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Class III antiarrhythmic medications inhibit inward potassium currents (Table 19-9),6 which leads to a significantly longer refractory period. Myocardial tissue in a refractory state is resistant to reentrant conduction circuits that may produce arrhythmia. These agents prolong the QT interval, which is associated with significant risk for torsades de pointes. Clinical indications for Class III antiarrhythmics are contrasted in Table 19-10.
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Amiodarone is a highly effective "broad-spectrum" antiarrhythmic indicated in the acute management and chronic suppression of supraventricular tachycardia and ventricular arrhythmias. Potential benefits of amiodarone must be weighed against an array of potentially serious adverse effects, and clinical use is further complicated by distinctive pharmacokinetics and significant drug interactions.
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Amiodarone possesses properties of all four classes of antiarrhythmics (Table 19-11).6,11
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The pharmacokinetics of amiodarone are listed in Table 19-12.6 Amiodarone is highly lipophilic and extensively distributed to bodily tissues.12 Although IV amiodarone produces a rapid antiarrhythmic effect, it quickly redistributes from the serum into tissue, causing a precipitous drop in serum concentration.13 Therefore, large oral or IV loading doses, generally given over a week or more, are needed to fill this large tissue reservoir and achieve sustained serum concentrations. As tissue stores become saturated after long-term oral therapy, terminal-phase elimination dominates and is characterized by a long half-life (≤55 days) and duration of action (≤50 days). Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion.
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Specific indications for amiodarone are listed in Table 19-13.7,10,14,15,16
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Dosing and Administration
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Amiodarone dosing is detailed in Table 19-14.6 Intravenous amiodarone is associated with bradycardia, hypotension, and phlebitis. Hypotension may be dose and infusion rate dependent; therefore, infusion rates should not exceed 30 milligrams/min, and total daily doses should not exceed 2.2 grams. Preparations of IV amiodarone should be mixed in 5% dextrose in water, as amiodarone has precipitated in compatibility studies with normal saline.17 Dose adjustments are not required for renal insufficiency but should be considered for severe hepatic dysfunction.
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Adverse effects of amiodarone are listed in Table 19-15.6,18 Long-term amiodarone has many common, serious, and potentially fatal adverse effects that limit widespread clinical use and require regular monitoring of liver, pulmonary, thyroid, and ocular function. As a result, patients should be regularly monitored for these toxicities. Although amiodarone prolongs the QT interval, it has a relatively low incidence of torsades de pointes even in patients with structural heart disease.
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Amiodarone is responsible for many clinically significant drug interactions. As a strong inhibitor of liver enzymes, amiodarone increases serum concentrations of many other medications. Amiodarone may also augment the effects of medications that concomitantly prolong the QTc interval or cause bradycardia. Specific dose reductions are required for digoxin, warfarin, procainamide, quinidine, simvastatin, and lovastatin when used concomitantly with amiodarone. Given amiodarone's extremely long half-life, drug interactions may persist for months after discontinuation of therapy.
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Dronedarone is a noniodinated, less lipophilic derivative of amiodarone, designed to have a more favorable adverse effect profile than its predecessor. Dronedarone is categorized as a Class III antiarrhythmic but has all four antiarrhythmic class effects and blocks α-adrenergic receptors. Electrophysiologic action is primarily mediated through Class III antiarrhythmic effects by prolonging the refractory period.6
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Pharmacokinetics of dronedarone are listed in Table 19-16. Dronedarone is ≤94% absorbed, but significant first-pass metabolism decreases the overall bioavailability to ≤15%. With sustained oral dosing, the half-life increases to 27 to 32 hours, and steady-state concentrations are achieved in 4 to 8 days. Dronedarone displays nonlinear kinetics, so doubling a dose may increase plasma concentrations by 2.5- to 3-fold.
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Dronedarone is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. It is less efficacious than amiodarone for maintenance of sinus rhythm.
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Dosing and Administration
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The dose of dronedarone is 400 milligrams orally twice daily and should be given with the morning and evening meal to increase bioavailability. Coadministration with grapefruit or grapefruit juice is contraindicated, as this may increase serum concentrations.
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Contraindications and significant adverse effects of dronedarone are highlighted in Table 19-17. Compared to amiodarone, dronedarone has lower rates of pulmonary toxicity and has not demonstrated adverse effects on thyroid function. Two clinical trials with dronedarone were prematurely discontinued due to significantly higher rates of serious adverse events in the dronedarone treatment groups, prompting black box warnings that dronedarone is contraindicated in severe or decompensated heart failure and in patients with permanent atrial fibrillation.5,19 ECGs should be monitored at least every 3 months while on dronedarone. If the patient is found to be in atrial fibrillation, he or she should be cardioverted (if clinically indicated) or dronedarone should be discontinued. Liver function should also be monitored periodically, especially during the first 6 months of therapy.
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Sotalol is a unique, noncardioselective β-blocker that exhibits electrophysiologic characteristics of Class III antiarrhythmics, thus prolonging repolarization and refractoriness without affecting conduction.
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The onset of action of sotalol is 1 to 2 hours for the oral formulation and 5 to 10 hours after IV administration, with a duration of action of 8 to 16 hours after one dose. The elimination half-life is 12 hours and increases with renal dysfunction. No metabolites are formed, and the drug is primarily eliminated unchanged in the urine.
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Sotalol is an effective agent for the suppression of life-threatening ventricular arrhythmias refractory to other antiarrhythmic drugs. It can suppress supraventricular tachycardia and atrial fibrillation but is not indicated for cardioversion of atrial fibrillation.10
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Dosing and Administration
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The usual starting dose is 80 milligrams PO twice daily (which can be titrated), and the usual maintenance dose is 160 to 320 milligrams/d; the dose should be reduced by 50% or more in patients with renal insufficiency (creatinine clearance <60 mL/min), and sotalol should not be used (except in special cases) if creatinine clearance is <40 mL/min. IV sotalol is indicated in the current advanced cardiac life support guidelines for hemodynamically stable monomorphic ventricular tachycardia at 1.5 milligrams/kg infused over 5 min. Monitoring of cardiac and renal function is recommended when sotalol is started. During initiation of sotalol therapy (pretreatment QTc should be <450 milliseconds), QTc intervals are measured 2 to 4 hours after each oral dose or at the end of an infusion, and therapy is discontinued if QTc measures ≥500 milliseconds.
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The most common adverse effects of sotalol are bradycardia and hypotension. Sotalol does possess a significant proarrhythmic effect with a 4.3% rate of new or worsened ventricular arrhythmias and a 2.4% rate of torsades de pointes.20
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Actions/Indications/Dosing
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Dofetilide is a pure Class III antiarrhythmic and is indicated for the conversion to, and maintenance of, normal sinus rhythm in patients with atrial fibrillation or flutter. Because dofetilide has a significant proarrhythmic effect, it is reserved for patients in whom atrial fibrillation or flutter is highly symptomatic. Dofetilide prescribing is restricted to physicians who have received specific education on dosing and administration and, therefore, is not covered here in detail.21
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Serious adverse effects of dofetilide are ventricular tachycardia and QTc interval prolongation, which can result in torsades de pointes. The risk of developing torsades de pointes is associated with higher dofetilide doses, initiation of therapy, and electrolyte abnormalities.
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Actions/Pharmacokinetics
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Ibutilide prolongs the refractory period in atrial and ventricular cardiac tissues. This action is caused by activation of a slow inward sodium current, as opposed to inhibition of outward potassium currents. Blockade of the delayed rectifier potassium current, which slows repolarization, may also contribute to its clinical effects. The onset of action of ibutilide is ~90 minutes after starting the infusion. Ibutilide is metabolized in the liver, is excreted in the urine and feces, and has a half-life of 2 to 12 hours after IV administration.
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Indications/Dosing and Administration/Adverse Effects
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Ibutilide is indicated for the rapid conversion of recent-onset atrial fibrillation or flutter (greater efficacy) to sinus rhythm.10 If effective, cardioversion is expected to occur within 1 hour of administration. For patients with atrial fibrillation and an accessory pathway, ibutilide is considered a reasonable option for pharmacologic cardioversion.16 Serum magnesium and potassium levels should be evaluated and resuscitation equipment made available before ibutilide administration. The loading dose is 1 milligram IV (weight ≥60 kg) or 0.01 milligram/kg IV (weight <60 kg) over 10 minutes and may be repeated once every 10 minutes after completion of the first dose. Electrocardiographic monitoring is continued for at least 4 hours or until the QTc interval returns to baseline (longer if arrhythmias are observed). Cardiovascular adverse effects of ibutilide include hypotension, hypertension, bradycardia, sinus arrest, syncope, QTc interval prolongation, congestive heart failure, and torsades de pointes.
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Vernakalant is a Class III antiarrhythmic that inhibits sodium and potassium currents. The atria are more susceptible to vernakalant-induced refractory period prolongation. Vernakalant is not U.S. Food and Drug Administration approved for use in the United States. In Europe, vernakalant is indicated for rapid conversion of recent-onset atrial fibrillation in adults.22