Class III Agents
Class III agents are potassium channel blockers that exert their effects by prolonging the action potential. This leads to prolongation of the QT interval, which increases the risk of torsades de pointes (TDP), a potentially lethal ventricular arrhythmia. Common class III agents used for maintenance of normal sinus rhythm include amiodarone, dronedarone, sotalol, and dofetilide (Table 1).
Amiodarone (Cordarone, Pacerone)
Amiodarone is a potent antiarrhythmic that has properties of all four Vaughan Williams classes (sodium channel blocker, potassium channel blocker, calcium channel blocker, beta-blocker).[1,9] Amiodarone and dofetilide are the only two antiarrhythmic agents that do not increase mortality in HF patients. Amiodarone is safe for patients with structural heart damage and generally is considered more efficacious for maintaining normal sinus rhythm than other antiarrhythmics; rates of 62% to 69% at 1 year have been reported.[1,3] The IV formulation has strong beta-blocking activity, whereas the oral formulation has more potassium channel– blocking activity. Because of its large volume of distribution (Vd) (approximately 60 L/kg), amiodarone requires a 10-g loading dose (oral or IV) before the dose is decreased to the lowest effective dose. Amiodarone inhibits numerous CYP enzymes, including 3A4, 2D6, 2C9, 2C19, and P-glycoprotein. Therefore, drug interactions and dose adjustments should be monitored closely when amiodarone is initiated or discontinued. Medications affected include digoxin, warfarin, and hydroxymethyl glutaryl coenzyme A reductase inhibitors (especially simvastatin).
Because of amiodarone's iodine moiety and affinity for adipose tissue, use of the drug will lead to numerous organ-system toxicities, including hypothyroidism, hyperthyroidism, retinal deposits, inflammatory hepatopathy, and pulmonary fibrosis.[1,9] Most of these adverse effects occur with doses exceeding 400 mg per day, which is the basis for the recommendation to reduce amiodarone to the lowest effective dose (commonly 200 mg daily for atrial fibrillation). Pulmonary-function tests, thyroid-function tests, liver-function tests, and chest radiographs are recommended at baseline, at 3, 6, and 12 months, and then annually thereafter to monitor for toxicity. An eye examination should be performed annually. Because of amiodarone's large Vd and slow rate of elimination (mean half-life of 58 days; range 15–142 days), antiarrhythmic effects will persist for weeks or months after the drug is discontinued.
Dronedarone is a modified analogue of amiodarone that possesses similar properties of all four Vaughan Williams classes.[1,10] Dronedarone is generally less efficacious than amiodarone, but has a lower incidence of organ toxicities. It is administered orally strictly at 400 mg twice daily. Contraindications to therapy include New York Heart Association func- tional class IV HF or recent HF exacerbation, severe hepatic impairment, second- or third-degree heart block, or heart rate under 50 beats per minute. Dronedarone also is not recommended for patients who are in permanent atrial fibrillation with no cardioversion planned. Dronedarone is not associated with the multitude of toxicities occurring with amiodarone, but adverse effects include abdominal pain, nausea, diarrhea, QT prolongation, and HF exacerbation. There have been recent reports of hepatic toxicity, including severe liver damage. Because dronedarone is a CYP3A4 substrate, it should be avoided with concurrent CYP3A4 inhibitors, such as ketoconazole, voriconazole, cyclosporine, and clarithromycin. Dronedarone will increase serum concentrations of digoxin and statins.
Although sotalol has effects on the potassium channel, its beta-blocking activity is more potent.[1,13] It is ineffective for conversion of atrial fibrillation and should be used only to maintain normal sinus rhythm. Sotalol is a modestly effective antiarrhythmic; approximately 37% of patients maintain normal sinus rhythm at 1 year, similar to the efficacy of class IC agents. Sotalol is dosed at 80 to 160 mg orally twice daily, and it is recommended to reduce the frequency to once daily if creatinine clearance (CrCl) is between 40 and 60 mL/min. Sotalol is contraindicated for atrial fibrillation when CrCl is less than 40 mL/min. Many of sotalol's adverse effects are due to the drug's beta-blocking activity, including HF exacerbation, bradycardia, atrioventricular block, and bronchospasm. Sotalol should be initiated in the hospital setting in order to monitor for QT-interval prolongation, because there is a risk of TDP within the first few days of initiation.
Dofetilide, a pure class III potassium channel blocker, is effective for both atrial fibrillation cardioversion and maintenance of normal sinus rhythm.[1,14] It is the only other medication, besides amiodarone, that does not increase mortality in patients with HF. The risks of QT prolongation and TDP upon initiation are high (4%), however, so dofetilide must be initiated in the hospital setting. It is generally efficacious, with approximately 58% of patients maintaining normal sinus rhythm at 1 year. The dose of dofetilide ranges from 125 to 500 mcg orally twice daily based on CrCl. Use is contraindicated if CrCl is less than 20 mL/min. The first five doses must be given in the hospital, with ECGs performed 2 to 3 hours after each dose to monitor for QT prolongation. Subsequent dose adjustments are based on these QT measurements. In order to prescribe and dispense dofetilide, the physician, hospital, and pharmacy must be registered with the manufacturer. Drug interactions that affect dofetilide concentrations include CYP3A4 inhibitors and medications that inhibit active tubular secretion in the kidneys.
US Pharmacist. 2013;38(2):20-23. © 2013 Jobson Publishing