Amiodarone is an effective antidysrhythmic drug because it has which mechanisms of action?

Sotalol is a non-cardioselective beta-blocker that also possesses potassium channel blocker properties. It classifies as a class III agent in the Vaughan-Williams classification system for antiarrhythmic medications due to its predominant potassium channel blocking effect. Sotalol prolongs the action potential duration and effective refractory period in the atrium, ventricle, and nodal and extranodal tissue. It is a potent competitive inhibitor for potassium current. Sotalol exhibits reverse use-dependent effects, meaning that the maximal potassium current blocking effect occurs when the heart rate is slow, increasing the risk of QT prolongation and torsades de pointes in bradycardic conditions. A low dose is enough to exert a beta-blocking effect. For example, 25 mg offers good beta-blocking activity, but a higher dose is necessary for class III antiarrhythmic effects (up to 80 mg). According to current research, The human Ether-à-go-go-Related (HERG) gene encodes potassium channels mediating the rapid delayed-rectifier K+ current, IKr, which is vital for normal repolarization of the ventricles of the heart. Consequently, HERG is a pharmacological target for class Ia and class III antiarrhythmic drugs. Class III agents now include voltage-dependent K+ channel blockers (Class IIIa), including nonselective (amiodarone) and selective (HERG; sotalol). Kv11.1 (HERG) channel-mediated rapid K+ current (IKr) blockers lead to prolonged atrial, Purkinje, and ventricular myocyte action potential recovery, increased effective refractory period (ERP), increase in AP recovery time, and resultant decreased reentrant tendency.

Pharmacokinetics 

Absorption: The bioavailability is 95% to 100% without the hepatic first-pass effect (metabolism). After a single oral dosage, it takes about 2.5 to 3 hours to reach its maximum (peak) serum concentration. On the other hand, the intravenous (IV) infusion takes around 2 hours to attain peak serum levels.

Distribution: The drug is water-soluble, which results in minimal blood-brain barrier penetration. Sotalol distributes to the heart, liver, and kidneys.

Metabolism:  Sotalol has no active metabolites.

Excretion: Sotalol is eliminated primarily from the kidneys, with up to 20%  excreted in the feces. Its half-life is 10 to 20 hours in a population with normal renal function.

Administration

Sotalol is available both in oral and intravenous formulations. There is a dosage conversion between oral and intravenous sotalol. Oral sotalol 80 mg is equivalent to 75 mg of IV, and similarly, 160 mg oral is equivalent to 150 mg of IV. If infusing intravenously, the recommendation is to administer the drug slowly as a rapid infusion can cause hypotension.

The most effective dosage for preventing atrial fibrillation is 120 mg twice daily, depending on renal function. There is no statistically significant difference between intravenous and oral sotalol in different parameters like prolonging QT interval, atrial effective refractory period and right ventricular effective refractory period, sinus cycle length, and atrioventricular node relative and functional refractory periods.

Use in Specific Patient Population

Patients with Renal Impairment: Sotalol is excreted mainly through the kidneys. Therefore dose adjustment is required if the eGFR is less than 60 ml/min. The recommended initial dose of sotalol is 80 mg given twice daily if GFR is more than 60 ml/min, with the dose increased (generally allowing 2 to 3 days between dosing increments), up to 320 mg, given in 2 or 3 divided doses. Sotalol should be prescribed once daily if the creatinine clearance is between 40 to 60 ml/min. Data suggest that the patient population with heart failure also needs a dose adjustment. The most effective dosage for preventing atrial fibrillation is 120 mg twice daily, depending on renal function. 

Patients with Hepatic Impairment: There is no alteration in the clearance of sotalol in patients with hepatic impairment.

Pregnancy Considerations: Half-life decreases to 10 hours in pregnancy due to the increased glomerular filtration rate. Data show that sotalol should be avoided in pregnancy. Sotalol can be teratogenic and hence, is not often the first choice in pregnant females. Close fetal monitoring is necessary when used.

Breastfeeding Considerations: Sotalol is extensively excreted into breastmilk and has minimal safety data in breastfed infants. Other drugs are preferred to sotalol, especially while nursing a newborn or preterm infant.

Adverse Effects

Sotalol's adverse effect profile is inherent in its mechanisms of action as both a potassium-channel blocker and a non-cardioselective beta-blocker. The potassium channel blockade, primarily in phase 3 of the cardiac action potential, prolongs the QTc. Thus the ECG must be monitored upon initiation of sotalol or addition of other QTc-prolonging medications. Prolongation of the QT interval occurs in 1% to 2% of cases, which could lead to torsades de pointes or new ventricular tachycardia/ventricular fibrillation. 

The adverse effect of sotalol on QT prolongation is directly related to its serum levels. Its side effects, especially torsades de pointes, are also dose-dependent; the rate of torsades is 1% with doses less than 320 mg and increases up to 5% at doses of more than 320 mg. Higher doses are possible if a patient has an implantable cardioverter-defibrillator. The incidence of QT prolongation occurs more frequently with the  IV formulation. 

Other adverse effects associated with its non-cardioselective beta-blockade include bradycardia, fatigue, dyspnea, and worsening heart failure.

Boxed Warning

Life-threatening Proarrythmias: To reduce the risk of drug-induced arrhythmia, start sotalol in a healthcare facility that can provide continuous electrocardiographic monitoring and cardiac resuscitation. Sotalol can cause life-threatening ventricular tachycardia associated with QT interval prolongation. If the QT interval ≥ 500 msec, decrease the dose, increase the dosing interval, or discontinue the drug. Before starting sotalol, calculate creatinine clearance to determine appropriate dosing. Drug isomers may differ in their risk of pro-arrhythmia. For example, sotalol, an antiarrhythmic drug, has d- and l- enantiomers. A recent study using molecular dynamics found that d-sotalol has a higher pro-arrhythmia risk of d-sotalol than l-sotalol.

Toxicity

Sotalol toxicity is inherent due to its mechanisms of action as both a potassium channel blocker and a non-cardioselective beta-blocker and mirrors its adverse effect profile. The most obvious and potentially problematic sign of toxicity is concentration-related QTc prolongation. If QTc is over 500 msec during initiation, the sotalol dose should be reduced or discontinued. If QTc exceeds 520 msec during the maintenance phase of dosing, the clinician should either reduce the dose or discontinue sotalol.

In addition, therapeutic measures may be required according to the manufacturer's labeling in case of massive overdose. Patients with bradycardia or cardiac asystole atropine or transvenous cardiac pacing are required. In addition, the bronchospasm associated with beta blockage requires higher than normal beta-2-agonist doses. Management of Torsade de Pointes is DC cardioversion, transvenous cardiac pacing, epinephrine, and magnesium sulfate. Hemodialysis can reduce sotalol plasma concentrations as sotalol does not bind to plasma protein. Due to the risk of TdP and asystole, patients should be closely monitored until QT intervals are normalized, and the heart rate is more than 50 bpm. A recent study evaluated the drug-specific risk of SQTP (Severe QT prolongation) after an acute drug overdose. Sotalol was one of the most common drugs implicated in acute drug overdoses related to SQTP.

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