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TitleAntiarrhythmic Drugs: Mechanisms of Antiarrhythmic and Proarrhythmic Actions
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LanguageEnglish
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Page 1

Breithardt et al.
Antiarrhythmic Drugs

Page 2

QH-CH
eH-OH

ANTIARRHYTHMIC DRUGS
Mechanisms of Antiarrhythmie
and Proarrhythmie Actions

Springer-Verlag Berlin Heidelberg GmbH

Page 207

PRIMARY EFFECT ON
REFRACTORINESS OR

EXCITABILITY

Mechanisms Responsible for Anitarrhythmic Drug Efficacy 199

u

RECOVERY OF A CIRCUIT
BARRIER. LEADING

TO"SHORT CIRCUITING"

COLLAPSE OF THE
ISTHMUS DUE TO

ElECTROTONIC DRAG

Fig.4. Possible mechanisms of drug-induced termination of ventricular tachycardia. The ori-
ginal tachycardia circuit is represented at the top of the figure. Infusion of antiarrhythmic
drugs during VT could conceptually cause VT termination by one of three mechanisms, which
are shown schematically below: (a) a preferential effect on conduction or refractoriness in a
critical portion within the circuit, (b) recovery of a refractory-dependent circuit boundary,
leading to "short -circuiting" and block within the isthmus, or (c) narrowing of the boundaries
leading to an increase in conduction slowing in the isthmus due to electrotonic drag

shown to change the circuit boundaries, even when the VT morphology remains
constant [34]. Finally, Lesh and coworkers [35] demonstrated the potential for
collapse of the central isthmus due to electrotonic drag (mechanism 3) in a com-
puter model of VI.

Thus, although it is somewhat speculative to conclude, drug-induced termina-
tion of clinical VT is most likely due to changes in the circuit boundaries that "de-
stabilize" the circuit, either due to "short circuiting" and encountering refractory
tissue (mechanism 2) or by collapse of the central isthmus (mechanism 3). These
mechanisms are particularly appealing as also they provide a framework for the
understanding of proarrhythmia, which could be caused by drug-induced altera-
tion of the circuit boundaries that stabilize the circuit (e.g., increased the path
length and the excitable gap). It may well be that various antiarrhythmic agents
have several different mechanisms depending on the particular characteristics of
the reentrant circuit, such as (a) the size of the excitable gap, (b) the location ofthe
area( s) responsible for slow conduction and their vulnerability to preferential drug
effects, and (c) the degree to which circuit boundaries are anatomically versus
functionally determined.

Page 208

200 D.J. Callans, and M.E. Josephson

Prevention of Recurrent Ventricular Tachycardia

Direct evidence about the mechanism of antiarrhythmic drug effects in the pre-
vention of recurrent VT is also relatively sparse. Clinical studies have typically used
inducible VT as a predictor for subsequent drug failure to prevent spontaneous VT,
although there is some consensus that the correlation between these end points is
not perfect. Many investigators have tried to establish a relationship between
electrophysiologic effects (usually assessed in normal RV myocardium) and
prevention of inducible VT [13,36-38]. This has been, for the most part, un-
rewarding. Furthermore, it is fairly clear from work by Morady et al. [38] that the
electrophysiologic effects of antiarrhythmic drugs are not linearly related to anti-
arrhythmic effect. In this study, progressive increases in procainamide dose
(7.5 - 30 mg/kg) which produced corresponding increases in electrophysiologic
effect, did not confer additional protection against inducible VT. In fact, 3 of 10
patients who were suppressed at a lower doses of procainamide again had inducible
VT when higher doses were infused.

There are limited data to allow speculation on mechanisms that may be respon-
sible for drug effects in prevention of VT recurrence. At slow heart rates, where
effects on refractoriness are not overwhelmed by effects on conduction, antiar-
rhythmic drugs may act to prolong the wavelength. In contrast to the above dis-
cussion for VT termination, increase in the wavelength until it is larger than the
circuit path could potentially be a mechanism for VT prevention. This is consistent
with the observation that rapid tachycardias (cycle length < 270 ms), with pre-
sumably smaller excitable gaps, are more likely to respond to antiarrhythmic
agents than slower tachycardias [39]. Drugs may also work by the creation of a to-
tally inexcitable segment within the circuit, mediated by effects on ionic currents
or by alterations in passive membrane properties. This is, in a sense, the ultimate
manner of extending the wavelength beyond the capacity of the path length.

A second potential mechanism for the prevention of recurrent VT is "accelerat-
ed termination:' It is sometimes observed clinically that the same morphology VT
is reproducibly inducible after antiarrhythmic drug therapy, but is always non-
sustained. This finding is considered highly predictive of clinical efficacy. Termi-
nation in this setting is often associated with progressive prolongation of the cycle
length prior to termination. The electrophysiologic mechanism is not clear, but
this also demonstrates that antiarrhythmic effect does not result in obliteration of
the circuit. Although it has never been studied in a systematic manner, this
response is probably unusual.

Antiarrhythmic drugs may also work by altering the effects of arrhythmia
triggers, such as spontaneous or induced premature beats, so that they do not result
in the establishment of unidirectional block and subsequent reentry within the
circuit. This could be accomplished by (a) effects on intervening tissue such that
sufficiently premature stimuli do not reach the circuit; or (b) effects on refrac-
toriness within the circuit such that premature beats result in bidirectional block.
Hook et al. studied 22 patients with reproducibly inducible VT in the baseline state
who were not inducible with programmed stimulation at twice diastolic threshold
after antiarrhythmic drug therapy [40]. In 10 patients, high current strength
programmed stimulation at right ventricular sites resulted in initiation sustained

Page 413

nervous system, autonomic 157
nitroprusside 151
- infusion 150
nodal conduction time, atrioventricular 158
node, atrioventricular 342
norepinephrine 151

oxotremorine 244

pacemaker 393
pacing threshold 151
percutaneous coronary intervention 152
pharmacodynamics 161, 290
- adverse cardiac events 161
- antiarrhythmic drugs 161
- betadrenergic modulation 161
- CAST 161
- hepatic and renal function 161
- ventricular tachycardia 161
pharmacokinetics 290
pharmacology 23, 63
phase 2 reentry 66
- circus movement tachycardia 73
2-phenylisopropyl 338
phenytoin 12
pilsicainide 155
pinacidil 66
pirmenol 307
post -repolarization refractoriness 159
potassium 158
potassium channel blockers 155
potassium channel openers 276
potassium current 152
practolol 159
prazosin 244
premature ventricular complexe 208
prenylamine 159
prevention of recurrent ventricular

tachycardia 200
pro arrhythmia 39, 113, 147, 301, 307
- sustained monomorphic ventricular
tachycardia 301
pro arrhythmic drug 15
procainamide 7, 37, 123, 148
programmed electrical stimulation 127
- assessment of antiarrhythmic drug

efficacy 146
- infarct-related artery patency 138
- limitation 137
- methodologic considerations 128
- ventricular refractory period 303
propafenone 9, 134, 147, 181
propensity to ischemia 145
- loading condition 145
- myocardial distribution 145

Subject Index 409

- pharmacokinetics 145
propranolol 244, 312, 346

QT prolongation 251
QTc prolongation 159
quinidine 7, 36, 123, 159

recanalization 152
rectifier current, delayed (I K) 47
- K+ current 152
- species-dependence 47, 59
reentry 65, 146, 179, 190, 301, 324, 335, 352
- bundle branch 146
- double-wave 151,187
reflex variability 312
refractoriness 152
refractory period 157
reperfusion 153
repolarization 57
resting membrane potential 158
revascularization 156
reverse use-dependence 92
- almokalant 98
- amiodarone 98
- ion channel 98
- N-acetyl-procainamide 97
- sotalol 97
rhythm
- automatic 393
- reentrant 210
right ventricular outflow tract 146
Romano-Ward syndrome 251

safety of conduction 149
scanning force microscopy (s. SFM) 116
screening strategy 46
- class III drugs 46
selectivity 99
- -blocker 100
- depolarized tissue 99
- ischemic tissue 100
- Purkinje
- SA 99
sematilide 44,155
senescence 160
serial drug testing 128
- reproducibility 128
SFM (s. scanning force microscopy) 116
"Sicilian Gambit" 243, 300, 399
signal averaged elctrocardiography 306
"size-solubility" hypothesis 38
sodium antagonistic drugs 162
sodium channel 6
- antagonistic drugs 148
- blockade 3, 154

Page 414

410 Subject Index

sodium channel
- function 3
- state-dependent block 7
sodium channel blockers 149, 300
- flecainide 301
- procainamide 301
- propafenone 301
- quinidine 301
- nonsustained 301
sotalol 136, 156, 307, 324
- survival with oral d-sotalol 144
stereoisomers 292
stretch 150 .
- myocardial 150
-induced arrhythmias 146

T type Ca channel (ic,t) 23
T-wave 255
tachyarrhythmia
- atrial 147
- inducibility ventricular 151
- management of patients 122
- sustained ventricular 122
- ventricular 300
tachycardia 92
- acceleration 151
- adenosine-sensitive ventricular 355
- atrial 352
- atrioventricular 353
- drug-induced termination of ventricular

197
- supraventricular 335, 346, 357
- ventricular 122, 173, 208, 247, 336, 346

initiation 146
- - "natural history" 126
- - recurrences 131
- - sustained 146
tetrodotoxin 17
theophylline 337
threshold potential 158
thrombolytic therapy 152
tocainide 12
tone
- autonomic 215
- sympathetic 155
torsade de pointes 14, 65, 159, 251, 294, 327,

474

- complementary DNAs 296
- dofetilide 295
- early afterdepolarizations 375
- flecainide-induced ventricular

tachycardia 295
- incessant ventricular tachycardia 309
- N-acetylprocainamide 295
- polymorphic ventricular tachycardia

309
- quinidine 295
- sotalol 295
- transient ischemia 109
transient outward current 152, 296
- blockers 63

amiloride 65
4-aminopyridine 65

- - Bay K8644 65
cesium 65

- - erythromycin 65
- - hypokalemia 64
- - hypomagnesemia 64
- - quinidine 65
transient outward current I to 58

U-wave 255
unblocking 96
- quinidine 97
use dependence 42, 92
- characteristics 45
- "reverse" 45
use-dependent block 38, 89
- reverse use-dependent block 89
- ischemia 90

Vaughan-Williams classification 241,397
ventricular dilatation 150
ventricular ectopy 208, 307
ventricular hypertrophy 150
ventricular late potentials 307
ventricular refractory period 210
ventricular repolarization 245
verapamil 355
vivo model 208
voltage clamp techniques 160
vulnerable parameters 399

whole-cell patch voltage-clamp studies 152

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