Sotalol hydrochloride

Sotalol hydrochloride is a potent and non-selective antagonist of β-adrenergic receptor. Sotalol is also an inhibitor of potassinm channels with the IC50 value of ~1.2mM in HEK cell lines [1].

As a class III antiarrhythmic drug, Sotalol hydrochloride has been reported to increase the functional refractory period without reducing conduction velocity, using an in vitro experimental rabbit heart model of reentrant tachycardia. In vivo, Sotalol hydrochloride has shown to lengthen atrial and ventricular monophasic action potential duration in the intact dog heart during constant atrial pacing [2].Besides, Sotalol is a β-adrenergic receptor blocker commonly used in rhythm-control treatment of AF (Atrial fibrillation) [3].

References:
[1] Vormberge T1, Hoffmann M, Himmel H. Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve. J Pharmacol Toxicol Methods. 2006 Sep-Oct;54(2):130-40. Epub 2006 Apr 25.
[2] Claudel JP1, Touboul P. Sotalol: from "just another beta blocker" to "the prototype of class III antidysrhythmic compound".Pacing Clin Electrophysiol. 1995 Mar;18(3 Pt 1):451-67.
[3] Sicouri S1, Pourrier M, Gibson JK, Lynch JJ, Antzelevitch C. Comparison of electrophysiological and antiarrhythmic effects of vernakalant, ranolazine, and sotalol in canine pulmonary vein sleeve preparations. Heart Rhythm. 2012 Mar;9(3):422-9.

[The effect of sotalol hydrochloride therapy on atrial signal-averaged ECG in patients with paroxysmal atrial fibrillation].[Pubmed:9273201]

Pol Merkur Lekarski. 1996 Nov;1(5):303-9.

The aim of this study was to evaluate of oral Sotalol hydrochloride effects on atrial signal-averaged ECG (ASAECG) during time- and frequency-domain analysis in patients with paroxysmal atrial fibrillation (PAF) during ischemic heart disease (IHD). The study population of 27 was composed of 16 female and 11 male, mean age 56.1 +/- 8.4. The dose of oral sotalol was 160 mg/day for all days. Recording of ASAECG and 24-hours Holter monitoring were made at baseline, after 10 days and after 6 weeks of sotalol therapy. For ASAECG were calculated time-domain parameters: the root mean square voltage of the signals in the last 10, 20, 30 ms of the filtered P-wave (RMS 10, 20, 30) and total time duration of filtered P-wave (PWD) and time duration of P-wave for Frank leads X, Y, Z (XP, YP, ZP). During frequency-domain analysis of the terminal part of P-wave we calculated the following parameters in range from 40 Hz to 400 Hz: energy spectrum > -60 dB (A) and decibel drop at 40 Hz (Dd) in logarithmic scale and area ratio 20-50/0-20 Hz (Ar), magnitude ratio (MR1-7) in linear scale for a vector magnitude. Supraventriculat arrhythmias were estimated quantitatively and qualitatively during Holter monitoring. The following parameters were estimated in a case of PAF recording: time of manifestation, duration, number of PAF episodes per day, mean heart rate during PAF and subjective symptoms. Moreover, comparable analysis of the following parameters: dimension of left atrial, age, gender, time duration of IHD and PAF and wall motion disturbances-hypokinesis and also left ventricular ejection fraction, mitral regurgitation was done between patients with effective and no effective of antiarrhythmic therapy. Our observation have indicated that oral sotalol therapy are responsible for statistically significant decrease of total time duration of filtered P-wave (PWD) and time duration of P-wave for Frank leads X, Y, Z (XP, YP, ZP) and increase area ratio 20-50/0-20 Hz in patients with PAF during IHD. Moreover, comparable analysis of above-mentioned parameters have not showed statistically significant differences between examined patients with effective and lack of effective sotalol therapy.

[Determination of sotalol hydrochloride by reversed-phase high performance liquid chromatography].[Pubmed:12541604]

Se Pu. 2000 Mar;18(2):178-80.

An RP-HPLC method for determination and detection of Sotalol hydrochloride is described. The baseline separation was achieved on ODS column within 15 minutes by using 0.1% HAc-acetonitrile (80:20, V/V) as mobile phase at a flow rate 1.5 mL/min, and the wavelength was set at 227 nm. The linear range was 5-45 mg/L (r = 0.9991) and the limit of detection was 1 mg/L(S/N > 3). The intra-day and inter-day RSDs were 0.20% and 0.93% respectively.

Pharmacokinetics of intravenously and orally administered sotalol hydrochloride in horses and effects on surface electrocardiogram and left ventricular systolic function.[Pubmed:26670333]

Vet J. 2016 Feb;208:60-4.

Arrhythmias are common in horses. Some, such as frequent atrial or ventricular premature beats, may require long-term anti-arrhythmic therapy. In humans and small animals, Sotalol hydrochloride (STL) is often used for chronic oral anti-arrhythmic therapy. STL prolongs repolarization and the effective refractory period in all cardiac tissues. No information on STL pharmacokinetics or pharmacodynamics in horses is available and the aim of this study was to evaluate the pharmacokinetics of intravenously (IV) and orally (PO) administered STL and the effects on surface electrocardiogram and left ventricular systolic function. Six healthy horses were given 1 mg STL/kg bodyweight either IV or PO. Blood samples to determine plasma STL concentrations were taken before and at several time points after STL administration. Electrocardiography and echocardiography were performed at different time points before and after IV STL administration. Mean peak plasma concentrations after IV and PO administration of STL were 1624 ng/mL and 317 ng/mL, respectively. The oral bioavailability was intermediate (48%) with maximal absorption after 0.94 h, a moderate distribution and a mean elimination half-life of 15.24 h. After IV administration, there was a significant increase in QT interval, but no significant changes in other electrocardiographic and echocardiographic parameters. Transient transpiration was observed after IV administration, but no adverse effects were noted after a single oral dose of 1 mg/kg STL in any of the horses. It was concluded that STL has an intermediate oral bioavailability in the horse and might be useful in the treatment of equine arrhythmias.

Stability of sotalol hydrochloride in extemporaneously prepared oral suspension formulations.[Pubmed:23925139]

Int J Pharm Compd. 2005 Sep-Oct;9(5):402-6.

The physical, chemical, and microbial stabilities of extemporaneously compounded oral liquid formulations of Sotalol hydrochloride were studied. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were prepared from commercially available tablets (Betapace) in a 1:1 mixture of Ora-Plus: Ora-Sweet, a 1:1 mixture of Ora-Plus:Ora-Sweet SF, and a 1:2.4 mixture of simple syrup:methylcellulose vehicle. Six batches of each formulation were prepared; three were stored at refrigerated temperature (2 deg to 8 deg C) and three at room temperature (20 deg to 25 deg C). Samples were collected from each batch weekly for 6 weeks, and again at 12 weeks. Samples were analyzed by means of a high-performance liquid chromatographic method, and the concentrations obtained were compared to the theoretical time zero value. Samples were examined for pH, odor, color, and consistency changes. The suspensions also were evaluated for their microbial stability. Sotalol hydrochloride oral liquid suspensions (5mg/mL) were chemically stable for 12 weeks regardless of storage conditions (room temperature or refrigerated). Bacterial growth was not supported by any of the formulations. Suspensions stored at refrigerated temperature retained better physical quality (e.g., odor, color, and consistency) than suspensions stored at room temperature. Overall, this study demonstrates that oral formulations of Sotalol hydrochloride can be readily prepared with commercially available vehicles. The method of preparation is relatively simple, the materials are relatively inexpensive, and the products have a shelf-life of at least 12 weeks.

Block of IKs by the diuretic agent indapamide modulates cardiac electrophysiological effects of the class III antiarrhythmic drug dl-sotalol.[Pubmed:9336319]

J Pharmacol Exp Ther. 1997 Oct;283(1):148-56.

Indapamide is a diuretic agent with direct electrophysiological effects on ionic currents involved in cardiac repolarization. In particular, indapamide blocks the slow component of delayed rectifier potassium current. In contrast, most class III antiarrhythmic agents, such as dl-sotalol, block the rapid component of delayed rectifier potassium current. Computer simulations have suggested potentiation of drug effects on cardiac repolarization by the combined block of the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current. Therefore, the objective of our study was to evaluate the modulation of cardiac electrophysiological effects of dl-sotalol by indapamide. Two indices of cardiac repolarization, monophasic action potential duration at 90% repolarization and effective refractory period, at two basic cycle lengths (800 and 400 msec) were determined in 24 anesthetized open-chest dogs. In two treatment groups (n = 6/group), data were obtained at base line and every 2 min during steadily increasing concentrations of dl-sotalol (0-40 microg/ml) either alone or in the presence of indapamide (500 ng/ml). Data were also obtained in dogs receiving either a low-dose (500 ng/ml) or a high-dose (up to 7.5 microg/ml) infusion regimen of indapamide alone. Administration of dl-sotalol was associated with concentration-dependent increases in monophasic action potential duration at 90% repolarization and effective refractory period, whereas repolarization was only slightly altered by the administration of indapamide alone. However, concentration-response curves of dl-sotalol were shifted to the left in dogs treated with the combination of dl-sotalol and indapamide, and the EC50 values of dl-sotalol estimated for the prolongation of monophasic action potential duration at 90% repolarization and effective refractory period were decreased 3-fold during the coadministration of both drugs (P < .05 vs. dl-sotalol alone). Thus, under conditions of normal K+ levels, clinically relevant concentrations of indapamide modulate dl-sotalol effects on cardiac repolarization. Additional block of cardiac K+ currents, especially the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current could explain these observations.

Sotalol: from "just another beta blocker" to "the prototype of class III antidysrhythmic compound".[Pubmed:7770366]

Pacing Clin Electrophysiol. 1995 Mar;18(3 Pt 1):451-67.

Sotalol is a beta-blocking drug devoid of membrane stabilizing properties, as well as intrinsic sympathomimetic actions, or cardioselectivity. In addition, sotalol prolongs atrial and ventricular repolarization (Class III antiarrhythmic activity). It appears to have less myocardial depressant effect than other beta-blocking agents. Given orally, bioavailability of the drug reaches 100%. Sotalol's plasma half-life is 15 hours (range 7-18) and is dependent only on renal function. In clinical practice, it has been found effective in the suppression of nearly all supraventricular and ventricular dysrhythmias except those related to prolonged ventricular repolarization. Most common adverse effects are dyspnea, bradycardia, and fatigue, which results in drug termination in 16% of the cases. Torsades de pointes usually associated with bradycardia and drug induced QTc prolongation has been reported in 1.9%-3.5% of the patients receiving sotalol. This complication may be reduced by limiting the dose (< 640 mg/day) especially in patients with impaired renal function. In addition hypokalemia must be avoided. To sum up, the combination of Class II and Class III effects may carry additional benefits. However, further studies are required to test such hypotheses.

Sotalol hydrochloride (MJ 1999) is a non-selective competitive β-adrenergic receptor antagonist that also exhibits Class III antiarrhythmic properties by its inhibition of potassium channels.

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