The antiarrhythmic medications have typically been categorized according to the Vaughan-Williams (VW) classification system. The system classifies the medications according to the main mechanism of action (although several of the agents retain properties from multiple classes). The VW classification breaks down into four main categories, with some references adding a fifth.
Class Ia: Causes moderate degree blockage of fast sodium channels. Drugs include quinidine, procainamide, and disopyramide. These are the most pro-arrhythmic of the sodium channel blockers due to prolonged QTc interval; use is limited due to pro-arrhythmic potential. Quinidine is used in selected patients with Brugada syndrome as an alternative to the implantable cardioverter-defibrillator placement (ICD). Treatment with quinidine can be useful in patients with short QT syndrome and recurrent ventricular arrhythmias (VA). In patients with short QT syndrome who undergone ICD placement, therapy with quinidine may reduce the number of shocks. Disopyramide still used occasionally with hypertrophic obstructive cardiomyopathy (HOCM). Particularly, as a combination with beta-blocker or verapamil in the treatment of symptoms such as angina or dyspnea in patients with HOCM who do not respond to beta-blockers or verapamil alone. Procainamide can be used as an agent to help unmask and diagnose Brugada syndrome in patients suspected of having Brugada syndrome, but without a definitive diagnosis. Procainamide is a recommended agent to restore sinus rhythm in patients with Wolff-Parkinson-White (WPW) in whom atrial fibrillation (AF) occurs without hemodynamic instability in association with a wide QRS complex or with a rapid pre excited ventricular response. It also can be useful in an attempt to terminate ventricular tachycardia and arrhythmia.
Class Ib: Causes mild degree blockage of sodium channels. Drugs include lidocaine, mexiletine. These drugs shorten the QTc interval, used for VA only, especially post-myocardial infarction VA, not useful for atrial arrhythmias. In long QT syndrome, mexiletine shortens the QTc interval and has been used to reduce recurrent arrhythmias and recurrent ICD arrhythmias.
Class Ic: Causes marked degree of sodium blockage and no effect on QT interval. Drugs include flecainide or propafenone. These drugs are reasonable for ongoing management in patients without structural heart disease, or ischemic heart disease who have symptomatic supraventricular tachycardia (SVT) and are not candidates for or prefer not to undergo catheter ablation. These agents are also useful for pharmacological cardioversion of AF. Some patients may use the "pill in pocket" strategy. The pill in pocket refers to a treatment plan where the patient with paroxysmal AF does not take a regularly scheduled maintenance dose of the medication but instead carries a loading dose of the agent with them. If the patient feels an episode of AF start, he or she takes their loading dose of the respective treatment medication as a one-time dose and essentially attempts chemical cardioversion back to a more regular rhythm. Flecainide, propafenone - should not be used for patients with any "structural heart disease." The Cardiac Arrhythmia Suppression Trials (CAST I and II) showed increased mortality in patients who had a previous myocardial infarction treated with class Ic agents (flecainide, encainide, moricizine) versus placebo when trying to reduce the frequency of premature ventricular contractions (PVCs). The implications of this trial are that class Ic agents are not routinely prescribed to patients with left ventricular dysfunction. This data essentially rules out the majority of ventricular arrhythmias for treatment with class Ic agents.
Beta-blockers are indicated for rate control in patients with paroxysmal, persistent, or permanent AF and atrial flutter. Oral beta-blockers are useful for ongoing management in patients with symptomatic supraventricular tachycardia (SVT). Because of their excellent safety profile and effectiveness in treating ventricular arrhythmias, beta-blockers are often first-line antiarrhythmic therapy. Therapy with beta-blockers is associated with a reduction in adverse cardiac events for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. In patients with symptomatic (PVCs) in an otherwise normal heart, treatment with a beta-blocker is useful to reduce recurrent arrhythmias and improve symptoms.
Potassium channel blockers decrease potassium efflux out of the cell and prolong the QTc interval.
Amiodarone additionally exerts sympatholytic, sodium, and calcium antagonistic properties that decrease conduction through the AV and sinus node. This drug is recommended in patients with AF to maintain sinus rhythm, especially in patients with left ventricular systolic dysfunction. It is also a reasonable option in pharmacological cardioversion. This agent can be used in critically ill patients without pre-excitation to attain ventricular rate control, although it is less effective than non-dihydropyridine calcium channel blockers. Amiodarone is the most common antiarrhythmic medication used for suppression of VA. In patients with hemodynamically unstable persistent VA after defibrillation, intravenous amiodarone should be administered to achieve a stable rhythm. And it has shown effectiveness in VA suppression in patients with ischemic heart disease with ongoing beta-blockers treatment.
Dronedarone reduces hospitalization rate for AF in patients in sinus rhythm with a history of non-permanent AF. Dronedarone should not be given to patients with AF who cannot be converted into normal sinus rhythm (permanent AF). According to the FDA review, it doubles the rate of cardiovascular death, stroke, and heart failure in such patients.
Dofetilide is used for atrial arrhythmias only. Oral dofetilide is useful for acute pharmacological cardioversion in patients with atrial fibrillation or atrial flutter.
Sotalol shares the effects of both class II and class II, non-cardioselective beta-blocker, and potassium channel blockers. It can be used for the treatment of both ventricular and supraventricular arrhythmias. It is not effective for the conversion of AF to sinus rhythm but may be used to prevent recurrent AF. Sotalol also showed its efficacy in suppressing VA.
Ibutilide is indicated for AF or atrial flutter only.
Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) decrease conduction velocity, slow conduction through the AV node, and are useful for ventricular rate control in both acute and chronic AF and atrial flutter. Diltiazem and verapamil are options in the acute treatment of hemodynamically stable patients with SVT, focal, and multifocal atrial tachycardias.
Other antiarrhythmic drugs
Adenosine is useful for diagnosis and termination of SVT that is due to either atrioventricular nodal reentrant tachycardia (AVNRT) or orthodromic atrioventricular reentrant tachycardia (AVRT). This drug may also be utilized diagnostically; adenosine helps to unmask atrial flutter or atrial tachycardia (AT). Adenosine is also useful in terminating focal AT of a triggered mechanism and differentiating focal AT from AVNRT and AVRT.
Digoxin. Although digoxin is not usually first-line therapy for ventricular rate control in patients with AF, a combination of digoxin and beta-blocker/or non-dihydropyridine calcium channel blockers is reasonable for rate control in patients with AF and heart failure.
Mechanism of Action
The cardiac action potential is the cycle of ion movement, which leads to successive depolarization and repolarization of the cardiac myocyte leading to muscle contraction. The resting phase of the cardiac myocyte has a resting membrane potential of negative 80 to negative 90 mV at baseline. The antiarrhythmic medications essentially slow ion movement in various phases of the cardiac action potential and get broken down as follows.
Phase 0: "the depolarization" phase of the action potential; occurs by the rapid movement of sodium ions (Na+) into the cell along an electrochemical gradient, which leads to a membrane potential of approximately positive 30 mV.
Phase 1: "The notch,"; initial or early repolarization phase of the action potential, involves efflux of potassium (K+) ions.
Phase 2: "The plateau" phase; this phase is a balance of inward calcium ion movement that balances the outward K+ movement.
Phase 3: "The repolarization" phase of the action potential; this phase is primarily caused by the movement of K+ ions along their electrochemical gradient out of the cell, essentially taking the positive charge of the K+ ion out of the cell. It restores the negative potential of the cardiac myocyte.
Phase 4: Restoration of the Na/K-ATPase, which restores the resting membrane potential of the cardiac myocyte.
Class, I antiarrhythmics are fast sodium channels blockers. They are responsible for phase 0 of fast-response cardiac action potentials. The three subclasses differ in their efficacy for reducing the slope of phase 0, with Ic drugs having the greatest and Ib drugs having the smallest effect on phase 0. Sodium-channel blockade: Ic > Ia > Ib. Class Ia prolongs the duration of action potential (AP), leading to an increase in QTc interval. Class Ib decreases the duration of AP, causing a shortening of QTc interval, and class Ic drugs do not affect AP duration; thus, no effect on the QTc interval.
Class II antiarrhythmics inhibit beta-adrenergic activation of adenylate cyclase, reduces intracellular cAMP levels, and hence reduces Ca2+ influx resulting in decreased sinoatrial node (SAN) pacing and triggered activity and increase in atrioventricular node (AVN) conduction time and refractoriness.
Class III antiarrhythmics block potassium channels resulting in prolonged atrial, Purkinje, and ventricular myocyte action potential recovery, increased ERP, reduced repolarization reserve, and prolonged QT intervals. Amiodarone also exerts sympatholytic, sodium, and calcium antagonistic properties that decrease conduction through the AV and sinus node. Sotalol shares class II and class III antiarrhythmic properties.
Class IV antiarrhythmics inhibit slow Ca2+ channels and decreases the slope of phase 0 and 4, resulting in inhibition of SAN pacing, inhibition of AVN conduction, prolonged ERP, and PR interval.
Adenosine causes a transient AVN block that terminates SVT via hyperpolarization by increasing K+ efflux and inhibiting Ca2+ current.
Digoxin is a Na/K-ATPase inhibitor. By binding with the sodium pump, it increases intracellular Na+ concentration that will drive Ca2+ influx. That will lead to increase contractility of the heart and prolongation of phase 4 and phase 0 of the cardiac action potential, thus slowing down conduction through the AVN.
Most of the antiarrhythmic medications may be administered intravenously and orally, depending on the acuity of condition. Among class I antiarrhythmics, procainamide, and lidocaine are drugs administered intravenously since its primary use is in acute treatment. Mexiletine is an oral analog of lidocaine. Quinidine is available in both intravenous and oral forms. Disopyramide is administered in capsules and controlled-release capsules. Oral administration of flecainide or propafenone is feasible and safe and appears to be effective in converting recent-onset atrial fibrillation to sinus rhythm. Adenosine should be administered via proximal IV as a rapid bolus infusion, followed by a saline flush. Digoxin administration may be via the oral or intravenous route, and as an intramuscular injection. Intravenous administration of antiarrhythmic drugs requires continuous cardiac monitoring.
Antiarrhythmic medications have several areas of concern. First and foremost, most agents also have some degree of pro-arrhythmic potential. Practically speaking, while trying to suppress arrhythmias with the medications, the medications themselves, can lead to other (potentially more dangerous) arrhythmias. For example, the class Ia sodium channel blockers (quinidine, procainamide, and disopyramide) all effectively prolong the QTc interval and thus increase the risk of ventricular tachycardia (torsades de pointes). Other side effects of class Ia antiarrhythmics are more drug-specific. Procainamide may induce lupus erythematosus that is reversible after discontinuation of the offending drug. An adverse effect caused by treatment with quinine is called cinchonism and includes nausea, dizziness, headache, tinnitus, and visual changes. Disopyramide has an anticholinergic effect and accounts for many adverse side effects, such as flushed and dry skin, thirst, hyperthermia, mydriasis, confusion, agitation, and urinary retention. Due to arrhythmogenic effects, class Ic antiarrhythmics are contraindicated in post-myocardial infarction patients.
Therapy with beta-blockers may have cardiovascular side effects such as bradycardia and AV block. Noncardiac side effects of beta-blockers include exacerbation of asthma and COPD, lethargy, and dyslipidemia.
All K+ channel blockers share this potential side effect. The reason for this is quite simple if one compares the phases of the action potential to the ECG. The T wave on the ECG represents ventricular repolarization. Phase 3 of the action potential represents repolarization. If a K+ channel blocker is given, this prolongs phase 3 of the action potential due to the slow efflux of K+ ions. If the repolarization phase of the action potential is prolonged, the T-wave on the corresponding ECG also gets prolonged, which creates an elongated QTc interval. Amiodarone side effects are wide-ranging and include corneal microdeposits of amiodarone, hypothyroidism, hyperthyroidism, pulmonary fibrosis, elevated liver function tests, nausea, and myopathy. Drodenadrone is not for use in a patient with severe heart failure or decompensated heart failure; it should not be used in cases of permanent atrial fibrillation (see Pallas trial).
Along with its needed effects, verapamil may cause some unwanted effects such as AV block, bradycardia, and constipation. The most frequently reported side effects of diltiazem include edema, headache, and dizziness.
Minor adenosine adverse effects include flushing, sense of impending doom, and sweating are usually transient due to short half-life of the drug. More severe side effects include hypotension, chest pain, AV block, and asystole. The adverse effect as bronchospasm makes it contraindicated in asthmatic patients. Adenosine should be avoided in patients with SVT involving accessory pathways (WPW, antidromic AVRT) due to the risk of tachycardia exacerbation.
Atrial tachycardia with AV block is arrhythmia specific for digoxin toxicity. Digoxin toxicity is also characterized by nausea, vomiting, abdominal pain, fatigue, confusion, and color vision alterations.
Nurses, pharmacists, and other healthcare workers who look after patients with heart disease should be very familiar with the different antiarrhythmic agents. All antiarrhythmic drugs are also potentially pro-arrhythmic. Intravenous administration should be performed only under cardiac monitoring.
Each agent in the Vaughn-Williams classification includes distinctive side effect profiles that require individual consideration. For example, procainamide may induce a lupus-like syndrome, while quinidine is known to produce cinchonism. The benefit of the classification is in the primary mechanism of action, and the broad, predictable side effects brought about by the primary mechanism. An example would include the class III K+ channel blockers or "repolarization" blockers producing a prolonged phase 3 of the action potential and, by definition, also leading to a prolonged QT interval on the corresponding ECG.
Amiodarone is an excellent antiarrhythmic agent, but long term use has correlations with corneal opacities, thyroid problems, and lung infiltrates. That is why amiodarone is not preferred in young patients and preferred choice in the old population. Digoxin has a narrow therapeutic index. The therapeutic serum digoxin levels range is 0.5 to 2 ng/mL. Serum concentrations of cardiac glycosides require monitoring closely to avoid digitalis toxicity. Amiodarone, verapamil, quinidine, and diltiazem increases the serum levels of digoxin and can lead to toxicity. The recommendation is to reduce digoxin dose by 25% to 50% with close monitoring of digoxin levels weekly for several weeks. Periodic electrolyte evaluation is a recommendation. Hypokalemia may make the patient more susceptible to digitalis toxicity. Only by being aware of the adverse effects can one reduce the morbidity associated with these agents.
Enhancing Healthcare Team Outcomes
The cardiologist, or more specifically, electrophysiologist, is generally responsible for starting the patient on an antiarrhythmic medication, but the patient requires monitoring by the primary care provider, nurse, and pharmacist. These medications are not benign, and all healthcare workers who look after patients on antiarrhythmic agents should be very familiar with the different antiarrhythmic agents. Cardiology specialty nurses are especially helpful in monitoring since they have the training to recognize adverse events and understand treatment goals, and can inform the specialist or other clinicians of any concerns. The pharmacist can also be a board-certified cardiology specialist and can assist in agent selection as well as ongoing monitoring, checking for drug interactions, and maintaining communication with the prescriber. All these are examples of interprofessional team dynamics that can drive positive outcomes for patients. [Level 5]
Each agent in the Vaughn-Williams classification includes distinctive side effect profiles that require individual monitoring. If there is ever a doubt about the medication, the clinician should seek a cardiology consult.
(Click Image to Enlarge)
Illustration of Anti-arrhythmic drugs with respect to cardiac action potential.
Contributed by Amandeep Goyal, MD
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