Ch3

C2H5

Lidocaine is a prototype of antiarrhythmic drugs of subgroup IB, and is widely used for treating and preventing ventricular ectopic activity during myocardial infarction.

Like procainamide, lidocaine is an amide with local anesthetizing action. Lidocaine is usually administered intravenously for short-term therapy of ventricular extrasystole, tachycardia, especially in the severe phase of myocardial infarction, arrhythmia of natural cause, and for arrhythmia that can originate in the heart during surgical manipulations. Synonyms of this drug are lidopen, xylocaine, xylocard, and others.

Tocainide: Tocainide, 2-amino-2',6'-dimethylpropionanilide (18.1.8), is synthesized by reacting 2,6-dimethylaniline with 2-bromopropionic acid bromide and subsequent substitution of the bromine atom in the resulting amide (18.1.7) with an amino group [13-16].

CH3 CH3 CH3

^/t"nh2 + B1--C-CH-CH3 -<c n_nh—C-CH-CH3 ---h— NH—C-CH-CH3

ch3 ch3 ch3

Tocainide is used for suppressing symptoms of ventricular arrhythmia and tachycardia, and for premature cardiac contractions. A synonym of this drug is tonocard.

Mexiletine: Mexiletine is 1-methyl-2-(2',2'-dimethylphenoxy)ethylamine (18.1.11). Mexiletine is synthesized by reacting the sodium salt of 2,6-dimethylphenol with chloroace-tone, forming 1-(2,6-dimethylphenoxy)-2-propanone (18.1.9). Reacting this with hydroxy-lamine gives the corresponding oxime (18.1.10). Reduction of the oximine group using hydrogen over Raney nickel gives mexiletine (18.1.11) [17-20].

CH3 ch3

ch3 ch3 18.1.9

CH3 0H ,CH3

Mexiletine is used for ventricular extrasystole and ventricular tachycardia, and ventricular fibrillation (including during the severe period of myocardial infarction). A synonym of this drug is mexitil.

Phenytoin: Synthesis of this anticonvulsant drug phenytoin (9.1.1) is described in Chapter 9.

Phenytoin has the same main effects on the heart as lidocaine. Its use is essentially limited, and it is primarily used only as an oral replacement of lidocaine for paroxysmal tachycardia that is caused particularly by intoxication of digitalis drugs. Synonyms of this drug are dilantin and diphenylan.

18.1.3 Subgroup IC

Drugs of this group are also referred to as sodium channel blockers. They substantially suppress depolarization of myocardial cells, while insignificantly reducing the time of their repolarization, and they also suppress automatism of sinoatrial nodes. These drugs differ from those examined above in that they reduce conductivity and increase the refractory period of the ventricles. Flecainide and encainide are included in this group. The indicated drugs are used for preventing and regulating supraventricular tachycardia and atrial fibrillation in patients with normal or close to normal ventricular function as well as for ventricular arrhythmia.

Flecainide: Flecainide, N-(2-piperidylmethyl)-2,5-to-(2,2,2-trifluoroethoxy)benzamide (18.1.14), is synthesized from 2,5-dihydroxybenzoic acid. Reacting this with trifluoroethyl-fluoromethylsulfonate gives 2.2.2-trifluoroethoxylation of all three hydroxyl groups, to produce 2,2,2-trifluoroethyl ester of 2,5-fe-(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) [21-24].

c o ch2cf3

cf3ch2 -o coo—nh-ch2 ^ch2cf3

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

These changes substantially alter the pharmacological properties of procainamide; however, flecainide maintains local anesthetic properties.

Flecainide, as with other local anesthetics, is used for naturally occurring ventricular arrhythmia. A synonym of this drug is tambocor.

Encainide: Encainide, 4-methoxy-N-[2-[2-(1-methyl-2-piperidinyl)ethyl]phenyl]-benza-mide (18.1.15), is synthesized by acylating 2-(1-methyl-2-piperidylethyl)aniline with 4-methoxybenzoic acid chloride. The chemical structure of encainide is substantially different than other local anesthetics and antiarrhythmics [25-27].

Clinical use of encainide is primarily associated with the presence of serious ventricular tachycardia; however, like flecainide, it is also sufficiently effective for atrial arrhythmia and is used for natural occurrences. A synonym of this drug is enkaid.

This group consists of /¡-adrenergic receptor blockers, the antiarrhythmic activity of which is associated with inhibition of adrenergic innervation action of the circulatory adrenaline on the heart. Because all /¡-adrenoblockers reduce stimulatory sympathetic nerve impulses of catecholamines on the heart, reduce transmembrane sodium ion transport, and reduce the speed of conduction of excitation, sinoatrial node and contractibility of the myocardium is reduced, and automatism of sinus nodes is suppressed and atrial and ventricular tachyarrhythmia is inhibited.

It is possible that /-adrenergic receptor blockers regulate heart rate and calm ischemia as well as reduce the heart's need for oxygen.

They are used for arrhythmias associated with nervous stress, myocardial infarction, and thyrotoxicosis accompanied by elevated adrenergic activity. Moreover, many antiarrhyth-mic drugs themselves can cause arrhythmia, especially in patients with ischemic heart disease. The examined /-adrenergic receptor blockers are an exception. Having said that, practically all /-adrenergic receptor blockers can be used as antiarrhythmics.

In applied medicine, however, only one drug of this group, propranolol, is represented. Publications on using atenolol as an antiarrhythmic have appeared. There is no contradictory evidence for using /-blockers with other antiarrhythmics.

Propranolol: The synthesis of propranolol, 1-isopropylamino-3-(1-napthyloxy)propan-2-ol (12.1.3) is described in Chapter 12.

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