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Antiarrhythmic Drugs
Gerda von Philipsborn, Knoll AG, Ludwigshafen, Federal Republic of Germany
Anton Oberdorf, Knoll AG, Ludwigshafen, Federal Republic of Germany
Fritz Binnig, Knoll AG, Ludwigshafen, Federal Republic of Germany
Albrecht Franke , BASF Aktiengesellschaft, Ludwigshafen, Federal Republic of Germany
1.2. Disorders of Cardiac Rhythm muscle. They trigger individual, premature heart
(Arrhythmias) beats, which are called extrasystoles. These may
occur either sporadically or frequently, irregu-
Diagnosis. Arrhythmias differ greatly in larly or firmly coupled to the normal rhythm
their etiology and symptoms. The most impor- of the heart. Polytopic extrasystoles originate
tant diagnostic tool is the electrocardiogram at several different foci simultaneously. De-
(ECG). pending on the anatomic position of the im-
The electrocardiogram reflects electrical po- pulse generation, extrasystoles are described
tential changes in the heart as a function of time. as supraventricular or ventricular. Supraven-
The potential differences originate from the so- tricular extrasystoles are triggered at points
called “action potentials” at all excitable cardiac above the His-Purkinje system. They include
cells (see Section 1.3); they are measured at vari- sinoidal, atrial, and atrioventricular extrasys-
ous sites on the body’s surface. For example, the toles. Ventricular extrasystoles originate in the
ECG in Figure 1 has been obtained from elec- His-Purkinje system or in the ventricular my-
trodes placed on the right arm and the left leg. ocardium.
A series of waves, designated P, Q, R, S, and Paroxysmal Tachycardia. Heterotopic disor-
T, is detected. The P – Q interval is the period ders of impulse generation also include sudden
between the beginning of the contraction of the and more or less prolonged phases of a highly ac-
atria and the beginning of the contraction of the celerated heart rate, which are known as parox-
ventricles. The QRS complex is caused by the ysmal tachycardias. Rapid regular impulse gen-
depolarization of the ventricles. The Q – T inter- eration (250 – 300/min) in the atrium is known
val reflects the duration of ventricular contrac- as atrial flutter. In this case, impulse conduction
tion. to the ventricles is disturbed. The same applies
A more accurate diagnosis of cardiac arrhyth- to atrial fibrillation, which is characterized by
mias is made possible by His bundle electrog- high-frequency (> 400/min) and irregular im-
raphy. In this method, the electrical activity of pulse generation. Because the ventricles may be
the heart is detected by intracardiac electrodes, refractory to most of these impulses, their ac-
which are inserted intravenously [5], [6]. In tivity becomes irregular; this results in absolute
addition, intermittent arrhythmias may be de- arrhythmia.
tected by 24-hour long-term electrocardiogra- Similar impulse-generation disorders may
phy (Holter monitoring) [7]. In certain types of also originate in the ventricles, namely ventric-
arrhythmias, auscultation of the heart sounds as ular flutter (with a frequency in most instances
well as palpation of the pulse in arteries and neck above 220/min) and ventricular fibrillation in
veins also provide information on the presence which irregular multifocal impulses occur si-
and type of arrhythmia. multaneously at high frequency. In ventricular
Arrhythmias are classified in two main flutter, the heart is still able to pump a small vol-
groups according to their etiology: disorders of ume of blood; in ventricular fibrillation, how-
impulse generation and disturbances of impulse ever, circulatory arrest occurs.
conduction.
Impulse-Conduction Disturbances. Im-
Disorders of Impulse Generation. Nomo- pulse transmission to lower sections of the heart
topic disorders involve the normal pacemaker, can be delayed or blocked at different points
i.e., the sinoatrial node. They occur either as si- of the conduction system. Atrial or ventricular
nus tachycardia (increased rate) or sinus brady- systoles can be blocked either partially or com-
cardia (reduced rate). Irregular functioning of pletely. In total sinoatrial block, sinus excitation
the sinus node also may cause sinus arrhyth- does not reach the atria and the ventricles at all.
mias. Impulse generation disorders are called Consequently, systoles cease until another pace-
heterotopic when the impulse originates not in maker situated at a lower level becomes active
the sinoatrial node but in one of the centers sub- as the automaticity center.
ordinate to it: in the AV node, at certain foci Intra-atrial disturbances affect impulse
in the ventricular conduction system with es- propagation within the atrial musculature. They
cape rhythms, or even at other sites of the heart
Antiarrhythmic Drugs 3
Figure 1. Normal ECG with bipolar recording from the body surface in the direction of the long axis of the heart
The times below the ECG curve are important limiting values for the durations of the parts of the curve [1].
are less significant provided regular conduction 1.3. Cardiac Action Potentials
to the ventricles remains intact.
However, atrioventricular block (AV block), In the heart, as in other excitable tissue, rest and
in which conduction between atria and ventricles excitation are accompanied by electrical phe-
is disturbed, is extremely important. Atrioven- nomena, the so-called action potentials, which
tricular block is characterized according to either are caused by ionic currents. The flow of ions
location or degree. In first-degree AV block, con- into and out of the cardiac cells is controlled
duction is still regular but in some cases delayed by changes in cell membrane permeability to
by several times the normal duration. In second- sodium, potassium, and calcium ions. For de-
degree AV block (incomplete AV block), conduc- tails, see [1–4], [6–9].
tion is interrupted sporadically or frequently. In Figure 2 shows transmembrane action poten-
third-degree AV block (total heart block) there tials of normal, nonautomatic cardiac cells, such
is no conduction of excitation between atria and as ventricular or atrial muscle cells (V), and of
ventricles. Both beat independently of one an- sinoatrial nodal cells (SA). Usually, five differ-
other, the atria generally at the sinus rate and the ent phases are distinguished [10].
ventricles about once every two seconds. In phase 0 rapid depolarization occurs on ex-
In intraventricular disturbances, impulse citation. The difference in membrane potential
conduction within the ventricular walls is de- decreases and the inside of the cell becomes
layed or interrupted. positive in relation to the outside during the
For more detailed information on causes and so-called overshoot. The ionic mechanism for
basic diseases, syndromes, diagnosis, therapy, phase 0 is an increase in sodium conductance.
and prognosis of cardiac arrhythmias, see [5–7],
[9].
4 Antiarrhythmic Drugs
Figure 3. Effects of various antiarrhythmic drugs on the ventricular action potential, the electrocardiogram, and the durations
of the effective refractory period (ERP), the relative refractory period (RRP), and the total action potential duration (APD)
[11].
The arabic numerals in parentheses indicate phases of the action potential1.3. The circles represent the level of repolarization
at which the fiber becomes reexcitable.
The classification of antiarrhythmic agents by channels of nerve fibers, which explains the
Vaughan Williams [12–14] (Table 1), is com- local-anesthetic effect of class I agents.
prised of four classes and three subgroups of Under block, the sodium channels may re-
class I; it is based primarily on electrophysio- cover quickly or slowly, depending on the
logical effects (class II is the exception). class of antiarrhythmic drug [15]. With class I b
Several of the drugs act in more than one of agents, such as lidocaine, phenytoin, tocainide,
the four ways; therefore, the classification does mexiletine, or sparteine, recovery time is less
not so much categorize the agents as it describes than 1 s. Therefore, this class of drugs can block
four ways in which abnormal cardiac rhythms premature and high-frequency excitation selec-
can be corrected or prevented. tively. With class I a or class I c agents, how-
ever, the recovery time of the sodium channels
Class I: Sodium Channel Blockers. All is longer (1 – 250 s); therefore, the blocking ef-
class I antiarrhythmic agents (I a, I b, and I c) fect also affects normal-frequency action poten-
decrease the rate of rise (upstroke velocity) of tials. This difference also is detected by ECG. In
phase 0 of the action potential by inhibiting the healthy heart, class I b antiarrhythmic agents
the rapid sodium influx. Under suitable condi- in therapeutic doses do not change the conduc-
tions these agents also can block the sodium tion times, whereas class I a and class I c agents
6 Antiarrhythmic Drugs
Table 1. Classification of antiarrhythmic drugs [14] , pp. 232, 234 [15]
lengthen the ECG times (Fig. 3). Some class I a In addition to this specific effect, high doses of β-
agents have an additional atropine-like effect. blockers also block membrane sodium channels
Occasionally this increases frequency and short- (membrane stabilizing effect). In antiarrhythmic
ens the P – Q interval. therapy, β-blockers are used primarily for tach-
The duration of the action potential and yarrhythmias resulting from sympathetic hyper-
the Q – T interval in the ECG are lengthened function or from increased catecholamine re-
by class I a agents (quinidine, procainamide, lease [17] (→ β-Receptor Blocking Agents).
disopyramide) and by some class I c agents
(ajmaline, propafenone) but are shortened by Class III: Agents That Increase Action
class I b agents (phenytoin, lidocaine, mexile- Potential Duration. Class III antiarrhythmic
tine). Phenytoin acts during repolarization: the agents lengthen the duration of the action poten-
membrane potential at which the fibers become tial without changing its rate of rise. The refrac-
reexcitable is shifted to a more negative value tory period of the heart fibers is therefore pro-
and the effective refractory period is lengthened longed. Currently, only three agents of this class
with respect to total action potential duration. are known: amiodarone, sotalol, and bretylium.
Class II: β-Receptor Blocking Agents. Class IV: Calcium Channel Blockers. Cal-
Two types of receptors exist in the sympathetic cium channel blockers also are known as cal-
nervous system: α- and β-receptors [16]. Stim- cium antagonists. In various excitable cells these
ulation of β-receptors produces increased sym- agents block the slow influx of calcium ions
pathetic activity of the heart, increasing contrac- through the cell membrane during excitation;
tility, oxygen consumption, and heart rate and the flow of sodium ions is not influenced. Cal-
accelerating impulse propagation. cium antagonists are applied chiefly in coronary
These effects are specifically, competitively, heart disease. Some of these substances also are
and reversibly blocked by β-receptor blockers. used in antiarrhythmic therapy: verapamil, gal-
Antiarrhythmic Drugs 7
In the United States procainamide is one of tant side effects are disturbances of the central
the most frequently used antiarrhythmics; in Eu- nervous system.
rope, it is of minor importance. Its mode of ac- Trade Names: Xylocain, Xylocaine, Xylo-
tion resembles that of quinidine. The substance card (Astra Chemicals); all preparations contain
may be administered parenterally and orally but lidocaine hydrochloride [73-78-9].
is only short acting. Side effects with longterm
therapy are gastrointestinal disturbances, agran- Phenytoin [57-41-0], 5,5-diphenylhydantoin,
ulocytosis, and lupus erythematosus. An antiar- C15 H12 N2 O2 , M r 252.3, mp 295 – 298 ◦ C.
rhythmic metabolite, acecainide page 13, was
detected in humans.
Trade Names: Novocamid (Hoechst), Pron-
estyl (Squibb) both contain procainamide hydro-
chloride.
Phenytoin is used primarily as an antiepilep-
Disopyramide [3737-09-5], (±)−4- tic. The compound finds its chief use as an an-
diisopro-pylamino-2- phenyl-2- (2-pyridyl) bu- tiarrhythmic in cases of cardiac glycoside over-
tyramide, C21 H29 N3 O, M r 339.5, mp 94.5 ◦ C. dosage. The effect of the substance is difficult
to control because of its long half-life. In addi-
tion, it has strong cardiac and extracardiac side
effects (gingival hyperplasia, osteomalacia, ane-
mia, hypertrichosis).
Trade Names: Dilantin, Epanutin (Parke
Davis), Phenydan (Desitin), Zentropil
Disopyramide has a pharmacological profile (Nordmark-Werke); all preparations contain
similar to that of quinidine and procainamide phenytoin sodium [630-93-3].
[26–29]. Clinically, it is active against most
forms of arrhythmias (supraventricular and ven- Tocainide [41708-72-9], (±)−2-amino-
tricular). However, the substance also can pro- N-(2,6-xylyl)propionamide, C11 H16 N2 O,
duce serious side effects, such as negative in- M r 192.1; the hydrochloride [35891-93-1] melts
otropic and hemodynamic effects, increased at 246 – 247.5 ◦ C.
oxygen consumption, and increased infarct size,
as well as anticholinergic activity.
Trade Names: Norpace (Searle), Rythmodan
(Roussel), Rythmodul (Albert Roussel), all con-
tain disopyramide phosphate [22059-60-5].
Tocainide corresponds to lidocaine in its ac-
tion profile and side effects. In contrast to li-
2.1.2. Class I b Drugs docaine it can be taken orally because it lacks
two ethyl groups that contribute to lidocaine’s
Lidocaine [137-58-6], lignocaine, N-(2,6- first-pass hepatic degradation after oral admin-
xylyl)-diethylaminoacetamide, C14 H22 N2 O, istration [27], [30], [31]. The substance has been
M r 234.4, mp 68 – 69 ◦ C. on the market in most European countries since
1981 – 1982.
Trade Names: Tonocard, Xyloctan (Astra
Chemicals); all preparations contain tocainide
hydrochloride.
Bunaftine [32421-46-8],
N-butyl-N-(2-diethylaminoethyl)-1-naphtha-
mide, C21 H30 N2 O, M r 326.7.
In addition to class IV effects, bepridil also
shows class I effects. The substance is active
against both supraventricular and ventricular ar-
rhythmias [56], [57].
Trade Name: Cordium (Lab. Mauverney);
contains bepridil hydrochloride monohydrate. Bunaftine is said to have a “quinidine-like”
effect.
Diltiazem [42399-41-7], Trade Name: Meregon (Malesci) contains
cis-(+)−3-acetoxy-5-(2-dimethylamino- bunaftine citrate.
ethyl)−2,3-dihydro-2-(4-methoxyphenyl)−1,5-
benzothiazepin-4(5H)-one, C22 H26 N2 O4 S, Moracizine [31883-05-3],
M r 414.5, mp 212 ◦ C (decomp.). ethyl[10-(3-morpholinopropionyl)phenothiazin-
2-yl]carbamate, C22 H25 N3 O4 S, M r 427.5,
mp 156 – 157 ◦ C.