Concentration-dependent pharmacologic properties of sotalol

doi:10.1016/0002-9149(86)90692-2

The American Journal of Cardiology

Volume 57, Issue 13, 1 May 1986, Pages 1160-1165

https://doi.org/10.1016/0002-9149(86)90692-2 Get rights and content

Abstract

Sotalol is a nonselective β-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of β-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). the responders to sotalol included 8 patients in whom therapy with conventional β-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.

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Cited by (96)

Single- and multiple-dose pharmacokinetics of sotalol hydrochloride in healthy cats
2024, Journal of Veterinary Cardiology
The objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats.
Six adult purpose-bred cats
Cats were administered 2 mg sotalol/kg body weight as a single intravenous bolus and as a single oral dose in a randomized crossover study with a two-week washout period. The same cats then received 3 mg sotalol/kg orally every 12 h for two weeks. Blood samples were collected at predetermined time points for 48 h postdose for quantification of sotalol using ultra-high-pressure liquid chromatography with mass spectrometry. Non-compartmental analysis was used to obtain pharmacokinetic parameters. Data are presented as median (min–max).
Following intravenous administration, plasma clearance and volume of distribution were 9.22 mL/min/kg (5.69–10.89 mL/min/kg) and 2175.56 mL/kg (1961–2341.57 mL/kg), respectively. Bioavailability was 88.41% (62.75–130.29) following a single oral dose. Peak plasma concentration (C_max) and time to C_max were 0.94 μg/mL (0.45–1.17 μg/mL) and 1.5 h (0.5–4 h) after a single oral dose (2 mg/kg), and 2.29 μg/mL (1.91–2.48 μg/mL) and 1.0 h (0.5–1.5 h) with chronic oral dosing (3 mg/kg), respectively. Elimination half-life was 2.75 h (2.52–4.10 h) and 4.29 h (3.33–5.53 h) for single and chronic oral dosing, respectively. Accumulation index was 1.17 (1.09–1.29) after chronic dosing. Urinary sotalol recovery was 81–108% of the intravenous dose.
Oral sotalol administration resulted in plasma concentrations reportedly efficacious in other species, with good to excellent oral bioavailability. Urinary excretion appears to be a major route of elimination. Following repeated oral dosing, minimal drug accumulation was estimated. Additional studies in cats are recommended due to the possibility of nonlinear kinetics.
Traditional risk factors for QT interval prolongation and torsades de pointes
2022, Torsades de Pointes
Risk factors are important for the development of torsades de pointes (TdP), and drug-induced TdP is extremely rare in the absence of risk factors. Traditional risk factors for QTc interval prolongation and TdP include acute myocardial infarction/ischemia, older age, anorexia/malnutrition, bradyarrhythmias, conversion from atrial fibrillation to sinus rhythm, elevated plasma concentrations of QT interval-prolonging drugs, female sex, heart failure with reduced ejection fraction, hepatic cirrhosis, electrolyte abnormalities (hypocalcemia, hypokalemia, and hypomagnesemia), hypothyroidism, history of TdP, possibly premature ventricular complexes, and prolongation of the QTc interval to ≥ 500 ms and/or > 60 ms from baseline (as a risk factor for TdP). Concomitant administration of multiple QT interval-prolonging drugs may be a risk factor for QTc prolongation and TdP, but not all studies support this concept, and whether a combination of QT interval-prolonging drugs increases the risk of QTc prolongation compared to that associated with individual QT-prolonging drugs alone likely depends on the specific drugs being combined. To minimize the risk of TdP, correctable risk factors should be ameliorated. In patients with non-modifiable risk factors who require therapy with a QT interval-prolonging medication, QTc interval-prolonging drugs should be used cautiously, and frequent QT interval monitoring should be implemented where feasible.
Capillary isotachophoresis with electrospray-ionization mass-spectrometric detection: Cationic electrolyte systems in the medium-alkaline range for selective analysis of medium strong bases
2020, Journal of Chromatography A
Citation Excerpt :
The sotalol concentration in the extract determined from peak area was 5.50 × 10−8 M, which corresponds to 468 ng/mL of sotalol in capillary blood. This value matches well with plasma levels reported for daily sotalol dosage of 160 mg [37] and is slightly below the lower therapeutic level of 500 ng/mL reported by other authors [38]. A comparison of panels B and C shows very similar characteristics of the records which indicates that the real sample does not represent any complication and allows straightforward and simple evaluation.
This work extends the present working range of isotachophoresis (ITP) with electrospray-ionization mass-spectrometric (ESI–MS) detection and describes for the first time a functional cationic electrolyte system for analyses at medium-alkaline pH. So far no ITP–MS application was published on the analysis of medium strong bases although there is a broad spectrum of potential analytes like biogenic amines, alkaloids or drugs, where this technique promises interesting gains in both sensitivity and specificity. The presented results include a selection of suitable sufficiently volatile ESI-compatible system components, discussion of factors affecting system properties, and recommendations for functional ITP electrolyte systems. Theoretical conclusions based on calculations and computer simulations are confirmed by experiments with a model mixture of beta-blockers. Practical applicability of the method is demonstrated on the example of analysis of sotalol in dried blood spots where direct injection of aqueous extract, ITP stacking and MS detection provide a fast, simple and sensitive technique with limits of quantitation on the sub-nM level.
Pharmacokinetics of intravenously and orally administered sotalol hydrochloride in horses and effects on surface electrocardiogram and left ventricular systolic function
2016, Veterinary Journal
Citation Excerpt :
Avoiding hypokalaemia, excessive QT prolongation and bradycardia is important to prevent ventricular tachycardia (Soyka et al., 1990; Anderson and Prystowsky, 1999). Underlying renal disease and the use of diuretics require dose adjustments (Wang et al., 1986; Singh and Nademanee, 1987). In human medicine, if high concentrations are required, effects on QT interval are monitored with prolongations of more than 20% being an indication to reduce the dose (Campbell and Williams, 1998).
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.
Clinical pharmacology of antiarrhythmic drugs
2012, Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease: Fourth Edition
Non-invasive telemetric electrocardiogram assessment in conscious beagle dogs
2009, Journal of Pharmacological and Toxicological Methods
The primary objective of this investigation was to evaluate the sensitivity of a non-invasive telemetry system for the detection of drug-induced electrocardiogram (ECG) changes in conscious, freely moving dogs. A secondary objective was to compare, in the same set of dogs, ECG data acquired by a non-invasive system with data acquired from a surgically implanted telemetry device (invasive system).
Continuous beat-to-beat Lead II ECG data were simultaneously acquired from 6 male dogs using a non-invasive and an invasive telemetry system for 1 h pre-dose and 6 h following a sham control dose or single oral doses of (±) sotalol (4, 8 or 16 mg/kg). ECG parameters of heart rate, RR, PQ, QRS, QT and QT corrected for heart rate according to Van de Water (QTcV) and by an individual linear regression formula (QTcR), were determined.
Statistically significant dose-dependent reduction of heart rate, and increases in PQ, QT and QTc (V and R) were detected at all dose levels of (±) sotalol, with partial recovery during the 6-hour monitoring period. Statistically significant correlations for heart rate, RR, PQ, QT and QTc (V and R) were found between the two systems. QRS duration did not correlate. However, the difference between the two systems was consistent over the range studied. Based on these findings, the non-invasive system is quantitatively comparable to invasive telemetry, and can be used successfully to acquire continuous ECG data on a beat-to-beat basis from conscious freely moving dogs for at least 6 h post-dose.

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^☆: This work was supported in part by Grants HL-26782, GM 31304, GM07569 and RR095 from the National Institutes of Health, Bethesda, Maryland.

¹: Dr. Roden is a recipient of the Clinician Scientist Award of the American Heart Association, Dallas, Texas.

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Concentration-dependent pharmacologic properties of sotalol☆

Abstract

Am J Cardiol

Am Heart J

Prolongation of the human cardiac monophasic action potential by sotaiol

Am J cardiol

Electrophysiological and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue

Circ Res

Sotalol induced delayed ventricular repolarization in man

Eur Heart J

A third class of antiarrhythmic action. Effects of atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1989 and AH 3474

Br J Pharmacol

Effects of sotalol in twenty patients with cardiac arrhythmias

Int J Clin Pharmacol Biopharmacol

The treatment of cardiac arrhythmias with sotaiol

Eur J Clin Pharmacol

The efficacy of sotalol in suppressing ventricular ectopic beats

S Afr Med J

Effects of the beta-adrenoceptor-blocking agent sotalol on ventricular arrhythmias in patients with chronic ischemic heart disease

Cardiology

Sotalol-propranolol comparison. Relationships amongst antiarrhythmic efficacy, class III electrophysiologic action and beta blockade (abstr)

JACC

An analysis of the time relations of electrocardiograms

Heart