Flecainide

Structural formula
	1: 1 mixture of ( R ) -form (top) and ( S ) -form (bottom)
General
Non-proprietary name	Flecainide
other names	( RS ) - N - (2-piperidylmethyl) -2,5-bis (2,2,2-trifluoroethoxy) benzamide ( IUPAC ); (±) - N - (2-piperidylmethyl) -2,5-bis (2,2,2-trifluoroethoxy) benzamide;
Molecular formula	C 17 H 20 F 6 N 2 O 3 (flecainide) ; C 17 H 20 F 6 N 2 O 3 · C 2 H 4 O 2 (flecainide · acetate) ;
External identifiers / databases
EC number	685-650-9
ECHA InfoCard	100.211.334
PubChem	3356
ChemSpider	3239
DrugBank	DB01195
Wikidata	Q421381
Drug information
ATC code	C01 BC04
Drug class	Antiarrhythmic
properties
Molar mass	414.34 g · mol -1 (flecainide) ; 474.39 g · mol -1 (· flecainide acetate) ;
Physical state	firmly
Melting point	145–147 ° C (flecainide acetate)
pK s value	9.3
solubility	Flecainide acetate: 3.0 mg / ml in ethanol ; 48.4 mg / ml in water
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 302-315-319-335-360
	P: 201-261-305 + 351 + 338-308 + 313
Toxicological data	1346 mg kg −1 ( LD 50 , rat , oral , acetate)
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Flecainide is a drug from the group of antiarrhythmics that is used to treat cardiac arrhythmias . As a sodium channel blocker with no effect on the duration of the action potential , it is counted in class Ic (without changing the duration of the action potential) of the Vaughan / Williams classification. Flecainide was manufactured in 1997 in the Riker Laboratories and is a further developed preparation from mexiletine . The acetate is used.

Presentation and extraction

The synthesis of flecainide takes place in three steps. In the first step, the starting material 2,5-dihydroxybenzoic acid is completely etherified and esterified by means of 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of sodium hydrogen carbonate . In the second step, an acid amide is formed by reaction with 2-picolylamine . The target compound is then produced by hydrogenating the pyridine ring in the presence of palladium carbon . The racemate [1: 1 mixture of ( R ) form and ( S ) form] results from the synthesis sequence.

application

Supraventricular tachycardias (e.g. AV-junctional tachycardias, supraventricular tachycardias in WPW syndrome , paroxysmal atrial fibrillation ), if they are symptomatic and require treatment. Life threatening ventricular tachycardias .

Contraindications and warnings

Three months after myocardial infarction (= heart attack ), with decompensated heart failure , significant electrolyte disturbance or pronounced hypotension , flecainide must not be used, with severe bradycardia , SA blockages and higher-grade AV blockages as well as sinus node syndrome only if a pacemaker is implanted. If the heart's pumping function is restricted (ejection fraction <35%), it may only be used in the case of life-threatening ventricular arrhythmias.

If the liver or kidney function is impaired , the dose must be adjusted. During therapy, kidney function and the width of the QRS complex should be monitored in the resting ECG . Flecainide has a very narrow therapeutic range between 0.2 and 1.0 μg / ml in serum. The toxic (harmful or poisonous) range begins at serum levels of 1.5 μg / ml. Overdoses - also due to reduced excretion in renal insufficiency - must be avoided.

possible side effects

Drop in blood pressure , heart failure , cardiac arrhythmias ( bradycardia , AV block , ventricular extrasystoles , ventricular flutter ), visual disturbances ( double vision ), dizziness , headache , confusion, nausea, increased transaminases , cholestatic hepatitis , shortness of breath and indigestion . Rarely tiredness and increased tendency to perspire . Very rarely dry mouth, fever , muscle or joint pain, anxiety , allergic skin reactions and temporary erectile dysfunction .

As early as 1991, the CAST study showed that in patients with coronary artery disease, drugs such as flecainide increase the risk of sudden cardiac death despite their proven effectiveness against ventricular arrhythmias. This is explained by the fact that the flecainide itself can trigger dangerous (malignant) arrhythmias (proarrhythmic effect). These proarrhythmic effects also seem to be genetically determined.

Trade names

Monopreparations

Aristocor (A), Flecagamma (D), Tambocor (D, CH), various generics (D)

literature

Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185–283, here: pp. 253 f. ( Flecainide ).

Individual evidence

^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 700, ISBN 978-0-911910-00-1 .
↑ ^a ^b ^c Entry on flecainide. In: Römpp Online . Georg Thieme Verlag, accessed on July 1, 2019.
↑ ^a ^b data sheet Flecainide acetate salt from Sigma-Aldrich , accessed on April 1, 2011 ( PDF ).
↑ Data sheet FLECAINIDE ACETATE CRS (PDF) at EDQM , accessed on August 3, 2008.
^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 164 .
↑ EH Banitt, WE Coyne, JR Schmid, A. Mendel: Antiarrhythmics. N- (Aminoalkylene) trifluoroethoxybenzamides and N- (aminoalkylene) trifluoroethoxynaphthamides . In: J. Med. Chem. , 18, 1975, pp. 1130-1134, doi: 10.1021 / jm00245a017 .
↑ EH Banitt, WR Bronn, WE Coyne, JR Schmid: Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N- (piperidylalkyl) trifluoroethoxybenzamides . In: J. Med. Chem. , 20, 1977, pp. 821-826, doi: 10.1021 / jm00216a016 .
^ Anne Paschen: Heart. 2016, p. 254.
↑ AM Nia, E. Caglayan, N. Gassanov, T. Zimmermann, O. Aslan, M. Hellmich, F. Duru, E. Erdmann, S. Rosenkranz, F. Er: Beta1-adrenoceptor polymorphism predicts flecainide action in patients with atrial fibrillation . In: PLoS ONE . tape 5 , no. 7 , July 2010, p. e11421 – e11421 , doi : 10.1371 / journal.pone.0011421 , PMID 20625396 , PMC 2896398 (free full text).
↑ Red List Online , as of August 2009.
↑ Swiss Medicines Compendium , as of August 2009.
↑ AGES-PharmMed, as of August 2009.

[MerckIndex-1] The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 700, ISBN 978-0-911910-00-1 .

[römpp-2] Entry on flecainide. In: Römpp Online . Georg Thieme Verlag, accessed on July 1, 2019.

[Sigma-3] ta sheet Flecainide acetate salt from Sigma-Aldrich , accessed on April 1, 2011 ( PDF ).

[Ph._Eur.-4] Data sheet FLECAINIDE ACETATE CRS (PDF) at EDQM , accessed on August 3, 2008.

[5] Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 164 .

[6] EH Banitt, WE Coyne, JR Schmid, A. Mendel: Antiarrhythmics. N- (Aminoalkylene) trifluoroethoxybenzamides and N- (aminoalkylene) trifluoroethoxynaphthamides . In: J. Med. Chem. , 18, 1975, pp. 1130-1134, doi: 10.1021 / jm00245a017 .

[7] EH Banitt, WR Bronn, WE Coyne, JR Schmid: Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N- (piperidylalkyl) trifluoroethoxybenzamides . In: J. Med. Chem. , 20, 1977, pp. 821-826, doi: 10.1021 / jm00216a016 .

[8] Anne Paschen: Heart. 2016, p. 254.

[PMID20625396-9] AM Nia, E. Caglayan, N. Gassanov, T. Zimmermann, O. Aslan, M. Hellmich, F. Duru, E. Erdmann, S. Rosenkranz, F. Er: Beta1-adrenoceptor polymorphism predicts flecainide action in patients with atrial fibrillation . In: PLoS ONE . tape 5 , no. 7 , July 2010, p. e11421 – e11421 , doi : 10.1371 / journal.pone.0011421 , PMID 20625396 , PMC 2896398 (free full text).

[RLO-10] Red List Online , as of August 2009.

[AMK-11] Swiss Medicines Compendium , as of August 2009.

[AGES-12] AGES-PharmMed, as of August 2009.