The Journal of Clinical Pharma - April 1984 - WILLIAMS - A Classification of Antiarrhythmic Actions Reassessed After A

J C/in Pharmacol. 1984; 24:129-147.
A Classification of AntiarrhythmicActions
ReassessedAfter a Decadeof NewDrugs
E. M. VAUGHAN WILLIAMS, D.M., D.Sc., F.R.C.P. Oxford, England
D URING the past decade, antiarrhyth- terfering

which
specifically
depolarizing
with
charge
the
is
process
transferred
by
mic drugs have been presented at a
frequency of one new compound about across the membrane,”3 (i.e., by fast inward
every six months. Some were developed for depolarizing current carried by sodium
quite different roles-mexiletine, for exam- ions). The effect was revealed as a depres-
ple, as an antiepileptic, melperone as a sion of the maximum rate of depolarization
tranquillizer-and were later discovered to (MRD), unless the interstimulus interval
have antiarrhythmic properties in the was so long that it permitted full recovery
heart. All of them, however, have been between beats. Sodium channels are rap-
found to possess one or more of four actions idly inactivated after depolarization and
upon which a classification of antiarrhyth- remain in the inactivated state until re-
mic drugs was based more than ten years polarization proceeds to voltages more
ago.12 A review of the attributes of all these negative than about -55 mV. It was sug-
agents would occupy a substantial volume, gested that the (class 1) antiarrhythmic
and attention will be confined here to dis- drugs interfered with the process by which
cussing the evidence for and against the Na channels were “reactivated in response
view that four particular properties are re- to repolanzation” and that in consequence
sponsible for antiarrhythmic effects. Sev- they “extended the effective refractory pe-
eral of the drugs studied had more than one riod to a point long after the time at which
of the four actions, so that it deserves em- repolarization was already complete.”3 The
phasis that the classification is not so much concept that these drugs were combined
categorization of drugs, in accordance with with the sodium channels in their inacti-
chemical structures or physical properties, vated form (i.e., after depolarization) was
but describes four ways in which abnormal supported by the very early finding that the
cardiac rhythms can be corrected or pre- compounds were more potent the faster the
vented. driving frequency.45

That this, historically the first, class of
Class 1 Antiarrhythmic Action action was responsible for the antiarrhyth-
The first class of action was that exerted mic effects was not universally accepted,
by quinidine and a number of other reme- and indeed Bigger and Mandel concluded
dies3 which, incidentally, at 10 to 100 times from their studies that “the results caused
us to reject the hypothesis that lidocaine
their antiarrhythmic concentrations be-
haved as local anesthetics in nerves. These exerts electrophysiological effects essen-
compounds, though differing in other re- tially like those of procainamide or quini-
spects, had in common the property of “in- dine.”6 Davis and Temte, discussing the ef-
fects of lidocaine and diphenylhydantoin
From the University Department of Pharmacology, Ox-
ford. Based on a lecture given at the Squibb Institute for
(DPH), concluded that “a reduction in ris-
Medical Research, Princeton, N.J., September 30, 1983. ing velocity is not a necessary feature for
April 1984 129

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VAUGHAN WILLIAMS
antiarrhythmic activity.”7 On the contrary, shorten action potential duration (APD) in

they concluded that “the most significant the ventricular conduction pathway, espe-
effect of lidocaine with regard to its antiar- cially in the preterminal Purkinje fibers, in
rhythmic action is the prevention of decre- which APD is normally much longer than
mental conduction in Purkinje fibers.” in the His bundle or ventricular muscle.
They considered that diphenylhydantoin Rosen et al.’4 observed that procainamide
(DPH) and propranolol acted in the same also acts preferentially on APD in the ven-
way as lidocaine. Bassett and Hoffman tricular conducting system “in such a way
also took the view that “DPH and lidocaine that a greater similarity of contour between
may abolish a re-entrant rhythm by im- proximal, gate [preterminal] and distal
proving conduction. DPH either increases sites developed than had existed under con-
or does not substantially alter membrane trol.” While heterogeneity of APD within a
responsiveness and conduction velocity.”8 block of myocardium may be arrhythmo-
There are two reasons why it might be genic, the long APD in preterminal Pur-
concluded that therapeutic concentrations kinje cells may have a protective function
of lidocaine would be insufficient to reduce against retrograde “backfiring”. Thus abo-
the rate of depolarization (MRD). The first lition of the disparity between preterminal
is that if the extracellular potassium con- and terminal cells is not necessarily bene-
centration is low, the resting potential will ficial. Nevertheless the finding of the dif-
be hyperpolarized and the depressant effect ferential shortening of APD by lidocaine
on MRD will be nullified.9 The second is led Wittig and his colleagues’5 to suggest
that lidocaine delays recovery from inacti- that the shortening of APD could constitute
vation, but for a brief period only, so that if an antiarrhythmic action. Premature ac-
the interval between action potentials is tion potentials, conducting slowly before
long, no effect on MRD will be seen.’#{176}Both the drug because they “took off’ from par-
these points are of clinical significance, be- tially depolarized tissue, would conduct
cause lidocaine may be ineffective in pa- more rapidly after the drug, because they
tients in whom, perhaps as a result of diu- would, as a result of the shortening of APD,
retic therapy, serum potassium has fallen.’1 be initiated from fully repolarized cells.
Secondly, even when no effect on H-V con- There are several reasons for not accept-
duction time or QRS is apparent in sinus ing this hypothesis. (1) Although it is sim-
rhythm, the class 1 effect of lidocaine could ple enough experimentally to select an ap-
nevertheless be responsible for depressing propriate interstimulus (S,-S2) interval to
or eliminating the conduction of premature ensure that the premature response to S2
ventricular beats or for slowing a ventricu- takes off from partially repolarized mem-
lar tachycardia. Recently, El-Sherif and branes in the stimulated region, to select
Lazzara studied experimentally induced re- the S,-S2 interval at a remote site (e.g., in
entrant ventricular arrhythmias in the late the bundle of His) to ensure that the second
myocardial infarction period in dogs, and action potential takes off from partially
found that at the time when lidocaine’2 and depolarized cells in the distal Purkinje sys-
DPH’3 exerted an antiarrhythmic action, tem may be made more difficult by varia-
the effect of both drugs was to slow conduc- tions in conduction time of the first and
tion. They concluded that “there is cur- second action potentials. (2) Because the
rently no basis to substantiate the concept second action potential conducts more
that both DPH and lidocaine can abolish slowly, it will lag behind the first, so that it
re-entrant rhythms by improving conduc- may again take off from a fully repolarized
tion in the re-entrant pathway.” membrane, and would then conduct as rap-
Another complicating factor is that some idly as the first. (3) There is no evidence
drugs, notably lidocaine and mexiletine, that premature action potentials occurring
130 The Journal of Clinical Pharmacology
CLASSIFICATION OF ANTIARRHYTHMIC ACTIONS
in man, rather than those from prepara- rent flows in a larger potential range than
tions artificially stimulated with paired in the myocardium.” Colatsky reported
stimuli, behave in this way; the occurrence similar results with rabbit Purkinje fibers.2#{176}
of “R on T” in ECG records, although it
All this recent work confirms that the ac-
indicates that depolarization starts in some
tions of lidocaine and other class 1 drugs
cells before repolarization has ended in
can be attributed to interference with re-
others, does not necessarily mean that de-
covery from inactivation of sodium chan-
polarization starts in an individual cell be-
nels, without involving other effects. Yet
fore that cell itself has been fully repolar-
antiarrhythmic drugs such as quinidine,
ized. (4) There is abundant evidence in
lidocaine, and disopyramide appear so dif-
animals’#{176} and man’6 that shortening of
ferent from each other in clinical use that
APD is an arrhythmogenic factor. (5) The
many physicians have been reluctant to
class 1 action of lidocaine provides a suffi-
accept that they could have a fundamen-
cient explanation for its antiarrhythmic
tally similar mode of antiarrhythmic ac-
effects. Thus, lidocaine is antiarrhythmic
tion. Many remedies that share the restric-
in spite of, rather than because of, the short-
tion of fast inward current have additional
ening of APD.
properties which distinguish them clini-
Nevertheless, shortening of APD in the
cally. The most important of these are the
ventricular conduction pathway is a fact
following:
which must have some explanation, and it
was concluded from voltage clamp experi- (1) Some class 1 drugs are anticholiner-
ments on sheep Purkinje fibers by Arns- gic, the most potent in this respect being
dorf and Bigger’7 that lidocaine, at a con- quinidine and disopyramide. Apart from
centration (2.14 X iO5M) considered equiva- the noncardiac complications of antimus-
lent to clinical plasma antiarrhythmic carinic actions, there are several cardiac
levels, “increased chord conductance for consequences. In a patient with substantial
the potassium ion (gK).” In contrast, Car- background vagal activity, sinus tachy-
cardia may supervene after administration
meliet and Saikawa,’8 who also studied
sheep Purkinje fibers under voltage clamp, of these drugs. Or, more seriously, an atrial
while observing that in the presence of fibrillation or supraventricular tachycar-

dia which was previously innocuous be-
(1.85 -3.7) X l05Mlidocaine “steady state
cause impulses were blocked at the A-V
currents were shifted outward,” found that
node may develop into ventricular tachy-
the “outward shift of current at the plateau
cardia when A-V conduction is improved
level by lidocaine was not observed in the
by the blockade of vagal tone. Secondly, the
presence of tetrodotoxin (TTX): in Na-free
fact that the drugs depress A-V conduction
medium the effect of lidocaine was totally
suppressed.” They concluded that “local by reason of their class 1 action may be
masked by the simultaneous improvement
anesthetics do not increase the K inward-
in conduction caused by the anticholinergic
rectifier current, and have no effect on
effect, and the result may be no change in
background current at potentials negative
A-V conduction time. In a patient with lit-
to -60 mV.” It would appear, therefore, that
tle vagal background, however, and with
in Purkinje fibers sodium channels are not
fully inactivated at the potential of the pla- depressed A-V conduction, the full class 1
depression by quinidine or disopyramide
teau. Coraboeuf and Deroubaix,’9 in a study
will be revealed, and serious A-V block may
of canine Purkinje fibers, came to a similar
occur.2’
conclusion, finding that TTX shortened
APD and stating that “the effect is prob- (2) Distribution into the CNS varies con-
ably due to the fact that in Purkinje fibers siderably between class 1 drugs, and more
the TTX-sensitive steady-state sodium cur- information is required concerning the ex-
April 1984 131

VA UGHAN WILLIAMS
TABLE I makes its oral use impracticable, since its
Elimination Half-Lives and half-life may be as short as half an hour in

Volumes of Distribution some patients. At the other extreme, aprin-
dine has an elimination half-life of two and
Elimination Volume of a half days. The half-lives and volumes of
half-life distribution
distribution of nine class 1 drugs are given
(hours) (liters/kg)
in Table I.
Lidocaine 1.8 1.6
(4) Some compounds, notably lidocaine,
Mexiletine 13.0 6.6
Tocainide 13.0 2.8 mexiletine, and tocainide, shorten action
Disopyramide 7.0 0.5
potential duration.
Quinidine 6.3 2.5
(5) There are wide variations in the rapid-
Procainamide 3.0 2.9
ity with which the drugs become attached
Flecainide 14.0
to and released from the sodium channels.
Lorcainide 7.7 7.9
Aprindine 50.0 4.0
The clinical differences between various
From Ronfeld with permission of CV. Mosby Co. drugs with class 1 action necessitated their
subdivision.23 The older compounds, quini-
dine, procainamide, and disopyramide, be-
tent to which this is influenced by fat solu-
came group 1 a. Lidocaine, mexiletine, and
bility, pK5, and molecular size. Certainly
tocainide (group ib) shorten action poten-
dizziness and other CNS effects, even con-
tial duration in vitro and shorten mono-
vulsions, limit the use of several class 1
phasic action potentials (MAPs) and Q-T
drugs, including lidocaine, mexiletine, and
intervals in vivo. They do not lengthen
lorcainide in high dosage, and quinidine
H-V conduction time or QRS in sinus
also presents CNS problems in addition to
rhythm, but prolong effective refractory pe-
its other side effects.
riod (ERP) as measured by programmed
(3) Metabolism and rates of excretion stimulation (a premature stimulus S2, in-
may vary enormously between drugs. Elimi- terpolated every nth pacing stimulus S1).
nation half-life depends on both factors, The most recently introduced class 1 drugs,
and the rapid metabolism of lidocaine flecainide, encainide, and lorcainide (group
TABLE II
Clinical Subdivision of Class 1 Antiarrhythmic Drugs
Effect on: Group B A C
lidocaine quinidine lorcainide

mexiletine procainamide encainide
tocainide disopyramide flecainide
(ORG 6001) (CCI 22277)
1.QRS none in sinus widen at high widen at low

rhythm concentration concentration
2. Conduction none in sinus slowed at high slowed at low

rhythm concentration concentration
3. ERP lengthened in lengthened very little

relation to APD absolutely and change
relative to APD
4. Action potential shortened lengthened at very little

duration high concentra- change
tion

ic), have little effect on APD or Q-T inter- pounds of considerable academic interest,
val or on ERP measured by programmed added to the relevant groups on the basis of
stimulation, but increase H-V conduction animal studies.24 An electrophysiologic ex-
time and widen QRS even in sinus rhythm. planation for the above subgrouping has
Quinidine, procainamide, and disopyram- been proposed in a series of recent
ide are intermediate, moderately prolong- papers.24 It was shown more than a quar-
ing ERP, and lengthen Q-T and widen QRS ter of a century ago that the sodium chan-
at high concentrations (a useful indicator nels of cardiac Purkinje cells were similar
of overdosage). The anticholinergic and to those of the squid axon29 in that they
APD-lengthening effects of quinidine and could exist in at least three states: (1) closed,
disopyramide are additional properties un- at potentials near the resting potential, but
related to their class 1 effect. Quinidine de- available to be opened by depolarization;
lays repolarization by restriction of out- (2) open, selectively permitting passage of
ward potassium current.’9 sodium ions; and (3) closed, but not avail-
The properties distinguishing the sub- able to be opened, i.e., inactivated. Many
groups have been summarized in Table II. models of sodium channels have been sug-
ORG 6001 and CCI 22277 are steroid com- gested with more states than the minimum
20
4’
-60
rnV
i
AE
300.
200
,00 -
V,s: _t0 1O
Fig. 1. Recovery of MRD in response to stimuli at intervals after an action

potential. Upper panels: Intracellularly recorded atrial potentials, and re-
sponses to stimuli at A, the absolute refractory period, when sufficient
sodium channels had recovered from inactivation to support a local but not a
propagated response. When stimuli were applied at E, the effective refrac-
tory period, enough channels had recovered to support a propagated re-
sponse. Left, controls; right, in the presence of quinidine. Lower panels:
Heights of columns are proportional to MRD in response to stimuli at
intervals after the action potentials depicted in upper panels. Left, solid
columns are controls; dashed columns are response expected if 40 per cent of
sodium channels had been permanently eliminated. Right, dotted line de-
picts envelope of the normal responses; columns represent MRD in response
to stimuli on assumption that no channels were permanently eliminated but
that at the start of diastole all channels were attached to a drug (which kept
them inactivated). MRD recovers as the drug rapidly (solid columns) or more
slowly (dashed columns) becomes dissociated from the channels. Published
with permission of Academic Press.
April 1984 133

VAUGHAN WILLIAMS
TABLE III
Some Class 1 Antiarrhythmic Drugs Arranged in Order of
Magnitude of the Time Constant of Recovery of MRD After
It Had Been Depressed to a Steady Level During a
Train of Stimuli at 33 Hz
Depression
of MRD
Molecular (% of that of Time constant
weight Concentration first response of recovery
Compound (daltons) (mole/liter) in train) (sec)
Mexiletine 179 20 49.2 0.47

ORG 6001 305 30 57.7 4.6
Disopyramide 339 100 50.9 12.2
Lorcainide 358 5 45.0 13.2

Flecainide 408 2 50.7 15.5
Encainide 371 3 50.0 20.3
three, but there is much evidence, discussed fractory period measured by programmed
in detail in the reports already cited, that stimulation. In the lower right panel, the
antiarrhythmic drugs are attached to so- dotted line depicts the “envelope” of normal
dium channels in their inactivated state responses. The columns represent responses
and interfere with the process by which to be expected if no channels had been per-
they recover from inactivation after repol- manently eliminated, but if all channels
arization of the membrane, as originally were temporarily out of action at the begin-
deduced.3 ning of diastole but recovered rapidly (solid
The maximum rate of depolarization columns) or more slowly (dashed columns),
upon stimulation at increasing intervals as the drug became detached and allowed
after repolarization can be taken as an ap- the channel to recover from inactivation. In
proximate measure of the number of chan- both cases ERP would be prolonged be-
nels which have recovered (although simul- cause no channels would be available at the
taneous or overlapping outward current start of diastole. At the end of diastole,
may complicate the picture to a small ex- however, all of the channels would have
tent), as depicted diagrammatically in Fig. been freed from the rapidly dissociating
1 (from Ref. 10). The heights of the columns drug, so that MRD (and conduction veloc-
in the lower left panel represent the magni- ity) would be unaffected at sinus rhythm.
tude of MRD in response to stimuli at vari- The more slowly dissociating drug would
ous times after the atrial action potential depress MRD in sinus rhythm to some
depicted in the upper panel. The solid co- extent.
lumns depict normal responses, the dashed The class 1 drugs can be tested by admin-
columns the responses to be expected if 40 istering to cardiac muscle trains of stimuli
per cent of the channels had been perma- sufficient in number to produce a steady-
nently eliminated by a drug. The remaining state depression of MRD at a given fre-
60 per cent, without drug attached, would quency, then stopping stimulation, and
be normal and so would recover at the same measuring the recovery of MRD in response
time as the controls. The electrical thres- to single stimuli administered at increasing
hold would be raised, because the total intervals after the train.24 The concentra-
number of channels had been reduced, but tions of drugs used were selected to achieve
there would be no increase in effective re- approximately a 50 per cent depression of

MRD at a frequency of 3.3 Hz within the frequency at which a pacing stimulus can
train. Table III shows that flecainide, br- be followed, both resting and frequency-
cainide, and encainide had time constants dependent blocks will influence the result,
of recovery many times longer than a nor- and all the drugs in groups la, ib, and ic
mal diastolic interval, so that the sodium would produce a reduction in “maximum
channels may be considered to have been following frequency” (MFF). The higher
“permanently” inactivated, as depicted on the frequency, the longer the total duration
the left of Fig. 1. Conversely, mexiletine of time in which the membrane is in its
was a rapidly dissociating drug, as on the depolarized-and-then-inactivated state.
right of Fig. 1, with disopyramide as a Empirically, MFF is a sensitive and useful
rather slowly dissociating drug. screening test for class 1 action.’#{176}3#{176}
The onset kinetics gave the same group- More than a decade ago, it was suggested
ings. Lidocaine, mexiletine, and tocainide that class 1 drugs “have a variety of chemi-
had time constants for attachment, as cal structures but are mostly lipophilic”
measured by the number of stimuli in a and “are taken up into the primary mem-
train required to produce a steady-state de- brane, from where they press their attack
pression of MRD, of half a second or less, so on the sodium channels. Class 1 action by
that the stable level of depression of MRD the local anesthetic type of drug may in-
was achieved within a couple of beats after volve restriction of the freedom of charged
the start of a train of stimuli. In contrast, elements controlling the ion gates to move
with flecainide, lorcainide, and encainide, a in response to changes of voltage across the
steady-state depression of MRD was not membrane.”3’ Others have preferred a
reached until 20 beats or more in a train. model in which local anesthetics gain ac-
Quinidine, disopyramide, and procainam- cess to the sodium channel from the inside
ide were intermediate. of the cell and are attached to it in ionized
Although the frequency dependence or form. Since, however, to gain access to the
“use dependence” of class 1 drugs implies cell interior the drugs probably traverse the
that they are mainly attached to channels membrane in nonionized form, the pK5 is of
in their depolarized or inactivated state, interest as well as the fat solubility (ex-
there is nevertheless some degree of “resting pressed as log P, the octanol-water parti-
block.” If cardiac muscle is exposed to the tion coefficient). These values for some of
drugs in the absence of stimulation, resting
block can be measured as the difference be-
TABLE IV
tween MRD before the drug application and
Fat Solubility* and Dissociation
during the response to the first stimulus
Constant of Some Class 1 Drugs
after the unstimulated period in the pres-
ence of the drug. Resting block is usually Fat
small and sometimes not statistically sig- Drug solubility plC.
niflcant.2420 Resting block could be ex- Lignocaine 2.76 7.85

plained if sodium channels are sometimes Mexiletine 1.3 9.3
Tocainide 0.8 7.8
randomly activated even at the resting po-
tential, thus providing a background in- Disopyramide 1.8 8.4
ORG 6001 3.93 8.0
ward sodium current and a steady but
Quinidine 3.6 8.8
small supply of channels available for Procainamide 0.8 9.2
“capture” by the drugs in unstimulated Flecainide 1.15 9.3
tissue. Encainide 0.91 10.2
Lorcainide 4.16 9.44
If refractory period is measured, not by
CCI 22277 7.19 9.5
the interpolated stimulus method, but as
the interstimulus interval at the maximum Log of octanol/water partition coefficient.
April 1984 135

VAUGHAN WILLIAMS
200
action of all class 1 drugs is fundamentally
50 similar, involving attachment to sodium
channels in their inactivated state and pro-
a 20 longing that state until after the drug has
0
a
been detached. Quantitative disparities in
E 10
the rapidity of attachment to and detach-

ment from the channels can account for the
0
a
observed differences in the clinical profiles
- 0_94 of the various compounds.
OP .0 00,)
It has already been emphasized that sev-
(0
eral class 1 antiarrhythmic drugs possess
other properties in addition. In this context
0
it is pertinent to mention a new compound,
0.1 L 150
I
200
I
250
I
300
I
350
I
400
______ cibenzoline, which has been shown to pre-
#{176}#{176}‘#{176}#{176}vent ventricular arrhythmias induced by
MoIec,,I, Wn.jI,I programmed electrical stimulation.32 Ci-
Fig. 2. Positive correlation between log of time

benzoline not only restricts fast inward
con8tant of recovery from frequency-dependent current but also delays repolarization in
block (rre) and molecular weight for seven anti- several cardiac tissues, and has some cal-
arrhythmic drugs. MMexiletine, 10 oM; cium antagonist action as well. Thus, over-
O=ORG 6001, 60 toM; D=disopyramide, 20 12M;
all efficacy may be increased by a combina-
E=encainide, 6 iM; L=lorcainide, 2 toM; F = fle-
cainide, 5 ,M; C = CCI 22277,4 toM. Reproduced tion of actions none of which alone may be
with permission ofT. J. Campbell, unpublished. sufficient to terminate an arrhythmia. More-
over, cibenzoline has the additional prop-
erty of reducing hypoxia-induced shorten-
the drugs studied are presented in Table IV. ing of action potential duration.33
It is clear from Table III that there was a
correlation (r = .0.94) between molecular
Class 2 and 3 Antiarrhythmic Actions
weight and the time constant of recovery,
and these two parameters have been plot- In Purkinje fibers, recovery from inac-
ted in Fig. 2. The conclusion to be drawn tivation follows repolarization very rap-
from this very close correlation is that al- idly.29 In atrial and ventricular muscle,
though fat solubility and dissociation con- however, recovery from inactivation fol-
stant may influence access to the sodium lows repolarization after a delay, and the
channels, once the agent has become at- latter is increased by class 1 drugs.3
tached, one of the determinants of the It was obvious that an alternative way of
strength of binding may be molecular size, delaying recovery from inactivation would
implying attachment by short-range van be to prolong the duration of the action po-
der Waals forces rather than electrostatic tential itself, and for many years a drug
forces. with this property was sought. Quinidine
From the clinical point of view, the main itself in high doses and at low stimulation
interest of the above subdivision of class 1 frequencies does cause some delay of re-
drugs into fast, intermediate, and slowly polarization, and it was once considered
dissociating groups is that this grouping, that this could be the main reason for its
based upon purely objective electrophysio- antiarrhythmic action.34 Nevertheless, it
logic results in vitro, corresponds closely was clear that although prolongation of ac-
with the subgrouping into la, ib, and ic on tion potential duration (APD) could be a
clinical grounds. Thus, the experiments contributory factor, quinidine still had a
support the view that the antiarrhythmic powerful effect in restricting fast inward

current in concentrations and at pacing interval could be an antiarrhythmic agent.

frequencies at which APD was unchanged.5 Not only was the familial propensity to
There is much evidence, including hu- fainting fits in children with a long Q-T,
man data obtained with monophasic action described independently by Romano4’ and
potential recording,35 that shortening of Ward,42 associated with ventricular tachy-
APD is an arrhythmogenic factor, which cardia or even fibrillation (precipitated by
may, at least in part, explain the high inci- emotion or exercise), but the phenomenon
dence of atriab fibrillation in the hyperthy- of “R on T” has long been regarded as a
roid state.36 Conversely, after thyroidec- harbinger of impending life-threatening
tomy, APD is prolonged, and since cardiac arrhythmias, and a long Q-T interval has
arrhythmias are rare in myxedema, this been proposed as a predictor of sudden
reinforced the theoretical view that a pro- death.43 The long Q-T syndrome will be dis-
longation of APD, provided that it were cussed again later, but meanwhile some-
uniform and homogeneous, might consti- thing must be said about the mode of action
tute a “third class” of antiarrhythmic ac- of beta blockers, which have been of value
tion (i.e., in addition to the two already es- in this condition.
tablished, restriction of fast inward current Beta blockers have been in use for nearly
and antisympathetic effects). There was, 20 years as a treatment for hypertension,
however, no drug available at that time yet the mechanism by which blood pressure
with which the hypothesis could be prop- is lowered has still not been fully explained.
erly tested. A question which aroused early interest
Amiodarone had already been in use for was why the hypotensive action of beta
several years as an anti#{224}nginal drug before blockers was often delayed in onset and
it was subjected to detailed electrophysio- why weeks or months of therapy might
logic study with microelectrodes. The find- sometimes be required to achieve an opti-
ing that it caused a large prolongation of mum result. The mode of action of a drug is
APD but had only a minor antisympathetic customarily analyzed in acute animal ex-
action and a negligible class 1 effect37 sug- periments, yet patients are treated with
gested that it might be the first “class 3” beta blockers for years, often for the rest of
antiarrhythmic drug for which we had been their lives. It seemed logical to study their
looking. We found that amiodarone was a effects in animals which also had been
very effective antiarrhythmic drug in treated for prolonged periods, and 10 years
guinea pigs, and Charlier and his col- ago a program was started to investigate
leagues38 observed an antiarrhythmic ef- the long-term effects of a number of beta-
fect in dogs. The first cardiologist to use it blocking drugs, with and without the sub-
as an antiarrhythmic in man was Ferrero,39 sidiary properties of cardioselectivity, in-
who had already employed the drug for trinsic sympathomimetic activity (ISA), or
many years in Switzerland as an antiangi- local anesthetic action. It was first neces-
nal agent. During the next couple of years, sary to establish what dosage regimen in
amiodarone was increasingly used in con- the animal we used, the rabbit, would be
tinental Europe (not in England) and South equivalent to therapeutic levels in man.
America in patients with arrhythmias, and Fortunately, the latter were accurately
it was found by Rosenbaum to be excep- known for propranolol and a few other beta
tionally useful for the control of preexcita- blockers. Coltart and Shand, for example,44
tion arrhythmias of the Wolff-Parkinson- found that exercise tachycardia was com-
White type.4#{176} pletely blocked by a propranolol plasma
In spite of this evidence, there was con- concentration of 100 ng/ml, but only minor
siderable reluctance among cardiologists to blockade was achieved when the concen-
accept that a drug which prolonged the Q-T tration had fallen to 10 ng/ml. They had
April 1984 137

VAUGHAN WILLIAMS
also measured the relationship between in the long Q-T syndrome and the efficacy
propranobol concentration and blockade of of therapy with beta blockers or by left stel-
the effects of injected isoprenaline, and we lectomy. It must be emphasized that the
found a good correspondence between rab- Q-T interval on the surface electrocardi-
bits and man for blockade and plasma lev- ogram does not necessarily measure action
els.4546 The rabbits were injected for several potential duration. Oppositely orientated
weeks twice daily subcutaneously with 4 late repolarization vectors may cancel each
mg/kg propranolol, which we knew would other, so that in some leads the end of the
provide clinical levels of blockade for at T-wave does not signal the end of repolari-
least two thirds of each day. The treatment zation. In particular, the septal and apical
was stopped 24 hours before the animals repolarization vectors cancel in left-right
were killed, so that when we did experi- leads. Beta-adrenergic stimulation shortens
ments on the heart there was no measur- (but alpha-adrenergic stimulation length-
able propranolol present in either the ens) APD and absolute refractory period.50’5’
plasma or the myocardium. In the heart, beta-adrenoceptors normally
There was no difference in responses to predominate.52 Thus, high sympathetic ac-
isoprenaline of hearts isolated from these tivity in the left ventricle could shorten a
animals, in comparison with hearts from late repolarization vector which normally
saline-treated litter mates, indicating the balanced a similar late repolanzation in
absence both of residual blockade and of the right ventricle, so that a T-wave which
any hypersensitivity induced by the treat- had previously been “silent” could become
ment. In an untreated rabbit, exposure of apparent. In the long Q-T syndrome, a
myocardium to a concentration of propran- paucity of right stellate innervation, caus-
olol (100 ng/ml) equivalent to clinical ing a reduced heart rate response to exer-
levels has hardly any effect on the action cise, is combined with a compensatory ex-
potential. At higher concentrations (200 to cess of left stellate activity.50 Reduction of
500 ng/ml), action potential duration right sympathetic activity, as we have
(APD) is shortened slightly and the maxi- seen, would lengthen right ventricular
mum rate of depolarization (MRD) is re- APD and excess left sympathetic stimula-
duced. We found that long-term treatment tion would shorten left ventricular APD,
with beta blockers induced a large prolon- causing great heterogeneity of ventricular
gation of APD, uniformly observed in both APDs, a highly arrhythmogenic factor.
atria and ventricles paced at a constant Hence the susceptibility of patients with
frequency. Since no drug was present at the the bong Q-T syndrome to ventricular ar-
time, this represented a secondary adapta- rhythmias. Treatment by beta blockers or
tion to the treatment. A uniform prolonga- by left stellectomy would reduce the imbal-
tion of ventricular APD should lengthen ance between left and right sympathetic ac-
the Q-T interval, and we found that we tivity, and left ventricular repolarization
were able to follow the rate of onset of the would be delayed, thus restoring the mutual
effect noninvasively by measurement of cancellation of late repolarization vectors
ECG records.47 The effect was not related to and shortening the Q-T interval on the sur-
ISA, cardioselectivity, or local anesthetic face electrocardiogram.
properties. One of the exciting developments of the
Several studies have established that a last few years has been the demonstration
similar prolongation of Q-T interval, per- that prolonged beta blockade protects a
sisting for days after cessation of treat- significant proportion of postinfarction pa-
ment, is induced by long-term beta block- tients from reinfarction and sudden
ade in man.48’49 These observations can death.57 The reason for the protection is
explain both the prevalence of arrhythmias unknown, but since a uniform prolongation

of APD constitutes an antiarrhythmic scribed as responsible for repolarization in

(class 3) action, this could be a contributory cardiac muscle, which are as follows:
factor in reducing the incidence of sudden
(1) Activation of two outward currents,
death.58’59 Prolonged beta blockade induces
designated Ix, and Ix2, described as con-
increased capillarity in the myocardium of
trolled in the range +20 to -40 mV in accord-
animals50 and, if it occurs in man, could
ance with Hodgkin-Huxley type kinetics
have some protective effect also.
by Noble and Tsien63 and carried mainly,
One of the beta blockers, sotalol, was
but not exclusively, by potassium ions.
shown long ago to delay repolarization on
(2) Calcium-activated outward potassium
acute administration and to have little
current described by Isenberg.6566
class 1 activity,6’ but it was difficult to ex-
trapolate from animal models of arrhyth- (3) Inactivation of slow inward current
mias to any firm conclusion that the pro- by a voltage and time-dependent mecha-
longation of APD had contributed an anti- nism.67 “Normal repolarization of sheep
arrhythmic action additional to the class 2 ventricle depends on a time-dependent de-
effect. crease of inward current (Na, Ca) rather
Amiodarone has proved outstandingly than on a time-dependent increase of out-
efficacious in the treatment of arrhythmias ward current (K).” In molluscan neurones,
of the Wolff-Parkinson-White type (WPW), it has been observed that calcium conduc-
for which class 1 drugs like lidocaine are tance is inactivated by raised intracellular
less suitable. It is of interest, therefore, to calcium (i.e., by direct negative feed-
compare the effects of amiodarone and sim- back), but whether this mechanism is
ilar agents with those of lidocaine on the present in cardiac muscle also is uncertain.
ventricular conduction pathway. It was (4) Return of potassium conductance by
found that amiodarone and L9146, a non-
reversal of inward-going rectification. Po-
halogenated analogue of amiodarone with tassium conductance is reduced in the pla-
a similar pharmacologic profile, length- teau region, but once repolarization has
ened APD in the bundle of His and ventric- begun, by whatever mechanism, the nearer
ular muscle much more than in the preter- EM approaches to Ex the higher the conduct-
minal Purkinje fibers or “false tendons.”62
ance becomes (i.e., there is positive feed-
Indeed, if electrophysiobogic studies had back).
been confined to such Purkinje fibers, the
class 3 effect of the drug would have been Thus, a drug that delays repolarization
missed. Thus, both in theory and in prac- could act in a variety of ways since there are
tice, prolongation of APD does appear to so many suggested mechanisms from which
constitute a true class of antiarrhythmic to choose. Repolarization could be delayed
action. In contrast, lidocaine, which is of by an increase in slow inward current or by
little value in WPW, has the opposite effect a delay of its inactivation; or by an interfer-
on APD in the ventricular pathway, short- ence with channels carrying outward cur-
tening APD in all tissues, but doing so pref- rent, normally activated either by a voltage-
erentially in the distal Purkinje cells in and time-dependent mechanism or by raised
which APD is normally longest. intracellular calcium concentration; or by a
It would naturally be of interest to know restriction of the reversal of inward rectifi-
whether amiodarone, sotalol, disopyra- cation. Delayed repolarization could even
mide, melperone, bretylium, and long-term be due to interference with the sodium-cal-
beta blockade, all of which prolong ventric- cium exchange mechanism, since it is now
ular APD, achieve this effect in the same believed that this exchange is electrogenic.
way. One can only speculate in terms of the The plateau may be maintained not only by
various mechanisms which have been de- slow inward current and inward-going rec-
April 1984 139

VAUGHAN WILLIAMS
tification but also by a net inward current thetic nerve endings (e.g. bretylium), as
provided by the entry of three or four so- well as those which compete post-synapti-
dium ions in exchange for a single calcium cally for receptors (e.g. beta-blockers), some
ion traveling outwards.69’7#{176} compounds not primarily regarded as anti-
The “pacemaker current,” i, originally arrhythmic may nevertheless reduce anx-
said to be a pure outward potassium current iety and so indirectly reduce sympathetic
activated by depolarization in the range -90 activity by their C.N.S. effects. The acute
to -55 mV, appears to have been an arte- antiarrhythmic action of class 2 drugs can
fact.71 Long-lasting clamp pulses in com- be attributed to removal of a background
plex tissues such as cardiac muscle alter the sympathetic activity which may be exces-
ionic concentrations in the intercellular sive and responsible for initiating or exac-
clefts. What may appear to be a voltage -and erbating an arrhythmia, especially in sit-
time-dependent conductance change could uations of low cardiac output (e.g. after
be secondary to a shift of EK, and it seems acute myocardial infarction).78 To this acute
possible that Ix2, for example, may have class 2 action of beta-blockers, must now be
been as artifactual as ik2. Thus, it is not added a class 3 action observed after pro-
possible to determine the selectivity of drug longed administration.
actions on individual ion channels con-
cerned in the delay of repolarization until Class 4 Antiarrhythmic Action
valid methods are available for measuring Finally, with regard to drugs with a class
the normal mechanism of repolarization 4 action, restricting the second slower in-
itself. ward current, some of the newer com-
Meanwhile, returning to consideration of pounds have proved disappointing as anti-
the heart just as an electrical network, it is arrhythmic remedies. The so-called “cal-
reasonable to conclude that a homogeneous cium antagonists” comprise a group of
delay of repolarization, however produced, drugs which are widely different in chemi-
constitutes a distinct class of antiarrhyth- cal structure and tissue selectivity. Nifedi-
- mic action. New support for this view has pine, for example, acts primarily on smooth
recently been provided by evidence that muscle, especially vascular smooth muscle,
sotalol has a greater antiarrhythmic effect and its cardiac effects are relatively less
than can be attributed to its beta-blocking pronounced than those of verapamil.79 It
action alone.72’73. Bretylium, which pro- has been suggested that although all car-
longs ventricular74 but not atrial APD, and diac tissues, apart from cells in and around
which has no class 1 activity,75 can some- the sino-atrial and atrio-ventricular nodes,
times have dramatic antiarrhythmic ef- are normally depolarized by fast inward
fects on ventricular muscle. Another long-estab- (sodium) current, in ischemia or in other
lished drug which prolongs APD in both situations causing partial diastolic depol-
atrial and ventricular muscle76 is the tran- arization and inactivation of fast current,
quillizer melperone, but whether it could be slow inward current may “take over,” as it
useful as an antiarrhythmic drug in man were, permitting the activation of slowly
remains to be established, although there conducting action potentials to initiate
are already some promising reports.77 The reentry. The antiarrhythmic action of cal-
possible efficacy or danger of combining cium antagonists is thus attributed to abo-
drugs delaying repolarization with other lition of these abnormal slow depolariza-
classes of antiarrhythmic action opens a tions.
new field for exploration. There are several reasons for doubting
With regard to the class 2 (antisympa- this hypothesis. (1) If it were true, calcium
thetic) drugs, which include those which antagonists should be especially effective
prevent release of noradrenaline from sympa- in ventricular arrhythmias associated with

ischemia. In practice, this is not so; the centration [Ca] rises.82 If the changes in
class 1 agents are more effective in these [Ca]s that are normally associated with the
conditions.50 Access to ischemic areas is, of activation of contraction are sufficient to
course, less rapid than to well-irrigated re- affect gap-junction resistance, then a con-
gions, but this would be true for all drugs. centration of verapamil causing a negative
(2) Verapamil is most effective in control- inotropic effect by reducing [Ca] should
ling supraventricular arrhythmias,8#{176} in- also decrease intercellular resistance. A
volving the nodes, which are normally de- secondary consequence should be an in-
polarized by slow inward current. (3) Ar- crease in conduction velocity. In an early
rhythmias induced by experimental ischemia paper on the electrophysiologic effects of
originate in the border zone outside the verapamil, it was indeed noted that there
ischemic region81; and although the action was a dose-related increase in conduction
potentials are of short duration, they are velocity (Table V) which was difficult to
initiated by fast inward current. explain, though the possibility of reduced
Nevertheless, verapamil has been re- cell-to-cell resistance was considered. “The
ported to be effective occasionally in ven- core resistance includes the specialized
tricular arrhythmias associated with ische- contacts at the intercalated discs, which
mia; and if the effect is not directly due to could be affected by drugs.”2 It was not then
block of slow action potentials, what is the known, of course, that gap junctions could
explanation? Cell-to-cell conduction is me- be controlled by [Ca]. Another conse-
diated through gap junctions, which pro- quence of opening up gap junctions should
vide a low-resistance pathway for intercell- be a smaller “foot” to the action potential
ular current. Recent evidence has indicated (indicated by arrows in Fig. 3), since the
that these junctions may be closed or nar- passive discharge of the membrane capa-
rowed when the intracellular calcium con- city into an approaching active region would
TABLE V
Effects of Verapamil on Spontaneous Rate, Maximum Driven
Frequency, Electrical Threshold, Conduction Velocity, and
Contraction Amplitude in Isolated Rabbit Atria
Concentration Maximum
of verapamil Spontaneous driven Electrical Conduction Contraction
mg/liter (,M) rate frequency threshold velocity amplitude
0.075 0 0 0 0 -32.8
(0.152) (4.9)
0.15 0 0 0 0 -56.7
(0.304) (4.3)
0.30 -8.6 +2.1 -3.9 +6.7 -67.4

(0.608) (2.2) (1.3) (1.2) (1.9) (5.9)
1.0 -21.5 +3.9 -10.4 +16.8 -78.7

(2.03) (3.1) (1.7) (2.8) (3.3) (8.2)
30 **
+14.1 -12.8 +19.7 -90.3
(6.08) (2.8) (3.1) (4.2) (9.4)
Each value indicated is a mean percentage change (± S.E.M.) from controls from
three experiments. The observations were made after a steady state was achieved at
60 minutes of exposure to the drug.
Spontaneous pacemaker frequency ceased in two preparations (at 30 minutes in

one and at 42 minutes in the other); the atria could still be driven electrically.
April 1984 141

VA UGHAN WILLIAMS
Control
I
Verapami I
1mg/litre
(2.02 x 106M)
Fig. 3. Effect of verapamil on intracellular potentials and contractions of

rabbit ventricular muscle, paced at 1 Hz. Horizontal traces: zero potential
with the microelect rode in the bath. Middle traces: intracellularly recorded
potentials at slow and fast sweep speeds. Lowest trace: contraction at the
slower sweep speed. Upper panel: control records; vertical calibration 1 Gm.
Lower panel: in the presence 012 hmole/liter verapamil; vertical calibration
100 mV, horizontal calibration 200 or 20 msec. Arrows indicate that in the
presence of verapamil the action potential took off more sharply from the
baseline, implying more rapid entry of passive depolarizing current causing
the cell in which the microelectrode was situated to reach its own firing
threshold more quickly. Verapamil did not depress MRD at this concentra-
tion. In vitro (without sympathetic compensatory reflexes), 2 ,mole/liter of
verapamil was sufficient virtually to abolish contractions.
have a shorter time constant. Reference to similar to that which lidocaine was once
the original records revealed that the foot of supposed to have, as already described.
the ventricular action potential was indeed Considerable support has been given to this
greatly attenuated (Fig. 3). hypothesis by a recent paper of El-Sherif
It is possible, therefore, that although the and Lazzara,50 who found that at the time
main antiarrhythmic effect of class 4 drugs experimental reentrant arrhythmias in the
is on transitional cells in and around the late myocardial infarction period were at-
nodes, which are normally depolarized by tenuated by verapamil and D600, although
slow inward current, they may exert an in- sinus rate and A-V conduction were slowed
direct action also in Purkinje cells and myo- as expected, ventricular conduction was
cardial cells normally depolarized by fast improved and the dispersion of abnormal
inward current. The primary effect is still activity reduced. Both these findings would
on slow inward current, of course, but be- be consistent with improved intercellular
cause [Ca} falls, gap junctions open up and coupling. It is noteworthy that the above
conduction is improved. The effect is thus effect, shown in Fig. 3, occurred at a con-

centration of verapamil at which no class tion? Effect of verapamil on ouabain

1 action was observed. toxicity, on atrial and ventricular in-
tracellular potentials, and on other
features of cardiac function. Cardio-
Summary
vasc Res. 1972; 6:109-119.
The past decade has seen the introduc- 3. Szekeres L, Vaughan Williams EM.
tion of many new class 1 drugs, restricting Antifibrillatory action. J Physiol.
fast inward current. Confirmative evidence 1962; 160:470-482.
has been obtained that the antiarrthymic 4. Johnson EA, McKinnon MG. The dif-
action of lidocaine and diphenylhydantoin ferential effect of quinidine and pyril-
is indeed due to their effect as class 1 agents amine on the myocardial action po-
depressing conduction. The original class 3 tential at various rates of stimulation.
drug, amiodarone, is increasingly in use as J Pharm Exp Therap. 1957; 120:
an antiarrhythmic of first choice for WPW 460-468.
and for arrhythmias associated with hy- 5. Vaughan Williams EM. The mode of
pertrophic myopathy,84 and as a reserve action of quinidine on isolated rabbit
drug in resistant arrhythmias of other atria interpreted from intracellular
types. Other compounds delaying repolari- potential records. Br J Pharmacol.
zation have proved to be clinically effective 1958; 13:276-287.
as antiarrhythmics.50 In addition to their 6. Bigger JT, Mandel WJ. Effect of lido-
class 2 antiarrhythymic action exhibited caine on conduction in canine Pur-
acutely, on long-term treatment beta block- kinje fibers and at the ventricular
ers have a class 3 action, which might be, at muscie-Purkinje fiber junction. J
least in part, responsible for the protection Pharm Exp Therap. 1970; 172:239-
of postinfarction patients against sudden 254.
death. Recent research suggests that inhi- 7. Davis LD, Temte JV. Electrophysiobog-
bition of slow inward current may lead, as a ical actions of lidocaine on canine
secondary consequence of lowered [Ca], to ventricular muscle and Purkinje fi-
improved cell-to-cell conduction. Finally, bers. Circ Res. 1969; 24:639-655.
all but one of the new antiarrhythmic 8. Bassett AL, Hoffman BF. Anti-ar-
drugs, none of which existed in 1972, have rhythmic drugs: electrophysiological
turned out to possess one or more of the four actions. Ann Rev Pharmacol. 1971;
classes of action originally described. This 11:143-170.
can hardly be a coincidence. The single ex- 9. Singh BN, Vaughan Williams EM. The
ception, alinidine, a selective bradycardic effect of altering potassium concen-
agent, may restrict anionic currents,86 tration on the action of lidocaine and
which would constitute a fifth class of ac- diphenylhydantoin on rabbit atrial
tion, but this is far from proved. and ventricular muscle. Circ Res.
1971; 29:286-296.
10. Vaughan Williams EM. Antiarrhyth-
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April 1984 147

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J C/in Pharmacol. 1984; 24:129-147.

D URING the past decade, antiarrhyth- terfering

vented. driving frequency.45

April 1984 129

antiarrhythmic activity.”7 On the contrary, shorten action potential duration (APD) in

while observing that in the presence of fibrillation or supraventricular tachycar-

April 1984 131

TABLE I makes its oral use impracticable, since its

Elimination Half-Lives and half-life may be as short as half an hour in

Effect on: Group B A C

lidocaine quinidine lorcainide

1.QRS none in sinus widen at high widen at low

2. Conduction none in sinus slowed at high slowed at low

3. ERP lengthened in lengthened very little

4. Action potential shortened lengthened at very little

132 The Journal of Clinical Pharmacology

Fig. 1. Recovery of MRD in response to stimuli at intervals after an action

April 1984 133

Mexiletine 179 20 49.2 0.47

Lorcainide 358 5 45.0 13.2

134 The Journal of Clinical Pharmacology

niflcant.2420 Resting block could be ex- Lignocaine 2.76 7.85

April 1984 135

the rapidity of attachment to and detach-

Fig. 2. Positive correlation between log of time

136 The Journal of Clinical Pharmacology

current in concentrations and at pacing interval could be an antiarrhythmic agent.

April 1984 137

138 The Journal of Clinical Pharmacology

of APD constitutes an antiarrhythmic scribed as responsible for repolarization in

April 1984 139

140 The Journal of Clinical Pharmacology

0.30 -8.6 +2.1 -3.9 +6.7 -67.4

1.0 -21.5 +3.9 -10.4 +16.8 -78.7

Spontaneous pacemaker frequency ceased in two preparations (at 30 minutes in

April 1984 141

Fig. 3. Effect of verapamil on intracellular potentials and contractions of

142 The Journal of Clinical Pharmacology

centration of verapamil at which no class tion? Effect of verapamil on ouabain

April 1984 143

144 The Journal of Clinical Pharmacology

April 1984 145

with cardio-selective and non-selec- trasting prophylactic efficacy of acute

146 The Journal of Clinical Pharmacology

clamp technique. J Gen Physiol. 1971; Ovesen L. Antiarrhythmic properties

April 1984 147

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