Sotalol

Structural formula
	( R ) -Sotalol (top) and ( S ) -Sotalol (bottom), 1: 1 mixture of stereoisomers
General
Non-proprietary name	Sotalol
other names	( RS ) -4 '- (1-Hydroxy-2-isopropylaminoethyl) -methanesulfonanilide ( IUPAC ); (±) -4 '- (1-Hydroxy-2-isopropylaminoethyl) methanesulfonanilide;
Molecular formula	C 12 H 20 N 2 O 3 S
External identifiers / databases
PubChem	5253
DrugBank	DB00489
Wikidata	Q413591
Drug information
ATC code	C07 AA07
Drug class	Beta blockers , antiarrhythmics
Mechanism of action	non-selective blockade of β-receptors
properties
Molar mass	272.36 g · mol -1
Physical state	firmly
Melting point	206.5-207 ° C
solubility	Water: 5510 mg l −1 at 25 ° C
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances (±) -Sotalol hydrochloride; Caution
H and P phrases	H: 315-319-335
	P: 261-305 + 351 + 338
Toxicological data	790 mg kg −1 ( LD 50 , mouse , ip )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sotalol is a drug from the group of beta blockers that is used to treat cardiac arrhythmias ( antiarrhythmic ). Chemically it is one of the few beta blockers without a phenol ether structure, which is why the substance was not given the ending -olol ; structurally it is similar to the beta sympathomimetics from the group of phenylethylamines such as B. Isoprenaline .

Pharmacological properties

Sotalol belongs to the group of non-selective beta blockers because it does not specifically bind to the β ₁ -adrenoceptors . In contrast to the beta blockers acebutolol and oxprenolol, it has no intrinsic sympathomimetic activity ( ISA ). Sotalol exists as a racemate , the D- and L-isomers, enantiomeric to each other, block potassium channels . The L-shape of the sotalol also acts as a beta blocker.

Effect of the stereoisomers	L -Sotalol	D -Sotalol
Effect of the stereoisomers	( R ) - (-) - sotalol	( S ) - (+) - sotalol
Inhibition of the potassium channels	Yes	Yes
Non-selective β-receptor blockade	Yes	No

The relative potency of Sotalol compared to Propranolol is 0.5.

Sotalol has a bioavailability of almost 100%. A plasma protein binding of the sotalol could not be proven. Sotalol is difficult to control because the plasma half-life , i.e. the time the body needs to excrete half of the administered sotalol, is around 15 hours. Excretion takes place via the kidneys , so the dose should be adjusted in case of renal insufficiency .

Side effects

Compared to other beta blockers, Sotalol has some special features due to its additional effect on potassium channels. Like all antiarrhythmics, Sotalol itself can also cause arrhythmias. Torsade de pointes tachycardia, which can develop from ventricular fibrillation to sudden cardiac death, is particularly feared . These cardiac arrhythmias can occur especially with high doses, kidney failure, electrolyte disturbances and the QT syndrome (with prolongation of the QTc time). In a large study in which several thousand patients were examined over 164 days, torsades occurred in 1.9% of the men and 4.1% of the women. After correcting for other risk factors, the risk for women treated with the drug is three times higher than that for men. Therefore sotalol is contraindicated for long QT periods .

Clinical information

Along with amiodarone and dronedarone, sotalol is a representative of the class III antiarrhythmics (potassium channel blockers), as it delays the repolarizing potassium current. Electrophysiological measurements of isolated heart muscle cells showed that the action potential was prolonged . The extension of the action potential also leads to an extension of the refractory period of the heart muscle cell. The prolongation of the action potential of the heart muscle cell is explained by a blockade of the potassium channels.

SWORD study

Since the dextrorotatory enantiomer D-sotalol has hardly any beta-blocking effect, there was hope that this substance could also be used for the prophylaxis of sudden cardiac death in patients with severely impaired pumping capacity of the heart. The SWORD study ( Survival With Oral D-Sotalol ) tested D-sotalol versus a placebo group in patients with impaired ventricular function (EF <40%) after a heart attack . The study was discontinued because of a statistically significantly higher mortality in the verum group . The excess mortality was attributed to the triggering of cardiac arrhythmias by the potassium channel-blocking property of D-sotalol.

Contraindications

Sotalol must not be used in certain cardiac diseases ( heart failure grade NYHA IV ; decompensated heart failure, acute myocardial infarction , AV block II and III degree, SA block , sinus node syndrome , pre-existing QT prolongation ), certain disorders in the electrolyte balance ( Hypokalaemia , hypomagnesaemia , metabolic acidosis ), hypotension , late stages of peripheral circulatory disorders, obstructive airways disease and untreated pheochromocytoma .

Manufacturing

A multi-stage synthesis for sotalol, starting from methanesulfonic acid chloride and aniline , is described in the literature.

Trade names

Monopreparations

Darob (D), Jutalex (D), Rentibloc (D), Sotalex (D, CH), numerous generics (D, A, CH)

literature

T. Karow / R. Lang-Roth: General and special pharmacology and toxicology . 2003 pp. 62-66.
G. Herold: Internal Medicine 2004.
Waldo AL et al .: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. The Lancet . 1996 Jul 6; 348 (9019): 7-12. Erratum in: Lancet 1996 Aug 10; 348 (9024): 416, PMID 8691967 .
Pratt CM et al .: Mortality in the Survival With ORal D-sotalol (SWORD) trial: why did patients die? At J Cardiol. 1998 Apr 1; 81 (7): 869-876, PMID 9555777 .

Individual evidence

↑ ^a ^b ^c Entry on sotalol in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ ^a ^b data sheet (±) -Sotalol hydrochloride from Sigma-Aldrich , accessed on April 23, 2011 ( PDF ).
↑ Connolly SJ, Dorian P, Roberts RS, et al. Comparison of β-Blockers, Amiodarone Plus β-Blockers, or Sotalol for Prevention of Shocks From Implantable Cardioverter Defibrillators: The OPTIC Study: A Randomized Trial. JAMA. 2006; 295 (2): 165-171. doi : 10.1001 / jama.295.2.165
↑ Mutschler, Ernst, Medicinal Effects, 6th edition 1991., ISBN 3-8047-1118-9
↑ Aktories: Pharmacology and Toxicology; 9th edition.
↑ Waldo, Albert L et al .: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The Lancet, 1996, Volume 348, Issue 9019, 7-12, doi : 10.1016 / S0140-6736 (96) 02149-6 .
^ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.

[ChemIDplus-1] Entry on sotalol in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[Sigma-2] ta sheet (±) -Sotalol hydrochloride from Sigma-Aldrich , accessed on April 23, 2011 ( PDF ).

[3] Connolly SJ, Dorian P, Roberts RS, et al. Comparison of β-Blockers, Amiodarone Plus β-Blockers, or Sotalol for Prevention of Shocks From Implantable Cardioverter Defibrillators: The OPTIC Study: A Randomized Trial. JAMA. 2006; 295 (2): 165-171. doi : 10.1001 / jama.295.2.165

[4] Mutschler, Ernst, Medicinal Effects, 6th edition 1991., ISBN 3-8047-1118-9

[5] Aktories: Pharmacology and Toxicology; 9th edition.

[6] Waldo, Albert L et al .: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The Lancet, 1996, Volume 348, Issue 9019, 7-12, doi : 10.1016 / S0140-6736 (96) 02149-6 .

[A._Kleemann-7] Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.