Flecainide

Description

From the chemical point, flecainide is an analog of procainamide, to which a 2.2.2-trifluoroethoxyl group was added at C2 and C3 of the benzene ring, and a diaminoethyl side chain is ended in the piperidine ring.

Chemical Properties

White Crystalline Powder

Originator

Tambocor,Kettelhack Riker,W. Germany,1982

Uses

Flecainide is an antiarrhythmic (class IC).

Uses

Flecainide, as with other local anesthetics, is used for naturally occurring ventricular arrhythmia.

Definition

ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid with the primary amino group of piperidin-2-ylmethylamine. An antiarrhythmic agent used (in the form of its acetate salt) to prev nt and treat tachyarrhythmia (abnormal fast rhythm of the heart).

Manufacturing Process

Under a nitrogen atmosphere 2-aminomethylpiperidine (0.249 mol, 28.4 g) is treated dropwise over 25 minutes with 2,2,2-trifluoroethyl 2,5-bis(2,2,2- trifluoroethoxy)benzoate (0.0249 mol, 10.0 g). After 3 hours 50 ml of benzene is added to the thick mixture and stirred for about 40 hours at 45°C. The mixture is then concentrated under vacuum with heating to remove the volatile components. The residue solidifies after cooling, is steam distilled for further purification and is separated by filtration and extracted into dichloromethane. The dichloromethane solution is washed with saturated sodium chloride solution, and the organic layer is dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and 4 ml of 8.4 N hydrogen chloride in isopropanol is added to the dichloromethane solution with stirring.After 2 hours the mixture is cooled to about 0°C and the crude product is collected by filtration, washed with diethyl ether and dried in a vacuum oven. After treatment with decolorizing charcoal and recrystallization from an equivolume mixture of isopropanol and methanol, the product, 2,5-bis(2,2,2- trifluoroethoxy)-N-(2-piperidylmethyl)benzamide hydrochloride has a MP of 228°C to 229°C.

brand name

Tambocor (3M Pharmaceuticals).

Therapeutic Function

Antiarrhythmic

World Health Organization (WHO)

The membrane-stabilizing antiarrhythmic agent flecainide was introduced into medicine in 1982. The decision to delete the indications for patients with asymptomatic and less severe symptomatic ventricular arrhythmias was taken on the basis of the results of a trial (CAST study) that showed a two-fold increase in deaths in post-myocardiac patients taking flecainide compared with the placebo group.

Hazard

Human systemic effects.

Mechanism of action

Flecainide is effective if administered intravenously and orally; its effect is long-lasting. The drug combines the modes of action of class I a and I b drugs with those of class III.

Clinical Use

Flecainide (Tambocor) is a fluorinated aromatic hydrocarbon examined initially for its local anesthetic action and subsequently found to have antiarrhythmic effects. Flecainide inhibits the sodium channel, leading to conduction slowing in all parts of the heart, but most notably in the His-Purkinje system and ventricular myocardium. It has relatively minor effects on repolarization. Flecainide also inhibits abnormal automaticity.
Flecainide is effective in treating most types of atrial arrhythmias. It is also used for life-threatening ventricular arrhythmias. However, flecainide should be used with extreme caution in any patient with structural heart disease. Flecainide crosses the placenta, with fetal levels reaching approximately 70% of maternal levels. In many centers, it is the second-line drug after digoxin for therapy of fetal arrhythmias. Because of the high incidence of proarrhythmia, initiation of therapy or significant increases in dosing should be performed only on inpatients.

Side effects

Most adverse effects occur within a few days of initial drug administration. The most frequently reported effects are dizziness, light-headedness, faintness, unsteadiness, visual disturbances, blurred vision (e.g., spots before the eyes, difficulty in focusing), nausea, headache, and dyspnea.
Worsening of heart failure and prolongation of the PR and QRS intervals are likely to occur with flecainide, and an increased risk of proarrhythmia has been reported.

Synthesis

Flecainide, N-(2-piperidylmethyl)-2,5-bis-(2,2,2-trifluoroethoxy)benzamide (18.1.14), is synthesized from 2,5-dihydroxybenzoic acid. Reacting this with trifluoroethylfluoromethylsulfonate gives 2.2.2-trifluoroethoxylation of all three hydroxyl groups, to produce 2,2,2-trifluoroethyl ester of 2,5-bis-(2,2,2-trifluoroethoxy)benzoic acid (18.1.12). Reacting this with 2-aminomethylpiridine gives the corresponding amide (18.1.13), which upon reduction of the pyridine ring with hydrogen gives flecainide (18.1.14).

Drug interactions

In patients whose condition has been stabilized by flecainide, the addition of cimetidine may reduce the rate of flecainide’s hepatic metabolism, increasing the potential for toxicity. Flecainide may increase digoxin concentrations on concurrent administration.

Precautions

Flecainide is contraindicated in patients with preexisting second- or third-degree heart block or with bundle branch block unless a pacemaker is present to maintain ventricular rhythm. It should not be used in patients with cardiogenic shock.