Antiarrhythmic Drugs

Antiarrhythmic Drugs

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Drugs used for preventing and treating irregular heart rate and heartbeat are called antiarrhythmic drugs. Arrhythmia results from disruptions in the formation of electric impulses and their conduction to the heart, or when both of these happen simultaneously. Heart rate is regulated by acetylcholine and norepinephrine (noradrenaline). Heart rate normally depends on the activity of pacemaker cells of the synoatrial ganglia. When their function is disrupted, heart rate is disturbed, thus resulting in various clinical symptomology. Arrhythmia may also be associated with ectopic centers, which generate impulses more frequently than normal pacemakers. The rhythm of heart contractions depends on many parameters: condition of pacemaker cells and the conduction system, myocardial blood flow, and other factors; consequently, arrhythmia can originate for different reasons that are caused by disruptions in electrical impulse generation or conduction. They can be caused by heart disease, myocardial ischemia, electrolytic and acid–base changes, heart innervation problems, intoxication of the organism, and so on. Drugs used for treating arrhythmia can have an effect on the electrical conduction system of the heart, its excitability, automatism, the size of the effective refractory period, and adrenergic and cholinergic heart innervation. Accordingly, compounds of various chemical classes can restore heart rate disturbances. As already noted, arrhythmia originates from problems forming electric impulses and propagating them to the heart, or when both of these happen simultaneously, which can be accomplished by transferring Na⫹, K⫹, and Ca2⫹ ions through cell membranes. Therefore, the mechanism of action of many antiarrhythmic drugs consists of blocking Na⫹ and Ca⫹ ion channels of the myocardium, which prolongs the time necessary for restoration after being activated by these channels, and which in turn acts on the electrical conduction system of the heart, its excitability, automatism, and so on. Based on an understanding of the mechanism that causes tachycardia, which requires a good understanding of electrophysiology, and an understanding of the effects of various group of drugs on this mechanism, in most cases a specific drug for a specific patient can almost always be selected. Classifying antiarrhythmic drugs is based on different principles; for example, the location of the drug action. They can be substances that act directly on the myocardium and the conduction system of the heart itself, or substances that have an effect on the efferent 245

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innervation of the heart. They can be viewed as groups of drugs effective for supraventricular arrhythmia, and those effective for ventricular arrhythmia. Currently, however, the more or less universally accepted classification of drugs used for treating tachyarrhythmia is based on the characteristics of their effect on electrophysiological or biochemical processes in the myocardium. Antiarrhythmic drugs can therefore be subdivided into four main groups. The first group is made up of drugs that block Na⫹ channels of the myocardium (quinidine, procainamide, disopyramide, lidocaine, tocainide, phenytoin, mexiletine, flecainide, encainide). Drugs that block action of endogenous catecholamines on the heart that have certain significance in the pathogenesis of arrhythmia belong to the second group of antiarrhythmia drugs (βblockers—propranolol etc.). The third group is made up of drugs, which predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased (amiodarone, bretylium). Finally, the fourth group of antiarrhythmic drugs is represented by antianginal drugs— Ca2⫹ channels blockers (verapamil). These groups, in particular the first group, are in turn subdivided based on specific characteristics of various substances within that group. Some researchers adhere to a system of dividing antiarrhythmic drugs into five groups without putting them in subgroups. 18.1

GROUP I DRUGS

Drugs belonging to this group are, with a few rare exceptions, local anesthetics which form complexes with lipoproteins of cell membranes of the myocardia, thus blocking Na⫹ channel conductivity and the flow of Na⫹ into the cell, and facilitate the release of K⫹ from myocardial cells, which as a result leads to a weak suppression of depolarization of myocardial cells, reduction of repolarization time, and a slowing of the propagation of excitation. This series of drugs prolongs action potentials and increases the effective refractory period of the myocardium. Automatism of ectopic centers is suppressed in the myocardium, primarily in the ventricles. 18.1.1

Subgroup IA

Drugs of this subgroup slow down the speed of transmitting excitation, reduce excitability of Purkinje fibers, suppress automatism of ectopic regions and increase the effective refractory period. They exhibit direct and mediated anticholinergic action. The antiarrhythmic drugs quinidine, procainamide, and disopyramide belong to this subgroup. Drugs of this subgroup are used for treating irregular sinus rhythm, paroxysmal, supraventricular, and ventricular arrythmia, preventing arterial fibrillation, and premature heartbeats. Quinidine: Quinidine, (5-vinyl-2-quinyclidinyl)-(6-methyoxy-4-quinolyl)-methanol (18.1.1) is the dextro-isomer of the alkaloid quinine and is one of the four most important alkaloids, which are isolated from the bark of the cinchona tree [1–3]. Quinidine is a secondary alcohol,

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the radicals in which are a 5-methyoxyquinoline ring and 3-vinylquinuclidine. Quinidine only differs from quinine in the configuration of the carbon atom of the carbinol group, and it can be made by isomerization of quinine (37.1.1.47) [4]. Quinidine is proposed to synthesize by different ways [5–7]. CH CH 2

H

H

N

HO C

HO C

CH 3O

CH CH 2 N

CH 3O N

N

37.1.1.47

18.1.1

Quinidine exhibits all of the pharmacological properties of quinine, including antimalarial, fever-reducing, and other properties. Quinidine is used in various forms of arrhythmia for preventing tachycardia and atrial fibrillation, and particularly for preventing ciliary fibrillation, paroxysmal supraventricular tachycardia, extrasystole, and ventricular tachycardia. However, it is a toxic drug and is used relatively rarely. It is also prescribed under the name cardioquin, duraquin, quinidex, and others. Procainamide: Procainamide, 4-amino-N-[2-(diethylamino)ethyl]benzamide (18.1.3), is synthesized by reacting 4-nitrobenzoic acid chloride with N,N-diethylethylendiamine and subsequent reduction of the nitro group of the resulting 4-nitro-N-[2-(diethylamino)ethyl]benzamide (18.1.2) into an amino group [8,9]. O2N

C 2H 5

C 2H 5 CO Cl

+

O2N

H 2N CH 2 CH 2 N C 2H 5

CO NH

CH 2 CH 2 N

18.1.2

C 2H 5

C 2H 5 H 2N

CO NH

CH 2 CH 2 N

18.1.3

C 2H 5

The chemical difference between procainamide and procaine lies in the replacement of the ester group with an amide group. The action of procainamide is qualitatively similar to the action of procaine. Its effect on the heart is identical to that of quinidine. As an antiarrhythmic, procainamide is preferred over procaine because unlike procaine, it is better absorbed when taken orally and it is more difficult for the esterases of the plasma to hydrolyze it, which results in long-lasting action. Procainamide is intended for treating paroxysmal atrial tachycardia, atrial fibrillation, premature ventricular contraction, and ventricular tachycardia. For quickly reaching therapeutic concentrations, parenternal introduction of procainamide is preferred over cynidine. Synonyms of this drug are amidoprocaine, cardiorythmine, novocainamide, pronestyl, and others. Disopyramide: Disopyramide, α-(2-diisopropylaminoethyl)-α-phenyl-2-pyridineacetamide (18.1.6), is synthesized by arylating benzylcyanide with 2-chloropiridine in the presence of sodium amide and subsequent alkylation of the resulting α-phenyl-α-(2-pyridyl) acetonitrile

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(18.1.4) with 2-diisopropylaminoethylchloride using sodium amide. Sulfuric acid hydrolysis of the resulting nitrile (18.1.5) leads to the formation of α-(2-diisopropylaminoethyl)α-phenyl-2-pyridineacetamide, disopyramide [10–12]. CH(CH 3)2 Cl CH 2 C N

CH(CH 3)2

NaNH 2

+ N

CH 2 CH 2 N

N C C H

Cl

N 18.1.4

CH(CH3)2 N C C

CH2 CH2 N CH(CH3)2

N 18.1.5

H2SO4

O H2N C

CH(CH3)2 C

CH2 CH2 N CH(CH3)2

N 18.1.6

Structurally, disopyramide does not belong to any of the known classes of antiarrhythmics; however, being a drug of the class IA sodium channel blockers, it exhibits membranestabilizing action and increases the effective refractory period and duration of an action potential in the atrium and ventricles. It causes a decrease in contractability and excitability of the myocardium, slowing of conductivity, and suppression of sinoatride automatism. Disopyramide is used for preventing and restoring atrial and ventricular extrasystole and tachycardia in order to prevent atrial flutter and arrhythmia. This drug is also prescribed under the name dicorantil, dimodan, napamid, norpace, rhythmilen, rhythmodan, and others.

18.1.2

Subgroup IB

Drugs of subgroup IB increase the electrical threshold of ventricular excitation during diastole, suppress automatism and diastolic depolarization, reduce the duration of the refractive period, and differ from drugs of subgroup IA in that if they block open Na⫹ channels, then drugs of subgroup IB mainly block inactive Na⫹ channels. This means that they have little effect on healthy regions of the myocardium because they are quickly eliminated from normal, open Na⫹ channels. In terms of myocardial ischemia, hypoxia causes cellular membranes to depolarize and arrhythmogenic centers to emerge. During this, many Na⫹ channels are inactivated and become sensitive to drugs of this class, which increase conductivity and reduce the repolarization time of heart cells. Drugs of subgroup IB have little effect on muscles of the atrium, arterioventricular conductivity, myocardial contraction, cardiac output, and systolic arterial pressure. Drugs of this subgroup—lidocaine, tocainide, and mexiletine are local anesthetics; however, they are used for severe ventricular arrhythmia that can originate during myocardial infarction, surgical intervention, catheterization of the heart, and intoxication by cardiac glycosides. Penytoin, which does not belong to the class of local anesthetics and is an anticonvulsant drug, is used only as an oral agent, thus replacing lidocaine in paroxysmal tachycardia caused by intoxication.

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Lidocaine: Lidocaine is 2-diethylamino-2⬘,6⬘-dimethylacetanilide (2.2.3). Synthesis of lidocaine is described in Chapter 2. CH 3 O NH CH 3

C 2H 5

C CH 2 N C 2H 5

2.2.3

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]. CH 3

CH 3

O NH 2

+

Br

CH 3 O

C CH CH 3

NH

Br CH 3

NH

C CH CH 3 Br

CH 3

O C CH CH 3 NH 2

CH 3 18.1.7

18.1.8

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 chloroacetone, forming 1-(2,6-dimethylphenoxy)-2-propanone (18.1.9). Reacting this with hydroxylamine gives the corresponding oxime (18.1.10). Reduction of the oximine group using hydrogen over Raney nickel gives mexiletine (18.1.11) [17–20]. CH 3

CH 3 O

ONa

+

Cl

O O CH 2

CH 2 C CH 3

CH 3

CH 3 OH

CH 3

N O CH 2 CH 3

C CH 3

18.1.10

-

NH 2OH

C CH 3

18.1.9 CH 3 NH 2

H 2 / Raney Ni

O CH 2 CH CH 3

CH 3

18.1.11

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.

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

N H O

N

O

H 9.1.1

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-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) [21–24]. CF 3CH 2

H O CF 3

O H 2N CH 2

SO2 CH 2 CF 3

O H CF 3CH 2

N

COO CH 2CF 3

COOH 18.1.12

O H 2 / Pd C COO

NH CH 2

O CH 2CF 3

N

O CH 2CF 3

CF 3CH 2

O COO

NH CH 2

N H

18.1.13

O CH 2CF 3

18.1.14

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

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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]-benzamide (18.1.15), is synthesized by acylating 2-(1-methyl-2-piperidylethyl)aniline with 4methoxybenzoic acid chloride. The chemical structure of encainide is substantially different than other local anesthetics and antiarrhythmics [25–27]. O

O Cl

NH 2 N

NH

+

OCH 3

OCH 3

N CH 3

CH 3

18.1.15

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. 18.2

GROUP II DRUGS

This group consists of β-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 β-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 β-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 antiarrhythmic drugs themselves can cause arrhythmia, especially in patients with ischemic heart disease. The examined β-adrenergic receptor blockers are an exception. Having said that, practically all β-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 β-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. OH

CH 3

O CH 2 CH CH 2 NH CH CH 3 12.1.3

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Propranolol has been studied most carefully in experiments and in clinics. It is used for ventricular tachycardia, arrhythmia caused by digitalis drug overdose, or as a result of thyrotoxosis or excess catecholamine activity. Despite the fact that there are a number of β-adrenoblockers, propranolol is considered the first choice of drugs although other blockers of calcium blockers can be just as effective. Propranolol slows heart rate, increases the effective refractory period of atrioventricular ganglia, suppresses automatism of heart cells, and reduces excitability and contractibility of the myocardium. It is used for supraventricular and ventricular arrhythmias. Synonyms of this drug are anaprilin, detensiel, inderal, novapranol, and others. 18.3

GROUP III DRUGS

Drugs of this group exhibit antiarrhythmic action, slow repolarization, and increase conductivity of potential action and effective refractory period in all parts of the heart. Amiodarone, a drug in this group, blocks some ion channels and α- and β-adrenergic receptors of the heart. They are used for treating ventricular arrhythmias, which do not respond to other antiarrhythmic drugs in life-threatening cases. Amiodarone: Amiodarone, 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone (18.1.21), is synthesized in the following manner. Benzofuran is acylated by butyric acid anhydride in the presence of phosphorous acid, forming 2-butyroylbenzfuran (18.1.16). Reduction of the carbonyl group in a Wolff–Kizhner reaction using hydrazine hydrate gives 2-butylbenzofurane (18.1.17). This is acylated with 4-methoxybenzoic acid chloride, giving 2-butyl-3-(4-methoxybenzoyl)benzofuran (18.1.18), which undergoes demethylation by pyridine hydrochloride, forming 2-butyl-3-(4-hydroxy-benzoyl)-benzofuran (18.1.19). The resulting product is iodized in the presence of potassium iodide, forming 2-butyl-3-benzofuranyl-4-(2-hydroxy-3,5-diiodophenyl) ketone (18.1.20), which is reacted further with 2-diethylaminoethylchoride, giving desired amiodarone (18.1.21) [28,29]. H 2NNH 2

H 3 PO 4

+ (C 3H 7 CO)2 O O

C 3H 7

O 18.1.16

O

CH 3O

O

. HCl

OCH 3

ClCO

O

C 4H 9

O

18.1.17

C 4H 9

18.1.18

HO

HO

(C 2H 5)2NCH 2CH 2O

I

I

O O 18.1.19

C 4H 9

N

I

I

O

I 2 / KI O 18.1.20

C 4H 9

O

(C 2H 5)2NCH 2CH 2Cl O 18.1.21

C 4H 9

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From the chemical point of view, amiodarone is completely different from other antiarrhythmics. It has two iodide atoms and a diethylaminoethanol group as substituents in the benzoyl part, and overall it is very similar to the structure of thyroxin-like molecules. Amiodarone’s antiarrhythmic action is connected to its ability to block K⫹, Na⫹, and Ca2⫹ channels while noncompetitively blocking α- and β-adrenergic receptors of the heart, thus prolonging the action potential and effective refractive period of atrial cells, atrioventricular junctions, and ventricles of the heart, which is accompanied by decreased automatism of sinus node and slowing of atrioventricular conductivity. Clinical use of amiodarone is limited because of its high toxicity, which consists of cardiac block, bradycardia, cardiac insufficiency, damaged thyroid gland function, neuropathology, and increased sensitivity to light, all of which significantly limit use of amiodarona, and it is only used in therapy for extremely serious tachyarrhythmias such as reoccurring ventricular fibrillation and hemodynamic unstable ventricular tachycardia, and only under supervision of a physician in a clinical situation. Synonyms of amiodarone are cordarone, rythmarone, and others. Bretylium: Bretylium, N-(o-bromobenzyl)-N-ethyl-N,N-dimethylammonium tosylate (18.1.22), is synthesized by reacting o-bromobenzyltosylate with ethyldimethylamine [30]. CH 2

OSO2

CH 3

CH 3 +

Br

CH 2

CH 3

N C 2H 5 CH 3

CH 3 + N C 2H 5

Br

CH 3

SO3

18.1.22

Bretylium is poorly absorbed when taken orally, and it is used only in the form of intravenous or intramuscular injections. However, like many other quaternary ammonium salts, it initiates a response of neuronal catechoamines, which can cause tachycardia, elevate blood pressure, and so on. Bretylium possesses sympatholytic action, which is associated with blockage of norepinephrine (noradrenaline) from presynaptic nerve endings. It also has a direct effect on ischemic myocytes. Bretylium is an urgent treatment that is used in situations of ventricular tachycardia and ventricular fibrillation, primarily in the severe phase of a myocardial infarction, during which use of other medications or procedures have proven unsuccessful. It requires great caution and should be used only in urgent situations. Synonyms of this drug are vretilol, ornid, and others.

18.4

GROUP IV DRUGS

Drugs of this group are calcium channel blockers that inhibit slow transmembrane calcium ion flow in the cell of the conductive system of the heart during depolarization, which causes a slowing of atrioventricular conductivity and increased effective refractive period of atrioventricular ganglia, which eventually leads to the relaxation of smooth muscle of heart musculature and restores normal sinus rhythm during supraventricular tachycardias. Today, this group is represented by a single calcium channel-blocking drug, verapamil, which is primarily used as an antianginal drug as well as for controlling hypertension.

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Verapamil: Synthesis of verapamil, 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4dimethoxyphenyl)isopropylvaleronitrile (19.3.15) will be described in Chapter 19. CH 3 O CH3 O

CH 3

CH 3 CH

O CH 3

C CH 2CH 2CH 2

N CH 2 CH 2

C N

CH 3

O CH 3

19.3.15

Verapamil is used as an antiarrythmic drug in treating supraventricular arrythmia such as paroxysmal atrial tachycardia, and for controlling atrial fibrillation. By blocking entrance of Ca2⫹ in the cell, verapamil exhibits a negative inotropic effect, and therefore it cannot be combined with β-adrenoblockers or cynidine since that would lead to an increased inotropic effect. Verapamil is primarily used as an antiarrythmic for treating ventricular arrhythmias; however, currently it is being forced out gradually by adenosine. Synonyms of this drug are isoptin, calan, finoptin, falicard, manidon, and many others.

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