Antiarrhythmic Drugs 1
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. Antiarrhythmic Drugs . . . . . . . . .
1.1. Physiology . . . . . . . . . . . . . . . . .
1.2. Disorders of Cardiac Rhythm (Ar-
rhythmias) . . . . . . . . . . . . . . . .
1.3. Cardiac Action Potentials . . . . . .
1.4. General Aspects of Pharmacology .
1.5. General Aspects of Chemistry . . . .
2. Individual Antiarrhythmic Drugs .
2.1. Class I Drugs: Sodium Channel
Blockers . . . . . . . . . . . . . . . . . .
2.1.1. Class I a Drugs . . . . . . . . . . . . . .
1. Antiarrhythmic Drugs
1.1. Physiology
Unimpaired functioning of the heart is the most
important requirement for the normal supply of
blood to all regions of the organism. The heart
rhythm is determined by the body’s changing re-
quirements for blood. This constant adjustment
is controlled by venous return from the body’s
periphery, which influences both the stroke vol-
ume of the individual heart beats and the con-
tractile force of the ventricular muscle. Heart
rate and contractile force are controlled by the
autonomic nervous system.
The individual heart beat begins with the
electrical excitation of the sinoatrial node (SA
node), a group of special pacemaker cells situ-
ated at the entrance of the superior vena cava.
The SA node generates impulses automatically;
their frequency is controlled largely by the au-
tonomic nervous system, although it also can
be affected by hormones, e.g., adrenaline, by
metabolic processes, and by wall tension. The
normal frequency of SA node excitation is about
70 – 80 impulses per minute. Within the heart,
excitation spreads via the conduction system
from the SA node to the atrial muscles and also to
the atrioventricular node, passes through it, and

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10.1002/14356007.a02 439
1 2.1.2. Class I b Drugs . . . . . . . . . . . . . . 8
1 2.1.3. Class I c Drugs . . . . . . . . . . . . . . 9
2.2. Class II Drugs: β-Receptor Block-
2 ing Agents . . . . . . . . . . . . . . 10
3
2.3. Class III Drugs: Agents Increasing
4
the Action Potential Duration . . . . 11
7
2.4. Class IV Drugs: Calcium Channel
7
Blockers . . . . . . . . . . . . . . . . . . 11
7 2.5. New Antiarrhythmic Drugs . . . . . 12
7 3. References . . . . . . . . . . . . . . . . . 13
travels along special fibers within the ventricular
walls (His-Purkinje system), thereby reaching
the ventricular muscle (working myocardium).
The atrioventricular node (AV node) is a sec-
ondary pacemaker; its natural frequency is lower
than that of the SA node (its intrinsic rhythm
is about 40 – 60 impulses per minute). Accord-
ingly, the higher frequency of the SA node de-
termines the normal heart beat. However, if the
SA node fails, the AV node can take over the
pacemaker function. A similar relationship ex-
ists between the AV node and the Purkinje fibers.
They also are capable of spontaneous rhythmic
activity if the AV node fails; however, their fre-
quency is at 15 – 40 impulses per minute.
Contraction of the heart muscle therefore is
the result of electrical, biochemical, and me-
chanical processes in the cell membranes and
within the myocardial cells (electromechanical
coupling). Blood is pumped by the contraction
of the heart wall muscles in coordination with
the functioning of the various heart valves. All
processes associated with the excitation and con-
traction of the heart are reversible. All the above-
mentioned phenomena and the automaticity of
the pacemakers, particularly the SA node, there-
fore enable the heart to function rhythmically.
For more information on the physiology of ex-
citation and contraction of the heart, see [1–4].
2 Antiarrhythmic Drugs
1.2. Disorders of Cardiac Rhythm
(Arrhythmias)
Diagnosis. Arrhythmias differ greatly in
their etiology and symptoms. The most impor-
tant diagnostic tool is the electrocardiogram
(ECG).
The electrocardiogram reflects electrical po-
tential changes in the heart as a function of time.
The potential differences originate from the so-
called “action potentials” at all excitable cardiac
cells (see Section 1.3); they are measured at vari-
ous sites on the body’s surface. For example, the
ECG in Figure 1 has been obtained from elec-
trodes placed on the right arm and the left leg.
A series of waves, designated P, Q, R, S, and
T, is detected. The P – Q interval is the period
between the beginning of the contraction of the
atria and the beginning of the contraction of the
ventricles. The QRS complex is caused by the
depolarization of the ventricles. The Q – T inter-
val reflects the duration of ventricular contrac-
tion.
A more accurate diagnosis of cardiac arrhyth-
mias is made possible by His bundle electrog-
raphy. In this method, the electrical activity of
the heart is detected by intracardiac electrodes,
which are inserted intravenously [5], [6]. In
addition, intermittent arrhythmias may be de-
tected by 24-hour long-term electrocardiogra-
phy (Holter monitoring) [7]. In certain types of
arrhythmias, auscultation of the heart sounds as
well as palpation of the pulse in arteries and neck
veins also provide information on the presence
and type of arrhythmia.
Arrhythmias are classified in two main
groups according to their etiology: disorders of
impulse generation and disturbances of impulse
conduction.
Disorders of Impulse Generation. Nomo-
topic disorders involve the normal pacemaker,
i.e., the sinoatrial node. They occur either as si-
nus tachycardia (increased rate) or sinus brady-
cardia (reduced rate). Irregular functioning of
the sinus node also may cause sinus arrhyth-
mias. Impulse generation disorders are called
heterotopic when the impulse originates not in
the sinoatrial node but in one of the centers sub-
ordinate to it: in the AV node, at certain foci
in the ventricular conduction system with es-
cape rhythms, or even at other sites of the heart
muscle. They trigger individual, premature heart
beats, which are called extrasystoles. These may
occur either sporadically or frequently, irregu-
larly or firmly coupled to the normal rhythm
of the heart. Polytopic extrasystoles originate
at several different foci simultaneously. De-
pending on the anatomic position of the im-
pulse generation, extrasystoles are described
as supraventricular or ventricular. Supraven-
tricular extrasystoles are triggered at points
above the His-Purkinje system. They include
sinoidal, atrial, and atrioventricular extrasys-
toles. Ventricular extrasystoles originate in the
His-Purkinje system or in the ventricular my-
ocardium.
Paroxysmal Tachycardia. Heterotopic disor-
ders of impulse generation also include sudden
and more or less prolonged phases of a highly ac-
celerated heart rate, which are known as parox-
ysmal tachycardias. Rapid regular impulse gen-
eration (250 – 300/min) in the atrium is known
as atrial flutter. In this case, impulse conduction
to the ventricles is disturbed. The same applies
to atrial fibrillation, which is characterized by
high-frequency (> 400/min) and irregular im-
pulse generation. Because the ventricles may be
refractory to most of these impulses, their ac-
tivity becomes irregular; this results in absolute
arrhythmia.
Similar impulse-generation disorders may
also originate in the ventricles, namely ventric-
ular flutter (with a frequency in most instances
above 220/min) and ventricular fibrillation in
which irregular multifocal impulses occur si-
multaneously at high frequency. In ventricular
flutter, the heart is still able to pump a small vol-
ume of blood; in ventricular fibrillation, how-
ever, circulatory arrest occurs.
Impulse-Conduction Disturbances. Im-
pulse transmission to lower sections of the heart
can be delayed or blocked at different points
of the conduction system. Atrial or ventricular
systoles can be blocked either partially or com-
pletely. In total sinoatrial block, sinus excitation
does not reach the atria and the ventricles at all.
Consequently, systoles cease until another pace-
maker situated at a lower level becomes active
as the automaticity center.
Intra-atrial disturbances affect impulse
propagation within the atrial musculature. They

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
to the ventricles remains intact.
However, atrioventricular block (AV block),
in which conduction between atria and ventricles
is disturbed, is extremely important. Atrioven-
tricular block is characterized according to either
location or degree. In first-degree AV block, con-
duction is still regular but in some cases delayed
by several times the normal duration. In second-
degree AV block (incomplete AV block), conduc-
tion is interrupted sporadically or frequently. In
third-degree AV block (total heart block) there
is no conduction of excitation between atria and
ventricles. Both beat independently of one an-
other, the atria generally at the sinus rate and the
ventricles about once every two seconds.
In intraventricular disturbances, impulse
conduction within the ventricular walls is de-
layed or interrupted.
For more detailed information on causes and
basic diseases, syndromes, diagnosis, therapy,
and prognosis of cardiac arrhythmias, see [5–7],
[9].
Antiarrhythmic Drugs 3
1.3. Cardiac Action Potentials
In the heart, as in other excitable tissue, rest and
excitation are accompanied by electrical phe-
nomena, the so-called action potentials, which
are caused by ionic currents. The flow of ions
into and out of the cardiac cells is controlled
by changes in cell membrane permeability to
sodium, potassium, and calcium ions. For de-
tails, see [1–4], [6–9].
Figure 2 shows transmembrane action poten-
tials of normal, nonautomatic cardiac cells, such
as ventricular or atrial muscle cells (V), and of
sinoatrial nodal cells (SA). Usually, five differ-
ent phases are distinguished [10].
In phase 0 rapid depolarization occurs on ex-
citation. The difference in membrane potential
decreases and the inside of the cell becomes
positive in relation to the outside during the
so-called overshoot. The ionic mechanism for
phase 0 is an increase in sodium conductance.
4 Antiarrhythmic Drugs
Figure 2. Action potentials of a ventricular muscle cell (V)
and a sinoatrial nodal cell (SA).
TP = Threshold potential
The first phase of repolarization (phase 1) is
quite rapid and is followed by a period of slow
repolarization (phase 2 or plateau). Repolariza-
tion speeds up again in phase 3 and completes
the process by returning the transmembrane po-
tential to the resting potential. The ionic mech-
anisms for repolarization are an increase in cal-
cium conductance (slow inward flow) and a de-
crease in potassium conductance. In ventricular
muscle cells, phase 4 is characterized by an elec-
trical quiescence in which depolarization cur-
rents and repolarization currents are in balance.
The action potentials of automatic cells, such
as those of the sinoatrial node, differ conspic-
uously from those of ventricular muscle cells:
First, the maximum diastolic potential reached
in these cells is less negative (−70 mV). Sec-
ond, the automatic SA nodal cells exhibit spon-
taneous diastolic depolarization. This is shown
by the gradual increase of transmembrane ac-
tion potential in phase 4. When the potential
difference reaches the threshold potential (TP;
about −50 mV in SA nodal cells), rapid de-
polarization (phase 0) occurs. This mechanism,
by which the heart generates its own impulse,
is called autorhythmicity. Finally, upstroke ve-
locity (phase 0) and amplitude are distinctly
smaller.
Further parameters of the transmembrane ac-
tion potential that are important in a discussion
of the mechanism of action of antiarrhythmic
drugs are:
1) Action potential amplitude: the total potential
change occurring during phase 0
2) Action potential duration (APD): the period
from the start of phase 0 to the end of phase 3
3) Conduction velocity: the speed at which a
stimulus or action potential is propagated
4) Automaticity: determined by the slope of
phase 4 (discussed previously)
5) Maximum upstroke velocity (V/s): the steep-
est slope of rise during phase 0
6) Excitability: dependent on the level of the
threshold potential
7) Effective refractory period (ERP): period of
repolarization during which no normal action
potential can be elicited, although a weak,
nonpropagated action potential can arise
8) Relative refractory period (RRP): period of
repolarization in which no propagated action
potential can arise
These parameters can be altered experimen-
tally by antiarrhythmic drugs. The therapeutic
antiarrhythmic activity of such drugs in humans
is associated with these changes also.
The most important antiarrhythmics are those
that inhibit pathologically accelerated impulse
generation and/or propagation, that is, any so-
called tachyarrhythmia. Such compounds are
also termed antifibrillatory drugs.
Bradyarrhythmias are disturbances of car-
diac rhythm caused by delayed or blocked im-
pulse generation and/or propagation; they are
rare. The bioelectrical phenomena of heart func-
tion insure that the heart always responds to
the more rapid pacemaker. Whenever impulse
generation in the SA node is delayed, nor-
mal cardiac function can be restored by im-
planting an electrical pacemaker. In emergen-
cies, but not in long-term therapy, sympath-
omimetic noradrenaline and parasympatholytic
atropine can be administered parenterally. Oral
β-sympathomimetics, such as isoprenaline and
orciprenaline, may be used until a pacemaker is
implanted.
1.4. General Aspects of Pharmacology
Antiarrhythmic agents act by changing the elec-
trical properties of the membrane of the heart
cell [11].
Figure 3 shows the characteristic changes
caused by various class I antiarrhythmic agents
in the ventricular action potential (Fig. 3 A), the
electrocardiogram (Fig. 3 B), the duration of the
effective refractory period (ERP), the relative re-
fractory period (RRP), and the total action po-
tential duration (APD; Fig. 3 C).
 Antiarrhythmic Drugs 5

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
Vaughan Williams [12–14] (Table 1), is com-
prised of four classes and three subgroups of
class I; it is based primarily on electrophysio-
logical effects (class II is the exception).
Several of the drugs act in more than one of
the four ways; therefore, the classification does
not so much categorize the agents as it describes
four ways in which abnormal cardiac rhythms
can be corrected or prevented.
Class I: Sodium Channel Blockers. All
class I antiarrhythmic agents (I a, I b, and I c)
decrease the rate of rise (upstroke velocity) of
phase 0 of the action potential by inhibiting
the rapid sodium influx. Under suitable condi-
tions these agents also can block the sodium
channels of nerve fibers, which explains the
local-anesthetic effect of class I agents.
Under block, the sodium channels may re-
cover quickly or slowly, depending on the
class of antiarrhythmic drug [15]. With class I b
agents, such as lidocaine, phenytoin, tocainide,
mexiletine, or sparteine, recovery time is less
than 1 s. Therefore, this class of drugs can block
premature and high-frequency excitation selec-
tively. With class I a or class I c agents, how-
ever, the recovery time of the sodium channels
is longer (1 – 250 s); therefore, the blocking ef-
fect also affects normal-frequency action poten-
tials. This difference also is detected by ECG. In
the healthy heart, class I b antiarrhythmic agents
in therapeutic doses do not change the conduc-
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]

Generic name Mode of action ECG changes ∗

Heart P–Q ∗∗ QRS ∗∗ Q–T ∗∗

rate interval duration interval

Class I a: quinidine sodium channel blockade inc. (inc.) inc. inc.

procainamide by classes I a, I b, I c; (dec.)
disopyramide rate of rise of phase 0
Class I b: lidocaine of action potential: dec. - - -
phenytoin delayed by I a, I b, I c;
tocainide action potential duration:
sparteine shortened by I b,
mexiletine not changed or prolonged
Class I c: ajmaline by I a and I c dec. inc. inc. -
prajmalium
aprindine
lorcainide
flecainide
propafenone
Class II: propranolol β-receptor blockade dec. inc. - -
and all other
β-blockers
Class III: amiodarone prolongation of action dec. - - inc.
sotalol potential duration
bretylium
Class IV: verapamil calcium channel blockade; dec. inc. - -
gallopamil action potential (SA node
diltiazem and AV node) duration
bepridil and plateau shortened

∗ dec., decrease; inc., increase; -, no or little change; ( ), change not pronounced.

∗∗ for definition, see 1.2.

lengthen the ECG times (Fig. 3). Some class I a
agents have an additional atropine-like effect.
Occasionally this increases frequency and short-
ens the P – Q interval.
The duration of the action potential and
the Q – T interval in the ECG are lengthened
by class I a agents (quinidine, procainamide,
disopyramide) and by some class I c agents
(ajmaline, propafenone) but are shortened by
class I b agents (phenytoin, lidocaine, mexile-
tine). Phenytoin acts during repolarization: the
membrane potential at which the fibers become
reexcitable is shifted to a more negative value
and the effective refractory period is lengthened
with respect to total action potential duration.
In addition to this specific effect, high doses of β-
blockers also block membrane sodium channels
(membrane stabilizing effect). In antiarrhythmic
therapy, β-blockers are used primarily for tach-
yarrhythmias resulting from sympathetic hyper-
function or from increased catecholamine re-
lease [17] (→ β-Receptor Blocking Agents).
Class III: Agents That Increase Action
Potential Duration. Class III antiarrhythmic
agents lengthen the duration of the action poten-
tial without changing its rate of rise. The refrac-
tory period of the heart fibers is therefore pro-
longed. Currently, only three agents of this class
are known: amiodarone, sotalol, and bretylium.

Class II: β-Receptor Blocking Agents.
Two types of receptors exist in the sympathetic
nervous system: α- and β-receptors [16]. Stim-
ulation of β-receptors produces increased sym-
pathetic activity of the heart, increasing contrac-
tility, oxygen consumption, and heart rate and
accelerating impulse propagation.
These effects are specifically, competitively,
and reversibly blocked by β-receptor blockers.
Class IV: Calcium Channel Blockers. Cal-
cium channel blockers also are known as cal-
cium antagonists. In various excitable cells these
agents block the slow influx of calcium ions
through the cell membrane during excitation;
the flow of sodium ions is not influenced. Cal-
cium antagonists are applied chiefly in coronary
heart disease. Some of these substances also are
used in antiarrhythmic therapy: verapamil, gal-

lopamil, diltiazem, and bepridil. Their antiar-
rhythmic effect is based on prolongation of the
impulse conduction in the AV node and to a
lower degree on inhibition of the impulse gen-
eration in the sinus node. They act especially on
tachyarrhythmias that originate in the atria (see
also → Calcium Antagonists).
1.5. General Aspects of Chemistry
Class I antiarrhythmic agents belong to two
groups: N-substituted carboxamides and ajma-
line derivatives. The group of N-substituted car-
boxamides includes lidocaine, tocainide, pro-
cainamide, disopyramide, lorcainide, flecainide,
bunaftine, and encainide; mexiletine usually is
included because of its similar structure. An-
tiarrhythmic drugs of the second group include
the ajmaline-type alkaloids and such derivatives
as prajmalium, detajmium, and lorajmine, as
well as quinidine and sparteine. Some other sub-
stances, e.g., phenytoin and aprindine, do not fit
into either group.
All N-substituted carboxamides have three
features in common: a lipophilic aromatic group,
an aliphatic spacer group, and an amino sub-
stituent. Lipophilicity is crucial for nonspecific
interaction with the alkyl chains of the mem-
brane’s phospholipids. Together with the ami-
no group, which can be protonated at physio-
logical pH values, this seems to be the molec-
ular requirement for antiarrhythmic activity in
this group of compounds. The molecular inter-
action between these drugs and the membrane
and quantitative structure – activity relations of
antiarrhythmic agents are described in more de-
tail in [18].
The class II antiarrhythmic agents (β-
receptor blockers) virtually all belong to
the group of aryloxyaminopropanols (→ β-
Receptor Blocking Agents). As mentioned
above, these compounds can even initiate a
membrane-stabilizing effect if administered in
relatively high concentrations. Predominantly
the l-isomers of the β-receptor blockers show β-
adrenolytic activity; the membrane-stabilizing
effect is observed in both isomers and depends
on the lipophilicity of the compounds [19], [20].
Structure – activity relationships are not ev-
ident in class III and class IV antiarrhythmic
agents.
Antiarrhythmic Drugs 7
2. Individual Antiarrhythmic Drugs
[6], [7], [9], [15], [21–24]
2.1. Class I Drugs: Sodium Channel
Blockers
2.1.1. Class I a Drugs
Quinidine [56-54-2], (+)-(αS)-α-(6-
methoxy-4-quinolyl)-α-[(2R,4S,5R)-(vinylqui-
nuclidin-2-yl)]methanol, C20 H24 N2 O2 , M r
324.4, mp 174 – 175 ◦ C.
Quinidine is one of the most widely applied
antiarrhythmics and has been used for 30 years.
It is used primarily against atrial flutter and fib-
rillation and against heterotopic extrasystoles.
Quinidine generally is administered orally,
although slow intravenous administration also
is possible [25]. Quinidine is the prototype of
class I antiarrhythmics; therefore, substances in
this group also are called “quinidine-like.” How-
ever, it differs, for example, from lidocaine by
the following effects: it increases the duration
of the action potential, in the ECG it increases
QRS duration and Q – T interval, and the refrac-
tory period is markedly prolonged. Quinidine
can accelerate the impulse conduction rate in the
AV node (atropine-like effect). Side effects in-
clude gastrointestinal disturbances and allergic
reactions.
Trade Names: Chinidin, Kinidin (Astra
Chemicals) contain quinidine hydrogen sul-
fate [747-45-5]; Duraquin (Parke-Davis),
Quinaglute (Berlex) contain quinidine gluconate
[7054-25-3].
Procainamide [51-06-9], 4-amino-N-(2-
diethylaminoethyl)benzamide, C13 H21 N3 O, M r
235.3; the hydrochloride [614-39-1] melts at
165 – 169 ◦ C.
8 Antiarrhythmic Drugs
In the United States procainamide is one of
the most frequently used antiarrhythmics; in Eu-
rope, it is of minor importance. Its mode of ac-
tion resembles that of quinidine. The substance
may be administered parenterally and orally but
is only short acting. Side effects with longterm
therapy are gastrointestinal disturbances, agran-
ulocytosis, and lupus erythematosus. An antiar-
rhythmic metabolite, acecainide page 13, was
detected in humans.
Trade Names: Novocamid (Hoechst), Pron-
estyl (Squibb) both contain procainamide hydro-
chloride.
Disopyramide [3737-09-5], (±)−4-
diisopro-pylamino-2- phenyl-2- (2-pyridyl) bu-
tyramide, C21 H29 N3 O, M r 339.5, mp 94.5 ◦ C.
Disopyramide has a pharmacological profile
similar to that of quinidine and procainamide
[26–29]. Clinically, it is active against most
forms of arrhythmias (supraventricular and ven-
tricular). However, the substance also can pro-
duce serious side effects, such as negative in-
otropic and hemodynamic effects, increased
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].
2.1.2. Class I b Drugs
Lidocaine [137-58-6], lignocaine, N-(2,6-
xylyl)-diethylaminoacetamide, C14 H22 N2 O,
M r 234.4, mp 68 – 69 ◦ C.
Lidocaine is used both as a local anesthetic
and as an antiarrhythmic. As an antiarrhythmic it
is administered only parenterally as an infusion
because it has a short half-life. The most impor-
tant side effects are disturbances of the central
nervous system.
Trade Names: Xylocain, Xylocaine, Xylo-
card (Astra Chemicals); all preparations contain
lidocaine hydrochloride [73-78-9].
Phenytoin [57-41-0], 5,5-diphenylhydantoin,
C15 H12 N2 O2 , M r 252.3, mp 295 – 298 ◦ C.
Phenytoin is used primarily as an antiepilep-
tic. The compound finds its chief use as an an-
tiarrhythmic in cases of cardiac glycoside over-
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
(Nordmark-Werke); all preparations contain
phenytoin sodium [630-93-3].
Tocainide [41708-72-9], (±)−2-amino-
N-(2,6-xylyl)propionamide, C11 H16 N2 O,
M r 192.1; the hydrochloride [35891-93-1] melts
at 246 – 247.5 ◦ C.
Tocainide corresponds to lidocaine in its ac-
tion profile and side effects. In contrast to li-
docaine it can be taken orally because it lacks
two ethyl groups that contribute to lidocaine’s
first-pass hepatic degradation after oral admin-
istration [27], [30], [31]. The substance has been
on the market in most European countries since
1981 – 1982.
Trade Names: Tonocard, Xyloctan (Astra
Chemicals); all preparations contain tocainide
hydrochloride.
Mexiletine [31828-71-4], (±)-1-methyl-
2-(2,6-xylyloxy)ethylamine, C11 H17 NO,
M r 179.3; the hydrochloride [5370-01-4] melts
at 203 – 205 ◦ C.

Mexiletine is effective both parenterally and
orally [32], [33]. Because the substance has a
large distribution volume, a high initial dose is
necessary. Side effects include bradycardia and
disturbances of the central nervous system.
Trade Name: Mexitil (Boehringer Ingel-
heim) contains mexiletine hydrochloride.
Sparteine [90-39-1], dodecahydro-7,14-
methano-2H, 6H-dipyrido-[1,2-a : 1 ,2 -e]
[1,5]diazocine, C15 H26 N2 , M r 234.4, bp 173 ◦ C
(at 11 kPa).
Sparteine is effective against sinoatrial and
atrial tachycardias, atrial extrasystoles, and also
against ventricular arrhythmias [34]. Despite
prolongation of the myocardial refractory period
in vitro, the ECG times are not prolonged in vivo.
Pregnancy in the last trimester is a contraindi-
cation because the substance can induce labor
through increased smooth muscle tone.
Trade Name: Depasan (Giulini) contains
sparteine sulfate [299-39-8].
2.1.3. Class I c Drugs
Ajmaline [4360-12-7], (17R,21R)-ajmalan-
17,21-diol, C20 H26 N2 O2 , M r 326.4, mp 195 ◦ C
(decomp.).
Ajmaline is active against both ventricular
and supraventricular arrhythmias [35–37]. Un-
like quinidine, procainamide, and disopyramide,
ajmaline has no anticholinergic activity and
Antiarrhythmic Drugs 9
shows only a weak negative inotropic effect.
The preferred route of application is slow in-
travenous infusion because oral bioavailability
varies greatly among individuals. Side effects
include disturbances of the central nervous sys-
tem and intrahepatic cholestasis.
Trade Names: Cardiorythmine (Servier),
Gilurytmal (Giulini).
Prajmalium bitartrate [2589-47-1], 4-pro-
pylajmalium hydrogen tartrate, C27 H38 N2 O8 ,
M r 518.6, mp 133 ◦ C (decomp.).
With at least five times the potency of ajma-
line, prajmalium is a most effective antiarrhyth-
mic, and it is superior to ajmaline in its reliable
oral effect and sustained action [37–39]. The ac-
tivity profile of prajmalium is very similar to
that of ajmaline, although the sodium channels
are blocked much longer by it than by any other
class I antiarrhythmic [15].
Trade Name: Neo-Gilurytmal (Giulini).
Detajmium bitartrate [53862-81-0], 4-(3-
dimethylamino-2-hydroxypropyl)ajmaline hy-
drogen tartrate, C31 H47 N3 O9 , M r 605.7, mp
123 – 125 ◦ C.
Detajmium is comparable to ajmaline but
shows better oral activity. In potency it ranges
between ajmaline and prajmalium [40].
Trade Name: Tachmalor (VEB Arzneimit-
telwerk, Dresden).
10 Antiarrhythmic Drugs
Aprindine [37640-71-4], N-(3-diethylami-
nopropyl)-N-indan-2-ylaniline, C22 H30 N2 , M r
322.5; the hydrochloride [33237-74-0] melts at
120 ◦ C.
Aprindine has a sustained activity. Because of
serious side effects (agranulocytosis), aprindine
should only be used for life-threatening arrhyth-
mias otherwise refractory to therapy [27].
Trade Names: Amidonal (Madaus), Fibocil
(Lilly), Fiboran (Christiaens); all preparations
contain aprindine hydrochloride.
Lorcainide [59729-31-6], 4 -chloro-N-(1-
isopropyl-4-piperidyl)−2-phenylacetanilide,
C22 H27 ClN2 O, M r 370.9; the hydrochloride
[58934-46-6] melts at 263 ◦ C.
Like lidocaine, lorcainide acts primarily on
ventricular arrhythmias but is stronger and also
orally effective [41], [42]. Side effects include
insomnia and gastrointestinal disturbances.
Trade Name: Remivox (Janssen) contains
lorcainide hydrochloride.
Flecainide [54143-55-4], (±)-N-(2-
piperidylmethyl)−2,5-bis-(2,2,2-trifluoro-
ethoxy)benzamide, C17 H20 F6 N2 O3 , M r 414.4;
the hydrochloride [54143-55-4] melts at
228 – 229 ◦ C.
Flecainide is effective if administered intra-
venously 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. Fle-
cainide shows few side effects; it does not affect
the central nervous system [29], [43]. The sub-
stance has been used increasingly since it was
first put on the market in 1982.
Trade Name: Tambocor (Kettelhack Riker)
contains flecainide acetate [54143-56-5].
Propafenone [54063-53-5], (±)−2 -
(2-hydroxy-3-propylaminopropoxy)−3-
phenylpropiophenone, C21 H27 NO3 , M r 341.5;
the hydrochloride [34183-23-8] melts at
173 – 174 ◦ C.
Propafenone has not only pronounced class I
effects but also class II (structure related) and
class IV activities [44–46]. Accordingly, it has
a broad spectrum of activity against ventricular
and supraventricular arrhythmias. Propafenone
can be administered intravenously and orally;
it is well suited for long-term anitiarrhythmic
treatment [9] and has been increasingly used
since it was first marketed in Germany in 1978.
Trade Name: Rytmonorm (Knoll) contains
propafenone hydrochloride.
2.2. Class II Drugs: β -Receptor
Blocking Agents
For more information, → β-Receptor Blocking
Agents.
Propranolol [525-66-6], (±)−1-isopro-
pylamino-3-(1-naphthyloxy)-propan-2-ol,
C16 H21 NO2 , M r 259.3; the hydrochloride
[318-98-9] melts at 163 – 164 ◦ C,
Major indications of propranolol, and of
many other β-blockers, include coronary heart
disease, hypertension, and cardiac arrhythmias.
These β-blocking agents are mainly used in
arrhythmias accompanied by increased cate-
cholamine levels, e.g., excitement, stress, or hy-
perthyroidism [17].
Trade Names: Dociton, Inderal (ICI) contain
propranolol hydrochloride.

2.3. Class III Drugs: Agents Increasing
the Action Potential Duration
Amiodarone [1951-25-3], (2-butylbenzofuran-
3-yl)-[4-(2-diethylaminoethoxy)−3,5-diiodophe-
nyl]ketone, C25 H29 I2 NO3 , M r 645.3; the
hydrochloride [19774-82-4] melts at 161 ◦ C.
Amiodarone was introduced as a coronary
therapeutic agent more than 20 years ago. Later,
its antiarrhythmic activity was discovered [47–
49]. Amiodarone increases the duration of the
refractory period and is active against supraven-
tricular as well as ventricular arrhythmias. Its
therapeutic spectrum is relatively broad. The
full activity of amiodarone only develops after
10 – 15 d of treatment. The drug is active up to
45 d after it is discontinued. Side effects include:
microcrystalline deposits in the cornea in 90 %
of the cases, impaired thyroid function, and pho-
tosensitivity.
Trade Names: Cordarex, Cordarone (Labaz),
both contain amiodarone hydrochloride.
Sotalol [3930-20-9], (±)−4 -(1-hydroxy-
2-isopropylaminoethyl)methanesulfoanilide,
C12 H20 N2 O3 S, M r 272.4; the hydrochloride
[959-24-0] melts at 207 ◦ C.
Sotalol acts as an antiarrhythmic by β-
receptor blockade as well as by prolonging the
action potential duration in atrium and ventricle
and the refractory period in atrium and AV node
[48]. Activity against supraventricular and ven-
tricular arrhythmias was demonstrated. The sub-
stance has the typical side effects of β-blockers.
Trade Names: Beta-Cardone (Duncan,
Flockhart), Sotalex (Lappe), Sotazide (Bristol-
Meyers Pharmaceuticals), all preparations con-
tain sotalol hydrochloride.
Bretylium tosylate [61-75-6], 2-bromo-
benzyl (ethyl) dimethylammonium toluene-
4-sulfonate, C18 H24 BrNO3 S, M r 414.4,
mp 97 – 99 ◦ C.
Antiarrhythmic Drugs 11
Bretylium tosylate is reported to be effec-
tive in the acute control of recurrent ventricular
tachycardia and even fibrillation [48], [50]. The
drug is contraindicated in arrhythmias caused by
digitalis intoxication.
Trade Names: Bretylol (American Critical
Care), Bretylate (Wellcome).
2.4. Class IV Drugs: Calcium Channel
Blockers
The main application of calcium antagonists is
the treatment of coronary heart disease. The sub-
stances mentioned below also are active against
arrhythmias.
Verapamil [52-53-9], (±)−5-[N-
(3,4-dimethoxyphenethyl)-N-methylami-
no]−2-(3,4-dimethoxyphenyl)−2-isopro-
pylvaleronitrile, C27 H38 N2 O4 , M r 454.6;
the hydrochloride [152-11-4] melts at
139.5 – 140.5 ◦ C.
Verapamil, the classic calcium antagonist,
has a negative inotropic, anti-ischemic, and
conduction-delaying effect on the heart [27],
[51–54]. Its antiarrhythmic effect is based pri-
marily on a prolongation of impulse conduction
time in the AV node and a reduction of frequency
of impulse generation in the SA node. Vera-
pamil has a very strong effect against paroxys-
mal supraventricular arrhythmias, although ac-
tivity against ischemic ventricular arrhythmias
has been demonstrated also [51]. The most im-
portant side effect is decreased blood pressure.
Trade Names: Isoptin (Knoll), Securon
(Knoll Ltd.), Calan (Searle), Cardibeltin
(Pharma Schwarz), Cordilox (Abbott); all prepa-
rations contain verapamil hydrochloride.
12 Antiarrhythmic Drugs

Gallopamil [16662-47-8], 2.5. New Antiarrhythmic Drugs

(±)−5-[N-(3,4-dimethoxyphenethyl)-N-
methylamino]−2-(3,4,5-trimethoxyphenyl)−2- Only limited clinical experience exists for these
isopropylvaleronitrile, C28 H40 N2 O5 , M r 484.7; drugs.
the hydrochloride [16662-46-7] melts at
145 – 148 ◦ C. Encainide [37612-13-8],
(±)−2 -[2-(1-methyl-2-piperidyl)ethyl]-
p-anisanilide, C22 H28 N2 O2 , M r 352.2,
mp 131.5 – 132.5 ◦ C.

Gallopamil has a distinctly stronger effect

than verapamil but a similar activity profile [54],
[55].
Trade Name: Procorum (Chemische Werke
Minden); contains gallopamil hydrochloride. Encainide is a membrane-active class I c
agent with complex metabolism and clinical
Bepridil [74764-40-2], N-(3-isobutoxy-2-
pharmacology [60], [61]. To date, its effective-
pyrrolidin-1-ylpropyl)-N-phenylbenzylamine,
ness has been proved against ventricular arrhyth-
C24 H34 N2 O, M r 366.3; the hydrochloride
mias. Side effects include central nervous sys-
monohydrate melts at 88 – 90 ◦ C.
tem activity.
Trade Name: Enkade (Bristol-Meyers).

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.
Diltiazem [42399-41-7],
cis-(+)−3-acetoxy-5-(2-dimethylamino-
ethyl)−2,3-dihydro-2-(4-methoxyphenyl)−1,5-
benzothiazepin-4(5H)-one, C22 H26 N2 O4 S,
M r 414.5, mp 212 ◦ C (decomp.).
Bunaftine [32421-46-8],
N-butyl-N-(2-diethylaminoethyl)-1-naphtha-
mide, C21 H30 N2 O, M r 326.7.
Bunaftine is said to have a “quinidine-like”
effect.
Trade Name: Meregon (Malesci) contains
bunaftine citrate.
Moracizine [31883-05-3],
ethyl[10-(3-morpholinopropionyl)phenothiazin-
2-yl]carbamate, C22 H25 N3 O4 S, M r 427.5,
mp 156 – 157 ◦ C.

Like verapamil and gallopamil, diltiazem has

both vascular (antihypertensive) and cardiac (an-
tianginal) activities and shows antiarrhythmic
activity similar to these drugs [58], [59].
Trade Names: Dilzem (Gödecke), Herbesser
(Tanabe), Cardizem (Marion); all preparations
contain diltiazem hydrochloride [33286-22-5].
Moracizine is said to have an activity similar
to but stronger than quinidine. Gastrointestinal
and neurological side effects are observed rarely
[27], [62].

Trade Name: Ethmozine (Riga Pharmaceuti-
cal “Alaine Pharm,” USSR).
Lorajmine [47562-08-3], ajmaline-17-
chloroacetate, C22 H27 ClN2 O3 , M r 402.9.
In electrophysiological studies, lorajmine has
been shown to exert a lidocaine-like (class I b)
rather than an ajmaline-like (class I c) effect
[63].
Trade Names: Ritmos Elle (Inverni della
Beffa), Viaductor (Lab. Servier); both contain
lorajmine hydrochloride [40819-93-0].
Acecainide [34118-92-8], 4-acetylami-
no-N-[2-(diethylamino)ethyl]benzamide,
C15 H23 N3 O2 , M r 315.65; the hydrochloride
melts at 190 – 193 ◦ C.
Acecainide, a main metabolite of pro-
cainamide, is a class I a antiarrhythmic agent
[64].
Trade Name: Napa (Medco).
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