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PubMed1993

Pharmacokinetic and pharmacodynamic profiles of d-sotalol and d,l-sotalol.

d,l-Sotalol is a racemic drug composed of equimolar amounts of d-(+)-sotalol and l-(-)-sotalol. The l-(-)-enantiomer has both beta-blocking (class II) activity and potassium-channel-blocking (class III) properties. The d-(+)-enantiomer has class III properties similar to those of l-sotalol. However, the affinity of d-sotalol for beta-adrenergic receptors is 30 to 60 times lower than the affinity of l-sotalol. The pharmacokinetics of d,l-sotalol are linear. Following oral administration, absorption and bioavailability are almost complete; apparent elimination half-life ranges from 7 to 18 hours. More than 80% of racemic sotalol elimination occurs by renal excretion of unchanged drug. Sotalol is not metabolized, nor is it significantly bound to plasma proteins. Thus, steady-state plasma concentration is reached within 3 days of treatment onset in patients without renal insufficiency. Dosage of sotalol should be adjusted to creatinine clearance. The pharmacokinetic profile of d-sotalol is similar to that of the racemate. Plasma concentrations of racemic sotalol associated with beta-adrenergic blockade are similar to those associated with its class III actions. QT interval prolongation with d,l-sotalol is dose- and concentration-dependent and decreases at rapid heart rates. Also, QT interval prolongation at a given plasma concentration during repeated dosing tends to be less pronounced than QT prolongation at the same plasma concentration during single dosing. The class III actions of d-sotalol in the sinus node are associated with slowing of sinus heart rate, whereas additional beta blockade contributes to the decrease in heart rate observed with l- or d,l sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1995

Positive and negative inotropic effects of DL-sotalol and D-sotalol in failing and nonfailing human myocardium under physiological experimental conditions.

BACKGROUND: DL-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as beta-adrenoceptor-blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to DL-sotalol, D-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium. METHODS AND RESULTS: Therefore, we investigated the effects of racemic DL-sotalol and its enantiomer D-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts. DL-sotalol and D-sotalol significantly (P < .01) increased peak developed force in atrial preparations by 14.0 +/- 3.4% and 16.7 +/- 3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both DL-sotalol and D-sotalol shifted the dose-response curve for isoproterenol to higher concentrations (P < .01); however, DL-sotalol was 100-fold more effective than D-sotalol. In non-failing myocardium, a positive force-frequency relation was found between 30 and 120 beats per minute, but isoproterenol was much more powerful in its inotropic effects. In failing myocardium, reduction in stimulation rate from 120 to 30 beats per minute increased peak developed force more pronounced than did the application of isoproterenol. CONCLUSIONS: (1) D-Sotalol has no relevant beta-adrenoceptor-blocking activity compared with DL-sotalol. (2) Neither DL-sotalol nor D-sotalol exhibit positive inotropic effects in human left ventricular myocardium. (3) Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force-frequency relation and thereby counteracts the potential negative inotropic properties of beta-blockade.

Adrenergic beta-Agonists↗
PubMed1996

Sotalol proarrhythmia: a report of five cases and an audit of the use of a sotalol in a teaching hospital.

BACKGROUND: Polymorphic ventricular tachycardia is an uncommon complication of sotalol use. AIMS: The aims of this study were: (1) to report five cases of sotalol proarrhythmia and (2) to audit the use of sotalol in a teaching hospital population. METHODS: Five patients with sotalol proarrhythmia (defined as new ventricular arrhythmias associated with sotalol administration) were identified over an 18 month period. Sotalol use for patients admitted to the John Hunter Hospital was audited over a six month period with 85 patients (55 males) identified from the pharmacy database. Medical records were reviewed and the details of treatment including sotalol dose and indication determined. Creatinine clearance was estimated by the Cockcroft and Gault regression equation. RESULTS: The audit indicated that sotalol was prescribed predominantly for management of atrial arrhythmias (80%). Paroxysmal atrial fibrillation was the most common indication (71%). Although female patients were older (72 +/- 13 vs 62 +/- 15 years, p < 0.001) and had a lower creatinine clearance (55 +/- = 24 vs 82 +/- = 32 mg/minute, p < 0.001) than male patients, they were prescribed similar doses of sotalol (206 +/- 112 vs 193 +/- 93 mg/day). The ratio of sotalol dose to creatinine clearance was higher in female patients (4.0 +/- 2.6 vs 2.16 +/- 1.5, p < 0.01). The five patients with proarrhythmia (torsades de pointes in four patients and polymorphic ventricular tachycardia in one patient) were all female. Daily sotalol dose (odds ratio for each 160 mg tablet 4.9 [95% confidence interval 1.5-16] and female gender (p < 0.01) were significant risk factors for proarrhythmia. CONCLUSION: Sotalol dose was not appropriately adjusted for creatinine clearance which is age and gender dependent. Female patients have an increased risk of proarrhythmia and should receive lower doses of sotalol.

Adult↗
PubMed1995

Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group.

Sotalol is the prototype class III agent that combines beta-blocking properties with the propensity to prolong the effective refractory period by lengthening the action potential duration. Its precise effect on the prevention of ventricular tachycardia-ventricular fibrillation (VTVF) compared to class I agents has not been evaluated in a blinded study. In a double-blind parallel-design multicenter study, the electrophysiologic and antiarrhythmic effects of intravenous and oral sotalol (n = 55) and procainamide (n = 55) were therefore compared in patients with VTVF inducible by programmed electric stimulation. Sotalol produced a greater effect on lengthening the ventricular effective refractory period (VERP). It prevented the inducibility of VTVF in 30% versus 20% for procainamide, but this was not significantly different. In an alternate therapy group (n = 41) of similar patients previously refractory to or intolerant of procainamide, intravenous sotalol prevented inducibility in 32%. The pooled overall sotalol efficacy rate was 31%. There was a significant relation between the increase in the VERP and the prevention of inducibility of VTVF (n = 56; p < 0.02). VERP of > or = 300 msec was critical for the prevention of VTVF inducibility. Thirteen sotalol and 6 procainamide responders from the randomized group and 30 from the nonrandomized groups completed 1 year of oral sotalol therapy follow-up. Life-table analysis of these patient in each group showed a trend in favor of sotalol; however, statistical analysis was not possible because of the small numbers of patients. Both sotalol and procainamide were well tolerated. In the randomized group there was one case of sudden death during treatment with sotalol and two cases of nonfatal torsades de pointes in the procainamide group and two in the sotalol group; in the nonrandomized alternate therapy group, there were 6 cases of nonfatal torsades de pointes. The data support the emerging role of sotalol in the control of symptomatic ventricular tachycardia and fibrillation.

Administration, Oral↗
PubMed1995

Intravenous sotalol for the termination of supraventricular tachycardia and atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled study. Sotalol Multicenter Study Group.

Sotalol is an antiarrhythmic agent with combined beta-blocking and class III antiarrhythmic properties. This study was designed to assess the safety and efficacy of sotalol in terminating supraventricular tachycardia (SVT), atrial fibrillation (AFib), and atrial flutter (AFl). Ninety-three patients with spontaneous or induced SVT (n = 45) or AF (AFib or AFl; n = 48) with a ventricular rate of > or = 120 beats/min were studied. In the first phase, the double-blind phase, patients were randomly assigned to receive placebo or intravenous (i.v.) sotalol, 1.0 or 1.5 mg/kg. If SVT or AF did not convert to sinus rhythm or if the ventricular rate did not slow to < 100 beats/min within 30 minutes, patients then entered the second phase, the open-label phase, which also lasted 30 minutes, and were given 1.5 mg/kg iv sotalol. In the SVT group, during the double-blind phase conversion to sinus rhythm occurred in 2 (14%) of 14 of patients who received placebo, 10 (67%) of 15 who received sotalol, 1.0 mg/kg (p < 0.05 vs placebo), and 10 (67%) of 15 who received 1.5 mg/kg sotalol (p < 0.05 vs placebo); during the open-label phase, 1.5 mg/kg i.v. sotalol converted 7 (41%) of 17 of patients. In the AF group, during the double-blind phase conversion to sinus rhythm occurred in 2 (14%) of 14 of patients who received placebo, 2 (11%) of 18 who received 1.0 mg/kg sotalol (p not significant [NS] vs placebo), and 2 (13%) of 16 who received 1.5 mg/kg sotalol (p = NS vs placebo); in these groups, a > 20% reduction of ventricular rate without conversion to sinus rhythm occurred in 0 (0%) of 14, 13 (72%) of 18 (p < 0.05 vs placebo), and 12 (75%) of 16 of patients (p < 0.05 vs placebo), respectively; during the open-label phase, 1.5 mg/kg i.v. sotalol converted 7 (30%) of 23 of patients. The most common adverse events were hypotension and dyspnea. During the double-blind phase they occurred in 10% of patients who received placebo, 9% of those who received 1.0 mg/kg i.v. sotalol (p = NS vs placebo), and 10% of those who received 1.5 mg/kg i.v. sotalol (p = NS vs placebo). Most of these events were mild to moderate, but all were transient and clinically manageable.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1998

Differential effects of d, l-sotalol and d-sotalol on isoproterenol-increased delayed rectifier outward potassium current in guinea pig single ventricular myocytes.

The aim of this study was to compare the effects of d, l-sotalol and d-Sotalol on the delayed rectifier K+ outward current in the presence of isoproterenol at different concentrations. Time-dependent delayed rectifier K+ outward currents were measured in isolated guinea pig single myocytes using the whole-cell configuration of the patch-clamp technique. Currents were measured in response to 300 ms depolarizing pulses from a holding potential of -40 mV in three experimental protocols [control, isoproterenol (10(-9) mol/L-10(-6) mol/L), and isoproterenol (10(-9) mol/L-10(-6) mol/L) plus either d, l-Sotalol (10(-4) mol/L) or d-Sotalol (10(-4) mol/L)]. IK tail currents were measured upon repolarization to -40 mV. It was found that IK was significantly amplified in the presence of isoproterenol (10(-9) mol/L-10(-6) mol/L) plus d-Sotalol. At 10(-8) mol/L isoproterenol, IK was increased by 92.7% +/- 17.1% (P < 0.05) and 54.3% +/- 13.4% after d-Sotalol addition (P < 0.05). In contrast, d, l-Sotalol completely conteracted the increase of Ik by isoproterenol (< 10(-8) mol/L), and compared to control, IK was decreased by 35.6% +/- 8.1% at 10(-8) mol/L isoproterenol plus d, l-Sotalol (P < 0.05). It is concluded that the beta-adrenergic blocking property of d, l-Sotalol but not that of d-Sotalol maintains the delayed rectifier K+ outward current blockade in the presence of isoproterenol in guinea pig myocytes. This might contribute to a superior antiarrhythmic efficacy as compared to d-Sotalol.

Adrenergic beta-Agonists↗
PubMed1993

Comparative hemodynamic effects of amiodarone, sotalol, and d-sotalol.

The effects of intravenous boluses of amiodarone (5 mg/kg), racemic sotalol (enantiomeric ratio d/l-sotalol 1:1;1.5 mg/kg), and d-sotalol (0.75 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), left ventricular end-diastolic pressure (LVEDP), and peak rate of change of left ventricular pressure (LV dp/dt) were assessed in conscious rabbits. Amiodarone and sotalol had a modest negative inotropic effect: amiodarone reduced peak LV dp/dt by 8 +/ 2% (mean +/- SEM) (p < 0.05) and sotalol by 6 +/- 2% (p < 0.05). These two drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: amiodarone caused a 13 +/- 3% (p < 0.05) increase in CO associated with a substantial vasodilatory effect (TPR reduced 25 +/- 3%; p < 0.01); sotalol did not produce any substantial change in either CO or TPR. Bolus intravenous injection of amiodarone was associated with a significant increase in HR (12 +/- 3%; p < 0.01), whereas sotalol reduced HR by 7 +/- 1% (p < 0.05). In contrast, administration of the dextro-rotatory optical isomer, d-sotalol, produced no significant change in peak LV dp/dt, LVEDP, CO, TPR, or HR. These results confirm that amiodarone and racemic sotalol have a comparatively weak cardiodepressant action. The experiments also show that the reduction in cardiac performance associated with racemic sotalol is mediated predominantly through the beta-adrenoreceptor blocking action of the levo-rotatory isomer (l-sotalol) rather than any substantial cardiodepressant effect of the dextro-rotatory isomer.

Amiodarone↗
PubMed1993

Electrophysiologic properties of sotalol and d-sotalol. A current view.

Although discovered more than two decades ago, the clinical applications of sotalol are still a matter of debate. Together with amiodarone, sotalol is considered a prototype of a new class of antiarrhythmic agents characterized by repolarization-prolonging effects (class III). Lengthening of repolarization is associated with an increase in the effective refractory period of cardiac tissues. There is no change in the maximum rate of rise during phase 0, a finding that supports the lack of sotalol effect on the fast sodium channel. The electrophysiologic action of the drug in humans provides evidence for direct cardiac effects of sotalol in addition to beta blockade. The beta-blocking properties play a major role in the sinus-rate slowing and lengthening of the atrioventricular nodal conduction time observed after sotalol administration. However, the drug also prolongs refractoriness in atria, His-Purkinje tissue, ventricular muscle and accessory atrioventricular connections. These latter changes are absent or minimal with conventional beta blockers and are likely to reflect sotalol-induced prolongation of cardiac repolarization. They result in an increase in the QT interval, an effect that is dose-dependent and more marked during chronic therapy. The dextrorotatory isomer, d-sotalol, shares a similar electrophysiologic profile. Lengthening of repolarization in cardiac cells following d-sotalol is of the same magnitude as that produced by the levoisomer. This finding provides further evidence for a class III action of sotalol, as the dextroisomer is almost devoid of beta-blocking properties. In humans, the electrical effects of both drugs are similar. However, d-sotalol-induced changes in sinus rate and atrioventricular nodal conduction are modest.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1998

Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol.

INTRODUCTION: Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects. METHODS AND RESULTS: We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7). CONCLUSION: In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.

Animals↗
PubMed1995

Pharmacodynamic, pharmacokinetic and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol.

In recent years, there has been a major shift from the use of antiarrhythmic drugs that act by slowing conduction to those that exert their beneficial actions by lengthening cardiac repolarisation. Such a shift is occurring because sodium channel blockers may increase mortality, especially in patients with structural heart disease, and because drugs such as sotalol and amiodarone are effective, with a potential for decreasing arrhythmic mortality. In this context, the electrophysiological and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol, are of major importance. d-Sotalol is essentially devoid of beta-blocking actions and may be considered a pure class III compound. It has been assumed that its clinical efficacy would approximate that of amiodarone and sotalol, but without the complex adverse effect profile of amiodarone and the adverse beta-blocker effects of racemic sotalol. d-Sotalol has pharmacokinetic properties that resemble those of the racemate. It lengthens the QT/QTc interval but does not affect other electrocardiographic (ECG) intervals. It increases the refractory period in the atria, ventricles, bypass tracts and the His-Purkinje system while minimally slowing the heart rate. In preliminary studies, it had a weak suppressant effect on premature ventricular contractions, prevented inducibility of ventricular tachycardia or fibrillation in about 40% of patients, and demonstrated the potential to terminate atrial flutter and fibrillation and maintain stability of sinus rhythm during prophylactic administration. The drug exhibits little or no negative inotropic actions. Thus, it is likely to be better tolerated in patients with congestive heart failure dependent on sympathetic stimulation for compensation. Because it produces less bradycardic effect than the racemate, it is believed that the drug might induce a lower rate of torsade de pointes. The role of d-sotalol in controlling cardiac arrhythmias is being addressed in a number controlled clinical trials. However, one such double-blind, placebo-controlled trial, Survival With Oral d-Sotalol (or SWORD), in survivors of myocardial infarction with depressed ventricular function was recently terminated prematurely because of a strikingly greater all-cause mortality compared with placebo (4.6 versus 2.6%). These preliminary findings, still to be fully analysed and interpreted for clinical significance, nevertheless raise valid concerns regarding the currently popular concept of controlling cardiac arrhythmias by the selective or isolated prolongation of repolarisation ('pure' class III action) as an antiarrhythmic principle.

Animals↗
PubMed1994

Pro- and antiarrhythmic effects of d-sotalol and dl-sotalol in an isolated tissue model of ischemia and reperfusion.

Pro- and antiarrhythmic effects of dl-sotalol and d-sotalol were compared with their electrophysiological actions in an isolated tissue model of simulated ischemia and reperfusion. Microelectrode recordings were made from endo- and epicardium of isolated guinea pig right ventricular free walls. An electrocardiogram also was recorded by two electrodes at opposite ends of the tissue bath. Regular stimulation was delivered to the endocardium. Tissues were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode's solution. Arrhythmias with characteristics of transmural reentry occurred in 33% of hearts in ischemia and 73% of hearts in early reperfusion. Arrhythmias were accompanied by prolongation of transmural conduction time (CT) and abbreviation of endocardial action potential duration (APD) and effective refractory period. Both dl-sotalol and d-sotalol (100 microM) significantly (P < .05) prolonged endocardial APD, effective refractory period and epicardial APD under preischemic conditions; however, these effects were lost during simulated ischemia and early reperfusion. dl-Sotalol abolished arrhythmias in ischemia and reduced the incidence of reperfusion arrhythmias to 30%. This agent attenuated prolongation of transmural CT by ischemia and decreased the incidence of conduction block. In contrast, d-sotalol (100 microM) increased arrhythmias in ischemia to 80% and did not change the incidence of reperfusion arrhythmias (60%). The proarrhythmic effects of d-sotalol were accompanied by prolongation of transmural CT, increased incidence of conduction block and decreased epicardial excitability. Thus, in this model of global ischemia and reperfusion, antiarrhythmic effects were observed with dl-sotalol but not with the predominantly type III isomer, d-sotalol.

Action Potentials↗
PubMed1991

Efficacy and safety of intravenous sotalol for termination of paroxysmal supraventricular tachycardia. The Sotalol Versus Placebo Multicenter Study Group.

A double-blind, placebo-controlled, crossover, multicenter study was conducted to study the efficacy and safety of a single intravenous dose of sotalol (1.5 mg/kg over 10 minutes) in achieving normal sinus rhythm in paroxysmal supraventricular tachycardia (SVT) lasting greater than or equal to 15 minutes. Patients were randomized to either sotalol or placebo as initial treatment, and if the SVT was not terminated a crossover was performed after 20 minutes. A total of 43 patients were enrolled, 38 of whom with spontaneous (n = 14) or induced (n = 24) SVT were analyzed for sotalol efficacy. Most patients (n = 27) had atrioventricular (AV) nodal reentrant tachycardia, and an important subgroup (n = 11) had circus movement tachycardia, using an accessory pathway for retrograde conduction. The number of patients converting to sinus rhythm as a result of the initial treatment was significantly higher in the sotalol group than in the placebo group, for spontaneous (p less than 0.005) as well as for induced tachycardia (p less than 0.001). Sinus rhythm was achieved within 30 minutes in 83% of all patients who received sotalol as the first drug, compared with 16% of the patients first receiving placebo (p less than 0.0001). For sotalol safety analysis, 42 patients were included. A total of 37 patients received sotalol, 19 as the first treatment, and 18 as the second treatment, while 25 patients received placebo. A total of 15 possible adverse effects were reported, occurring in 10 patients with sotalol versus 4 with placebo. The only severe side effect (hypotension) necessitating termination of drug administration occurred with placebo. No proarrhythmic effects were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Comparison of sotalol with digoxin-quinidine for conversion of acute atrial fibrillation to sinus rhythm (the Sotalol-Digoxin-Quinidine Trial).

We randomized 61 patients with paroxysmal atrial fibrillation (AF) ( < 48 hours from onset) to either sotalol or quinidine treatment. Conversion of rhythm was recorded by Holter monitoring. The starting 80 mg dose of sotalol was repeated at 2, 6, and 10 hours if AF persisted (heart rate > 80 beats/min), and if systolic blood was > or = 120 mm Hg. In the quinidine group, if heart rate > 100 beats/min, it was decreased with intravenous digoxin, whereafter 200 mg of oral quinidine sulfate was given maximally 3 times, each dose 2 hours apart. Conversion of AF to sinus rhythm occurred in 17 or 33 patients (52%) taking sotalol, and in 24 of 28 patients (86%) taking quinidine (p < 0.0001). Electric cardioversion was necessary in 39% of the former and in 14% of the latter group. The mean delay from first trial drug to sinus rhythm with the trial medication was 10.2 +/- 7.6 hours in the sotalol group and 4.0 +/- 2.9 hours in the quinidine group (p < 0.01). Treatment was discontinued in 16 patients taking sotalol (48%) because of asymptomatic bradycardia or hypotension, and in 20 taking quinidine (71%) because of rhythm conversion. Asymptomatic wide complex tachycardia (QRS > 0.12 second) was found in 13% and 27% of patients taking sotalol and quinidine, respectively. The longest RR intervals were 6.4 and 3.8 seconds in the sotalol and quinidine groups, respectively. Oral sotalol did not appear as effective as quinidine sulfate treatment in conversion of paroxysmal AF.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Comparative effects of d-sotalol and l-sotalol on the atrioventricular node of the rabbit heart.

The purpose of this study was to compare the dose-dependent effects of d-sotalol and l-sotalol (3 x 10(-7) M to 10(-4) M) on electrophysiological parameters in isolated preparations of the rabbit atrioventricular (AV) node. Standard microelectrode techniques were used in recording transmembrane action potentials from cells of the upper and lower AV node. Twelve New Zealand white Rabbits of either sex weighing between 1.5 and 2.6 kg were used. In both cell types studied, d-sotalol as well as l-sotalol prolonged action potential duration to the same extent. No significant effects were observed with either isomer on maximum diastolic potential, action potential amplitude, or maximum upstroke velocity of the action potential (Vmax). The rate of spontaneous discharge in AV nodal cells was decreased to the same extent by both isomers; this effect was caused by action potential prolongation; no effect on the rate of diastolic depolarization or Vmax was observed. Both d-sotalol and l-sotalol prolonged AV nodal conduction to the same degree by lengthening the action potential duration in AV nodal cells. The effects of 10(-4) M d-sotalol on AV nodal reentrant tachycardia were studied in one preparation in which AV nodal reentrant tachycardias could reproducibly be initiated by atrial premature stimulation. d-Sotalol abolished the occurrence of this tachycardia by lengthening refractoriness in AV nodal cells; this effect can be ascribed to a Class III antiarrhythmic effect.

Action Potentials↗
PubMed1992

High-performance liquid chromatographic determination of sotalol in plasma. I. Application to the disposition of sotalol enantiomers in humans.

Two high-performance liquid chromatographic analytical methods have been developed for the measurement of dl-sotalol or d-sotalol and l-sotalol in plasma, using dl-atenolol as internal standard. Quantitation of dl-sotalol was carried out, following solid-phase extraction, on a 5-microns C18 reversed-phase column, with a mobile phase containing acetonitrile, ion-pairing reagent and distilled water, using ultraviolet detection at 235 nm. Quantitation of d-sotalol and l-sotalol was based on derivatisation with the chiral agent S-(-)-alpha-methylbenzyl isocyanate, followed by chromatographic separation on a 3-microns C18 reversed-phase column, with a mobile phase containing methanol, glacial acetic acid and distilled water, with fluorimetric detection at 220 nm excitation and 300 nm emission. A preliminary application of the latter method suggests that the disposition of sotalol in humans is not enantioselective.

Aged↗
PubMed1999

Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group.

BACKGROUND: Patients with implantable cardioverter-defibrillators often receive adjunctive antiarrhythmic therapy to prevent frequent shocks. We tested the efficacy and safety of sotalol, a beta-blocker with class III antiarrhythmic effects, for this purpose. METHODS: In a multicenter trial, patients were stratified according to left ventricular ejection fraction (< or =0.30 or >0.30), randomly assigned to double-blind treatment with 160 to 320 mg of sotalol per day (151 patients) or matching placebo (151 patients), and followed for 12 months. Kaplan-Meier analyses of the time to an event were performed. Three end points were used: the delivery of a first shock for any reason or death from any cause, the first appropriate shock for a ventricular arrhythmia or death from any cause, and the first inappropriate shock for a supraventricular arrhythmia or death from any cause. RESULTS: Compliance with double-blind treatment was similar in the two groups. There were seven deaths in the placebo group and four in the sotalol group. As compared with placebo, treatment with sotalol was associated with a lower risk of death from any cause or the delivery of a first shock for any reason (reduction in risk, 48 percent; P<0.001 by the log-rank test), death from any cause or the delivery of a first appropriate shock (reduction in risk, 44 percent; P=0.007), or death from any cause or the delivery of a first inappropriate shock (reduction in risk, 64 percent; P=0.004). Sotalol also reduced the mean (+/-SD) frequency of shocks due to any cause (1.43+/-3.53 shocks per year, as compared with 3.89+/-10.65 in the placebo group; P=0.008). In the sotalol group, the reduction in the risk of death from any cause or the delivery of a first shock for any reason did not differ significantly between patients with ejection fractions of more than 0.30 and those with ejection fractions of 0.30 or less. CONCLUSIONS: Oral sotalol was safe and efficacious in reducing the risk of death or the delivery of a first defibrillator shock whether or not ventricular function was depressed.

Adrenergic beta-Antagonists↗
PubMed1986

Effect of sotalol, aprindine and the combination aprindine-sotalol on monophasic action potential duration.

The effects of sotalol, aprindine and the combination aprindine-sotalol in the intact dog heart were evaluated during constant atrial pacing with the use of monophasic action potential (MAP) recording. A first group of five dogs was given 1.5 mg kg-1 body weight of sotalol, followed by a second infusion of 1.5 mg kg-1 30 min later. Both doses of sotalol produced a statistically significant increase in right atrial MAP duration at 50% of repolarization (RAMAP50) and right ventricular MAP duration at 90% of repolarization (RVMAP90). To a second group of six dogs aprindine 1 mg kg-1 and aprindine 2 mg kg-1 were administered intravenously. The infusion of aprindine did not alter right atrial and right ventricular MAP duration. The addition of 1.5 mg kg-1 of sotalol to the dogs pretreated with aprindine 2 mg kg-1 resulted in a 25% increase in RAMAP50 and a 21% prolongation of RVMAP90. In summary, sotalol lengthens atrial and ventricular monophasic action potential duration and still prolongs repolarization of monophasic action potentials after previous administration of aprindine. A combination of sotalol, a beta-adrenergic blocker possessing class III efficacy, with a class I antiarrhythmic agent may be useful with respect to their electro-physiological action.

Animals↗
PubMed1995

Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group.

BACKGROUND: There is increasing interest in pure class III antiarrhythmic compounds, ie, drugs in which the electrophysiological effect is confined to the propensity for producing an isolated lengthening of action potential duration. d-Sotalol represents the prototype of such pure class III agents. This double-blind, placebo-controlled, randomized dose-finding study evaluated the antiarrhythmic efficacy and safety of d-sotalol in patients with symptomatic chronic ventricular ectopy. METHODS AND RESULTS: A total of 233 patients presenting with > or = 30 premature ventricular contractions (PVCs) per hour during drug-free Holter monitoring randomly received placebo or d-sotalol at dosages of 50, 100, or 200 mg BID. Drug efficacy was assessed by repeat Holter monitoring at the end of double-blind therapy. There was a dose-dependent increase in QT and QTc duration, indicating class III activity. A dose-related decrease in hourly PVC counts was observed, reaching statistical significance for patients receiving 200 mg d-sotalol BID (311 PVCs/h during baseline compared with 135 PVCs/h during active treatment, P < .05). Analysis of the primary efficacy criterion (ie, > or = 75% reduction in total PVCs/h) revealed a significant treatment effect only for the highest d-sotalol dose, with 8 patients (14%) meeting this criterion. Eighteen patients reported side effects, which led to drug discontinuation in 5. One sudden death and one nonfatal cardiac arrest occurred in patients with dilative cardiomyopathy receiving 200 mg d-sotalol BID. No incidence of torsade de pointes was reported. CONCLUSIONS: d-Sotalol exerts dose-dependent class III activity in patients with symptomatic ventricular ectopy. Its PVC-suppressing activity is modest and becomes evident predominantly at dosages of 200 mg administered BID. The observation of drug-associated serious adverse arrhythmic events emphasizes the need for individualized careful dose titration, particularly in patients with advanced organic heart disease.

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