecainide 100 mg bid. On flecainide, he remained free of AF for 3 years.
• Under the modified Singh-Vaughan Williams classification, sodium channel blocking drugs are class I drugs that further subdivide into three classes (See Table 29-1).
TABLE 29-1 Harrison Modification of Class I Agents
Class IA Agents
• Quinidine has a direct suppressant effect on the sinus node, AV node, and His-Purkinje system. In the innervated human heart, quinidine also has indirect vagolytic and sympathomimetic effects on sinus node and AV node function.
• Most of quinidine is metabolized in the liver with 20% of the parent drug and metabolites being excreted via kidney. Elimination is reduced in patients with congestive heart failure, renal disease, or liver disease.
• The blood pressure may decrease from the α-blocking property, but it does not have any significant negative inotropic action.
• Quinidine is effective in the treatment of supraventricular tachycardias (SVT) including AF, but its utility is limited secondary to an increase in mortality from proarrhythmia most commonly due to torsades de pointes.
• It is also effective in suppressing ventricular premature complexes (VPCs) and ventricular tachycardia (VT) by decreasing cardiac conduction velocity and increasing repolarization duration.
• Gastrointestinal side effects such as diarrhea are common. Central nervous system symptoms such as hearing loss and cinchonism have been reported; thrombocytopenia and immune-mediated reactions may also occur.
• Polymorphic VT is observed in up to 1.5% of patients from torsades de pointes (TdP). Incidence of TdP is not always dose-related and can occur anytime during the treatment course.
• Procainamide has variable effects on sinus node and AV node function. It often increases the HV conduction time and prolongs the QT interval.
• The liver metabolizes 30% to 50% of procainamide into a cardioactive metabolite (N-acetylprocainamide [NAPA]), which is cleared by the kidney. Patients with renal dysfunction have a markedly prolonged half-life of NAPA. Both procainamide and NAPA levels should be monitored to evaluate plasma concentration of the drug.
• Oral procainamide does not significantly affect the blood pressure. Rapid IV injection may result in hypotension, decrease in pulmonary vascular resistance, and decline in cardiac output. Procainamide has a strong negative inotropic effect.
• Procainamide is effective in treatment of AF. It also suppresses antegrade and retrograde conduction over accessory bypass tracts by prolonging the bypass tract refractory period, making it an effective treatment for WPW or bypass tract-related SVT.
• Procainamide increases the effective ventricular refractory and can effectively suppress VPCs, slow down the rate of VT, and terminate VT.
• GI and CNS side effects are common. Pancytopenia and agranulocytosis can be life-threatening. Systemic lupus erythematosus syndrome is observed in 15% to 20% of patients taking procainamide for more than a year, especially in slow acetylators.
• Disopyramide has a variable effect on sinus node function because of its strong anticholinergic effect in addition to its sodium channel blocking property.
• The liver eliminates 15% of disopyramide in the first pass. It is then cleared by renal excretion.
• Disopyramide has a substantial negative inotropic effect and decreases cardiac output significantly. It should be avoided in patients with ventricular dysfunction.
• Disopyramide is effective in preventing AF. Due to its vagolytic properties it is especially effective in young patients with vagally mediated AF.
• It has been shown that disopyramide is effective in suppressing VPCs and sustained VT. Its use in treatment of ventricular tachyarrhythmia is limited because of its strong negative inotropic effect.
• Anticholinergic side effects such as dry mouth, urinary retention, and dry eyes are common. TdP has been reported from QT prolongation, but the incidence is less compared to quinidine or procainamide. Avoid the drug in patients with glaucoma, benign prostatic hypertrophy, and congestive heart failure (CHF).
Class IB Agents
• Lidocaine has minimal effect on the sinus node, AV node, or His-Purkinje system function. It does not affect the ventricular refractory period.
• Lidocaine undergoes rapid extensive first pass elimination by liver and then is bound to adipose tissue. It can only be used in intravenous form, and the dosage should be adjusted in patients with hepatic dysfunction or congestive heart failure.
• Hepatic enzyme inducers like phenytoin, rifampin, and barbiturates lower the levels.
• At therapeutic levels, lidocaine causes minimal hemodynamic effect and is generally well tolerated even in patients with ventricular dysfunction or CHF.
• Lidocaine increases the ventricular fibrillation threshold and thus is effective in treatment of ventricular fibrillation in the setting of ischemia. It has minimal effect in on either the atrial or ventricular refractory period, and its use in treatment of atrial tachyarrhythmias and monomorphic VT is limited.
• Prophylactic use of Lidocaine for post-MI VPCs is no longer supported.
• CNS side effects such as tremor, confusion, and seizures can occur, especially in elderly patients. It does not prolong the QT interval, and it is not common to see ventricular proarrhythmic side effects. Lidocaine levels should be checked if used more than 24 hours.
• Similar to lidocaine, mexiletine has no significant effects on the sinus node, AV node function, or atrial and ventricular refractory periods.
• Mexiletine is well absorbed in the GI tract without significant first pass elimination. It has a large volume distribution. The liver metabolizes 90% of mexiletine.
• Mexiletine has minimal hemodynamic effects and is usually well tolerated in patients with ventricular dysfunction.
• Mexiletine is effective in the treatment of VT but has limited utility for treating atrial tachyarrhythmias.
• GI and CNS side effects, similar to lidocaine, are common with mexiletine. When compared to other antiarrhythmic drugs, the risk of ventricular proarrhythmic side effects is low.
Class IC Agents
• Flecainide slows conduction in all cardiac tissues, and thus the PR and QRS are often both lengthened. There is minimal QT prolongation.
• Seventy-five percent of the drug is eliminated hepatically with 25% eliminated unchanged by kidneys.
• Flecainide is very effective in suppressing VPCs and nonsustained ventricular tachycardia. Its utility in treatment of ventricular tachyarrhythmias is limited because of an increase in mortality when it is used in patients with cardiomyopathy.2
• In patients with a structurally normal heart, flecainide is effective in preventing paroxysmal AF. When 300 mg of oral flecainide is given within 2 hours of onset of atrial fibrillation, 92% of atrial fibrillation is terminated within 3 hours. This makes flecainide an acceptable antiarrhythmic drug to be used as a pill in a pocket treatment for patients with sporadic rare occurrences of atrial fibrillation.3
• Flecainide has a significant negative inotropic effect and may exacerbate congestive heart failure in patients with underlying ventricular dysfunction. It should be avoided in patients with cardiomyopathy because of increasing cardiac mortality in this subgroup of patients.
• Flecainide may convert AF into atrial flutter with a fast ventricular response, and therefore the concomitant use of an AV nodal blocking agent is generally recommended.
• CNS side effects such as headache and tremor are the most common noncardiac side effects, but are usually not severe.
• Propafenone, like flecainide, increases both PR and QRS intervals. It has both β-blocker and calcium channel blocker properties and thus should be used cautiously in patients with underlying sick sinus syndrome, conduction disease, or asthma.
• Propafenone is rapidly metabolized in the liver by the P-450 system into two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. The active metabolites are eliminated by renal clearance. The dosage of the drug needs to be reduced in patients with severe hepatic and renal insufficiency.
• Propafenone is very effective in suppressing VPCs and nonsustained ventricular tachycardia. Although it was not studied in the CAST trial, given its similarity to flecainide, propafenone should not be used in patients with a structurally abnormal heart.
• Propafenone is effective in maintaining sinus rhythm in patients with paroxysmal atrial fibrillation when compared to placebo. It decreases both antegrade and retrograde conduction via accessory bypass tracts and can be considered for treatment of bypass-related supraventricular tachycardia.
• Propafenone causes mild CNS side effects such as nausea, vomiting, and metallic taste.
Tables 29-2 to 29-5 discuss the pharmacokinetics, interactions, and various effects of class I drugs.
TABLE 29-2 Typical Effects on ECG and Intracardiac Intervals
TABLE 29-3 Pharmacokinetics of Class I Antiarrhythmic Drugs
TABLE 29-4 Interaction with Common Cardiovascular Drugs
TABLE 29-5 Effect of Class I Antiarrhythmic Drugs on Thresholds
1. Harrison DC. Antiarrhythmic drug classification: new science and practical applications. Am J Cardiol. 1985;56(1):185-187.
2. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo—The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-788.
3. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med. 2004;351:2384-2391.