Prescribing and monitoring pearls for atrial antiarrhythmic therapies

Issue: December 2010

ByMichael Serra, PharmD

As the general population continues to age, atrial and ventricular arrhythmias are of a growing concern.

Despite modern technology, pharmacotherapy utilizing antiarrhythmic medications remains a mainstay for the treatment of cardiac arrhythmias. These high-risk medications should be closely monitored, especially in the elderly and when combined with nonpharmacologic therapies. This review will focus on the monitoring of antiarrhythmic therapies currently utilized in the pharmacologic management of atrial arrhythmias.

Vaughan Williams classification system

Michael Serra, PharmD
Michael Serra

The Vaughan Williams system of classifying antiarrhythmic medications assigns agents to one of three groups based on their electrophysiological actions on the cardiac conduction of the heart. Class I antiarrhythmic agents are sodium (Na⁺) channel blockers and are further subdivided down into three subclasses: class Ia antiarrhythmics (ie, quinidine, procainamide and disopyramide) block Na⁺ channels in the active state and serve to decrease conduction velocity and automaticity while extending the refractory period; class Ib antiarrhythmics (ie, lidocaine and mexiletine) serve to decrease conduction velocity, automaticity and the refractory period; class Ic antiarrhythmics (ie, flecainide, propafenone and moricizine [Ethmozine, Shire]) block Na⁺ channels in the inactive state and serve to decrease conduction velocity and automaticity while having no effect on the refractory period.

Class II antiarrhythmic medications are beta-blockers. Competitive blockade of the beta-receptor minimizes the influence of endogenous catecholamines on the chronotropic and inotropic state of the myocardium. Class III antiarrhythmic drugs are potassium (K⁺) channel blockers and include amiodarone, dronedarone (Multaq, Sanofi-Aventis), dofetilide (Tikosyn, Pfizer), sotalol and ibutilide. Amiodarone and dronedarone are unique in that they have effects on multiple channels (K⁺, Na⁺ and calcium ions, as well as beta-receptors). Class IV antiarrhythmic medications are nondihydropyridine calcium channel blockers (specifically L-type) and include verapamil and diltiazem.

In summary, class I agents are considered broad-spectrum antiarrhythmics in that they are effective for supraventricular and ventricular arrhythmias. Class II agents are useful in slowing ventricular response in atrial tachycardias (eg, atrial fibrillation) by their effects on the atrioventricular node as a result of their antiadrenergic actions. Class III agents are effective for most supraventricular arrhythmias because of their effects on atrial and ventricular tissue, with amiodarone solely having supporting data for use in treatment of ventricular arrhythmias. Besides supraventricular arrhythmias, class IV agents are effective in automatic or re-entrant tachycardias because of their effects on the L-type channels in sinoatrial and atrioventricular nodal tissues.

Safety considerations

Several factors should be considered for the safe selection of an agent for the maintenance of sinus rhythm for patients with AF. For patients without structural heart disease and normal renal function, treatment guidelines recommend initiation of first-line therapy, including flecainide, propafenone or sotalol. These agents are considered first-line because of their low toxicity and reduced monitoring requirements compared with other class III agents.

Second-line agents for patients without structural heart disease include amiodarone or dofetilide. Sotalol is contraindicated in patients with creatinine clearance of less than 40 mL/min, and dofetilide is contraindicated in patients with creatinine clearance of less than 20 mL/min. Sotalol and dofetilide are also contraindicated in patients with renal insufficiency because of a dose-dependent increased risk for torsades de pointes. Dofetilide is contraindicated in patients concomitantly taking any medication that either inhibits metabolism of dofetilide via inhibition of CYP3A4 (ie, verapamil, ketoconazole and cimetidine) or inhibits the renal tubular secretion of dofetilide (prochlorperazine, hydrochlorothiazide and trimethoprim-sulfamethoxazole because the accumulation of this agent can increase the likelihood of dofetilide toxicity). Hydrochlorothiazide can also increase the risk for dofetilide-induced torsades de pointes by thiazide diuretic-induced hypokalemia or hypomagnesemia.

AF patients with structural heart disease (CAD, left ventricular hypertrophy or HF) should be managed with amiodarone. Currently, expert opinion and clinical trials support the use of dronedarone as a treatment option in patients with LV hypertrophy; however, dronedarone was not available when the last guidelines were written. Dronedarone is contraindicated in patients with NYHA Class IV HF or recently decompensated Class II to III HF and in patients with a PR interval exceeding more than 280 ms.

Key prescribing and monitoring pearls associated with use of antiarrhythmic agents are as follows:

Flecainide, a class 1c agent, should be avoided in all patients with any form of structural heart disease.
Propafenone, a class 1c agent that predominately affects sodium channels, also has significant beta-blocking properties and is capable of causing significant beta-blocker adverse effects (ie, bradycardia, heart block). Concurrent propafenone and digoxin may lead to increased digoxin levels.
Dronedarone is structurally related to amiodarone; however, it does not contain iodine and, thus, has less potential thyroid toxicity. Dronedarone also has a smaller volume of distribution, is less lipophilic, has a faster onset and has a shorter half-life than amiodarone. Common adverse effects associated with dronedarone include gastrointestinal effects such as diarrhea and nausea, as well as bradycardia. Similar to amiodarone, dronedarone is rarely associated with the incidence of torsades de pointes.
Amiodarone has low incidence of proarrhythmic events and negligible negative inotropic effects, but disadvantages include an extensive adverse event profile (affects every organ system, except for the kidney), a very long half-life and an extensive drug interaction profile. Amiodarone interacts with many agents by its additive QT interval prolonging effects (ie, amitriptyline, levofloxacin and moxifloxacin), interacts with agents via a pharmacokinetic interactions (ie, inhibition of the metabolism of CYP enzymes; amiodarone plus simvastatin leads to an increased risk for rhabdomyolysis due to inhibition of simvastatin metabolism) or interacts with other agents via additive effects on adrenergic receptors (amiodarone plus carvedilol may lead to increased risk for beta-blocker toxicities).
Sotalol has significant beta-blocking effects and can cause common beta-blocker adverse effects. Sotalol is also associated with QT prolongation that can lead to torsades des pointes. Patients receiving sotalol should be monitored periodically (during routine medical checkups or during hospitalizations) to ensure that they have not developed renal dysfunction or electrolyte abnormalities that may lead to an increased risk for sotalol toxicity.

Michael Serra, PharmD, is a clinical pharmacy specialist at the Gagnon Cardiovascular Institute at Morristown Memorial Hospital in Morristown, N.J.

For more information:

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