Sotalol

Mechanism of Action

Sotalol is a non-cardioselective β-blocker that possesses potassium channel-blocking properties. Due to the predominant potassium channel–blocking effect, this drug is classified as a class III agent in the Vaughan-Williams classification system for antiarrhythmic medications. Sotalol prolongs the action potential duration and effective refractory period in the atrium, ventricle, and nodal and extranodal tissue. This agent is a potent competitive inhibitor of potassium current.

Sotalol exhibits reverse use-dependent effects, meaning the maximal potassium current blocking impact occurs when the heart rate is slow, increasing the risk of QT prolongation and torsades de pointes in bradycardic conditions. Although a low dose of sotalol (25 mg) is adequate to exert a β-blocking effect, a higher dose (up to 80 mg) is necessary for class III antiarrhythmic effects.[12] 

According to current research, the human Ether-à-go-go-related gene (HERG) encodes potassium channels mediating the rapid delayed-rectifier K+ current, IKr, vital for normal repolarization of the heart's ventricles. Consequently, HERG is a pharmacological target for class Ia and III antiarrhythmic drugs.[13] 

Class III agents now include voltage-dependent K+ channel blockers, categorized as class IIIa, which include nonselective agents, such as amiodarone, and selective agents, such as sotalol, acting on the HERG channel. Blockade of the Kv11.1 (HERG) channel-mediated rapid K+ current (IKr) leads to prolonged action potential recovery in atrial, Purkinje, and ventricular myocytes, resulting in increased effective refractory period, prolonged action potential recovery time, and consequently decreased reentrant tendency.[14]

Pharmacokinetics 

Absorption: The bioavailability is 95% to 100% without the hepatic first-pass effect (metabolism). After a single oral dosage, the drug takes about 2.5 to 3 hours to reach its maximum (peak) serum concentration. On the other hand, the IV infusion takes around 2 hours to attain peak serum levels. IV administration of sotalol reduces the time required to reach steady-state plasma concentration from 3 days to just 1 to 2 days, which includes a single IV dose followed by 1 or 2 oral doses.[15]

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

Metabolism:  Hepatic metabolism of sotalol is minimal; sotalol has no active metabolites.[16]

Elimination: Sotalol is eliminated primarily from the kidneys, with up to 20% excreted in the feces. The drug's half-life is 10 to 20 hours in a population with normal renal function.[17]

Administration

Available Dosage Forms and Strengths

Sotalol is available both in oral and IV formulations. Dilute IV sotalol in normal saline, Ringer lactate, or D5W to achieve a concentration of (15 mg/mL). There is a dosage conversion between oral and IV sotalol. Oral sotalol 80 mg is equivalent to 75 mg of IV; 160 mg oral is equivalent to 150 mg of IV. If infusing IV, the recommendation is to administer the drug slowly, as a rapid infusion can cause hypotension.[18]

Adult Dosage

The most effective dosage for preventing atrial fibrillation is 120 mg twice daily, depending on renal function. No statistically significant difference between IV and oral sotalol is evident in different parameters such as prolonged QT interval, atrial effective refractory period and right ventricular effective refractory period, sinus cycle length, and atrioventricular node relative and functional refractory periods.[19] According to the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines, sotalol is ineffective for converting atrial fibrillation to sinus rhythm but can be used for atrial fibrillation recurrence prophylaxis. Sotalol achieves 30% to 50% success rates in maintaining sinus rhythm over 1 year.[20]

Specific Patient Populations

Renal impairment: Sotalol is excreted mainly through the kidneys. Therefore, dose adjustment is required if the estimated glomerular rate (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.[21]  Sotalol should be prescribed daily if the creatinine clearance (CrCl) is between 40 and 60 mL/min. Data suggest that the patient population with heart failure also needs a dosage adjustment.[22] The most effective dosage for preventing atrial fibrillation is 120 mg twice daily, depending on renal function.

Hepatic impairment: No alteration in the clearance of sotalol is apparent 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 during pregnancy. Sotalol is teratogenic and not often the first choice in pregnant females. Close fetal monitoring is necessary when used.[12][23]

Breastfeeding considerations: Sotalol is extensively excreted into breast milk and has minimal safety data in breastfed infants. Other drugs are preferred to sotalol, especially when patients are nursing a newborn or preterm infant.[24]

Pediatric patients: For children aged 2 and older with normal renal function, the initial dosing of sotalol is 1.2 mg/kg 3 times (3.6 mg/kg total daily dose). The maximum dose is 2.4 mg/kg 3 times daily (360 mg total daily). Dosing should be guided by clinical response, heart rate, and QTc interval—increased doses preferably in a hospital setting, allowing at least 36 hours between increments. A nomogram should determine the appropriate pediatric sotalol dosage for children aged 2 or younger. In a multicentered registry study, IV sotalol was evaluated in pediatric patients, including those with congenital heart disease and severe myocardial dysfunction.

The typical acute and maintenance treatment dose was 1 mg/kg over approximately 60 minutes. Out of 85 patients, 79 were treated with IV sotalol for SVT, while 4 for ventricular arrhythmias. The study found that 49% of patients had successful termination of arrhythmia, and another 30% experienced improvement in rhythm control. In addition, QTc prolongation (>465 milliseconds) occurred in 16% of patients. IV sotalol demonstrated safety and effectiveness in treating tachyarrhythmias in pediatric patients.[25]

Older patients: Impaired renal function in older patients can result in an extended terminal elimination half-life of sotalol, leading to elevated drug levels. As sotalol is predominantly excreted through the kidneys, the drug should be used cautiously in older adults with reduced renal clearance.[26]

Adverse Effects

Sotalol's adverse effect profile is inherent in the mechanisms of action as both a potassium channel blocker and a non-cardioselective β-blocker. The potassium channel blockade, primarily in phase 3 of the cardiac action potential, prolongs the QTc. Thus, the electrocardiogram (ECG) must be monitored upon initiating sotalol or adding 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 serum levels.[18] The adverse 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 ICD. The incidence of QT prolongation occurs more frequently with IV formulation.

Other adverse effects associated with the non-cardioselective β-blockade include bradycardia, fatigue, dyspnea, and worsening heart failure. According to AHA/ACC 2022 guidelines, sotalol should be avoided in decompensated heart failure due to its pro-arrhythmogenic properties and β-blockade.[27]

Drug-Drug Interactions

Sotalol is not susceptible to pharmacokinetic drug interactions involving the cytochrome P450 system, as it does not undergo hepatic metabolism. Pharmacodynamic interactions are given below.

• Digoxin: Digoxin and sotalol slow AV conduction and decrease heart rate, increasing the risk of bradycardia with concomitant use.[28]

• Calcium channel blockers (CCB): Combining sotalol and CCBs can reduce atrioventricular conduction, adversely affecting ventricular function and blood pressure.[29]

• Insulin and oral hypoglycemics: β-blockers, including sotalol, may mask symptoms of hypoglycemia. Conversely, their use may also lead to hyperglycemia, necessitating dose adjustments of insulin and antidiabetic drugs.

• Clonidine: Coadministration of sotalol increases the risk of bradycardia. To mitigate the risk of rebound hypertension, sotalol should be withdrawn several days before gradually discontinuing clonidine.

• β-2 agonists: Concomitant use of sotalol with albuterol, terbutaline, and isoproterenol may require increased dosages.

• Catecholamine-depleting agents: Concurrent use of reserpine and guanethidine with β-blockers may result in a disproportionate decrease in sympathetic nervous tone, leading to hypotension, significant bradycardia, and syncope. Close monitoring is advised.[30]

Drug-Food Interactions

Coadministration of food or antacids with sotalol may result in a slight decrease in plasma concentrations.[31] 

Drug-Laboratory Test Interactions

Sotalol in the urine may yield falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods.[32]

Contraindications

Box Warning

Life-threatening proarrythmias: To reduce the risk of drug-induced arrhythmia, start sotalol in a facility that can provide continuous ECG monitoring and cardiac resuscitation. Sotalol can cause life-threatening ventricular tachycardia associated with QT interval prolongation. If the QT interval is ≥500 ms, decrease the dose, increase the dosing interval, or discontinue the drug. Before starting sotalol, calculate CrCl to determine the 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 molecular dynamics study found that d-sotalol has a higher pro-arrhythmia risk of d-sotalol than l-sotalol.[13]

Warnings and Precautions

Contraindications related to non-cardioselective β-blockade:

• Bronchial asthma or other bronchospastic conditions [33]

• Sinus bradycardia

• Second- or third-degree AV block absent a functioning pacemaker

• Cardiogenic shock

• Decompensated heart failure due to a negative inotropic effect [27]

• Sick sinus syndrome (without a pacemaker)

• Labile diabetes (due to hypoglycemia)

• Left ventricular hypertrophy (which also increases the risk of arrhythmia) 

Contraindications related to QTc prolonging effects:

• CrCl less than 40 mL/min when used for atrial fibrillation or flutter

• Acquired or congenital long QTc syndromes

• Uncorrected hypokalemia or hypomagnesemia (increased risk of prolonging QT  and causing torsades de pointes)

Other contraindications: They include previous evidence of sotalol hypersensitivity or allergy.[34]

Monitoring

Patients initiated on sotalol should be hospitalized for at least 3 days with cardiac rhythm monitoring and assessment. Blood pressure and heart rate require monitoring. Sotalol should not be initiated with a baseline QTc greater than 450 ms. Providers should have magnesium over 2 mEq/L and potassium greater than 4 mEq/L available when patients receive sotalol. Serum creatinine should be measured, and the dose requires adjustment according to renal function. The recommendation is that the dose of sotalol should be gradually increased over 3 days. Most cardiologists recommend observing the patient in a hospital with serial ECGs for at least 3 days after starting sotalol.[35]

A study demonstrated that outpatient initiation and maintenance of sotalol therapy for atrial fibrillation could be effectively monitored in carefully selected patients with cardiac implantable electronic devices equipped with continuous remote monitoring capabilities.[36]

Toxicity

Sotalol toxicity is inherent due to the mechanism of action as both a potassium channel blocker and a non-cardioselective β-blocker and mirrors the adverse effect profile. The most obvious and potentially problematic sign of toxicity is concentration-related QTc prolongation. If QTc is over 500 ms during initiation, the sotalol dose should be reduced or discontinued. If QTc exceeds 520 ms 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 a massive overdose. Patients with bradycardia or cardiac asystole atropine or transvenous cardiac pacing are necessary. In addition, the bronchospasm associated with β-blockage requires higher than normal β-2-agonist doses. Management of torsades 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 torsades de pointes 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.[37] According to the evidence-based consensus of the American Association of Poison Control Centers, ingesting sotalol exceeding 4 mg/kg indicates referral to the emergency department. For an asymptomatic patient who has unintentionally ingested sotalol, a minimum observation period of 12 hours is recommended.[38][39] According to EXTRIP (Extracorporeal Treatments In Poisoning) guidelines, sotalol is dialyzable. Indications for extracorporeal treatments include refractory bradycardia, recurrent torsades de pointes, and hypotension.[40]

Enhancing Healthcare Team Outcomes

The effective initiation and monitoring of sotalol therapy require collaboration among an interprofessional healthcare team comprising cardiologists, clinicians, and pharmacists to minimize the risk of toxicity. Without proper management, the risk of toxicity can increase.[22] Essential elements of coordinated care involve evaluating vital signs, electrolytes, and cardiac function, as well as monitoring for QTc changes and arrhythmias. Patient education, especially focusing on glucose monitoring for individuals with diabetes, is paramount. Pharmacists are integral in assessing drug interactions, making renal dosing adjustments, and providing medication education. Nurses contribute by identifying adverse events, reporting therapeutic effectiveness, and facilitating timely adjustments to therapy to ensure optimal outcomes while minimizing adverse effects.

Care coordination involves the following steps:

• Evaluating blood pressure and heart rate before and after the initial dose, as well as after any dosage adjustments.

• Obtaining serum creatinine, magnesium, and potassium levels.

• Monitoring cardiac activity for QTc changes and arrhythmias.

• Assessing cardiac and pulmonary status. 

• Providing guidance to patients with diabetes regarding the need for close monitoring of glucose levels due to potential alterations in glucose tolerance caused by β-blockers.

• Assessing additional medications taken by the patient and considering alternative therapies or dosage adjustments, as necessary.

• Ensuring the involvement of a pharmacist to evaluate drug interactions, make renal dose adjustments, and provide medication education.

A board-certified pharmacist specializing in cardiology can assist the clinical team with sotalol dosing and monitoring. Nurses should familiarize themselves with the signs of adverse events linked to sotalol administration and report the effectiveness of the regimen to enable necessary therapy adjustments. Adopting an interprofessional team approach to sotalol usage facilitates achieving optimal outcomes while minimizing adverse effects.