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Antiarrhythmic electrophysiology and pharmacotherapy

Antiarrhythmic
Electrophysiology and
Pharmacotherapy

CHAPTER

40

Ibrahim O. Almasry, Cory M. Tschabrunn
Physiology

Sicilian Gambit

His-Purkinje Action Potential

Antiarrhythmics of Clinical Relevance in the CCU

SA Node and AV Node Action Potential

Conclusion


Classification

Cardiac arrhythmias continue to be a significant cause of morbidity
and mortality in the developed world and add to the complexity
of management of critically ill patients. Over the past 2 decades
treatment strategies have expanded to include other approaches
such as catheter ablation and implantable cardiac defibrillators.
Although these strategies have demonstrated significant superiority over antiarrhythmics, they have not eliminated the problem of cardiac arrhythmias. Furthermore, these approaches can
be difficult to apply to patients in the acute setting. Antiarrhythmic agents continue to be a vital adjunct to these therapeutic
approaches.
Despite the important role that antiarrhythmics play to combat cardiac arrhythmias, it has been difficult to overcome the
stigma associated with these drugs. This stigma has stemmed
from earlier published trials such as the CAST and CAST II trials evaluating class IC antiarrhythmics and the SWORD trial
evaluating sotalol in patients with coronary artery disease and
left ventricular dysfunction. These trials demonstrated increased
mortality, significant side effects, and marginal efficacy.1,2,3 The
Achilles heel of these agents is their propensity for proarrhythmia that results in more dangerous arrhythmias than the ones
they were initially intended to treat. This led to a re-evaluation
of the wisdom of using relatively simple agents that took aim
at single molecular targets, such as sodium or potassium channels. Subsequently, researchers pursued the development of
newer antiarrhythmic agents that target multiple molecules
or complex arrhythmogenic pathways, such as amiodarone or
d,l-sotalol. There was a renewed interest and emphasis on the
use of β-blockers, which do not specifically target ion channels.
In addition there has been significant interest in understanding
the genetic basis of susceptibility to serious arrhythmias in individuals with genetic syndromes such as long QT and Brugada
syndromes.
Despite their potentially serious side effects, antiarrhythmics
continue to be a valuable tool when used appropriately and in
a targeted manner. The aim of this chapter is to provide a clear
and concise overview of the physiologic basis and applicable
pharmacology that makes these drugs useful, and to discuss the
ones most clinically relevant to the management of the acutely
ill patient.

Physiology
Normal cardiac electrical activity is determined by the shape of
the cardiac action potential. Antiarrhythmic agents exert both
desirable therapeutic effects and undesirable side effects by their
capacity to alter the shape of the action potential. These actions


are mediated by their ability to affect the ion channels that control it. Therefore, a review of the basic physiology of the cardiac
action potential is imperative to understanding the mechanism
of action of these drugs.
Over the past 2 decades our knowledge and understanding
of cardiac cellular electrophysiology has increased as a result of
cutting edge techniques, such as the cloning and sequencing of
proteins and ion channels. A detailed description of the many ion
channels discovered to date, and their respective roles, is beyond
the scope of this chapter. A more fundamental approach to the
basic principles that produce the action potential is described.
A simplified model of the His-Purkinje action potential (fast
response tissue) is discussed first followed by descriptions of the
action potential of the sinoatrial (SA) and atrioventricular (AV)
nodes (slow response tissue).

His-Purkinje Action Potential
The His-Purkinje action potential can be conceptually divided
into periods of depolarization, repolarization, and resting states.
However, the action potential is traditionally divided into five
different phases (phases 0-4) to describe the activity of various
ion channels that bring about any of these three states (Fig. 40-1,
A and B). Phase 4 corresponds to the resting state when the cell
is not being stimulated and is ready for subsequent depolarization. Phase 0 corresponds to depolarization of the myocardial
cell. It initiates a cascade of events involving the influx and efflux
of multiple ions, leading to phases 1-3, manifesting in repolarization and refractoriness.
Phase 4
The normal resting membrane potential in the ventricular myocardium is between −85 to −95 mV. This membrane potential is
determined by the balance of inward sodium (Na+) and calcium


Antiarrhythmic Electrophysiology and Pharmacotherapy

IKto, fast
IKto, slow

+50

1

2

IKur + IKATP

mV

0

ICa(L)

0

3

–50
4
–90

A

4

IKs + IKr

INa
IK1 + Na-K pump

+50

IK1 IK1 + Na-K pump

K+ out
1

Phase 1 (Early-Rapid Repolarization)
This phase represents the initial stages of cellular repolarization
and is caused predominantly by closure of the fast acting Na+
channels. However, the net downward deflection of the action
potential is also attributable to transient outward flux of K+ ions
as a result of two K+ channels (Ito, fast and Ito, slow) opening and
then closing.

+
2 K out

mV

0
0

4
–90

B

3
Ca2+ in

–50

Na+

4
in

K+ out

­ embrane permeability to Na+. The slope of phase 0 represents
m
the maximum rate of cell depolarization (Vmax) and governs
the conduction velocity of a cardiac impulse through cardiac
cells. This can be altered by drugs such as the class I antiarrhythmics, which retard conduction velocity, and Vmax.
Voltage-gated Na+ channels can exist in either the resting,
open (phase 0), or inactive state. The response of these Na+
channels is dependent on the membrane potential at the time of
stimulation. If the membrane potential is at baseline (−95 mV),
then all resting Na+ channels open simultaneously, resulting in a
dramatic influx of Na+ ions. If, however, the membrane potential is above baseline (less negative), then some Na+ channels
may be in the inactive state and unable to open, resulting in a
smaller response with less influx of Na+ ions (lower Vmax). This
has clinical relevance as class I antiarrhythmics prefer binding to
inactive Na+ channels. Furthermore, this reduced cellular excitability may render cardiac cells prone to variable refractoriness,
delayed conduction, and various arrhythmias.

K+ out

Figure 40-1.  A, Ion channels responsible for the His-Purkinje action
potential. This diagram shows the action of the various ion channels
responsible for the His-Purkinje action potential over the time it takes
for a complete cycle of depolarization and repolarization. B, Ion flux
responsible for the His-Purkinje action potential. This diagram shows
the influx and efflux of various ions in the His-Purkinje action potential
over a single complete cycle of depolarization and repolarization; this
corresponds to the action of their respective ion channels seen in A.

(Ca2+) currents and outward potassium (K+) current. The equilibrium potential for a given ion is determined by the concentrations of that ion inside and outside the cell. K+ is the principal
cation intracellularly, whereas phosphate and conjugate bases of
organic acids are the dominant anions. Extracellularly, Na+ and
chloride (Cl−) are the principal cation and anion, respectively.
Therefore, when K+ channels open, K+ ions flow outside the cell
along their concentration gradient, leaving the cell with a more
negative membrane potential.
The resting membrane potential is generated by the inward
rectifier current (IK1), the predominantly open channel during
this phase. The maintenance of this electrical gradient is because
of various ion pumps and exchange mechanisms, such as the
Na+-K+ ion exchange pump and the Na+-Ca2+ exchanger current.
This phase of the action potential is associated with cardiac
diastole.
Phase 0 (Depolarization)
Rapid depolarization occurs when the resting cell is brought
to threshold causing activation (opening) of fast Na+ channels.
This results in rapid influx of Na+ ions caused by increased cell

Phase 2 (Plateau)
Although this phase may appear to be a particularly stagnant part
of the action potential, it is in fact one of the most complex and
dynamic portions. Multiple ions make small contributions resulting in a relatively constant, positive value of the membrane potential. The predominant forces are outwardly directed K+ ions and
inwardly directed Ca2+ ions, which maintain an equal balance. The
outward flux of K+ through the delayed rectifier K+ channel (IKur)
and through the ADP activated K+ channel (IKATP), is balanced
against rapid inflow of Ca2+ through L-type Ca2+ channels (ICa, L).
The plateau phase is unique to the cardiac cell and represents
an interruption to rapid repolarization, extending the duration
of the action potential and therefore the refractoriness of the
cardiac cell. The benefit of this is to allow for a single contraction
of myocardium to occur before the generation of a subsequent
action potential, thus the heart can never be “tetanized,” which
would be incompatible with cardiac function.4
Phase 3 (Repolarization)
L-Type Ca2+ channels are now closed while slow delayed rectifier K+ (IKs) channels are open and trigger opening of other
channels, such as the rapid delayed rectifier K+ channel (IKr).
This results in a net outward flux of positive cations, thereby
facilitating cellular repolarization. The IK1 channel is activated
late in phase 3 and continues on to contribute to the resting
membrane potential of phase 4.

SA Node and AV Node Action
Potential
SA and AV nodal action potentials are very similar with only
minor differences between them in phase 0. They are significantly different from fast response tissue's action potentials
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40


Pharmacologic Agents in the CICU

current” (If ) and an inward flow of calcium through T-type calcium channels (ICa T) all make the cell more positive. When the
threshold potential (−40 mV to −50 mV) is reached, the cells
enter the depolarization phase.

+30

IK

mV

0
0
–30

3

Threshold
4

4
–60

A

If

ICa(T)

ICa(L)
If

Phase 3—Repolarization
Calcium channels are rapidly inactivated with simultaneous decrease in sodium permeability. This is combined with
increased potassium permeability with resultant efflux of
potassium, slowly repolarizing the cell once more to its resting
­potential.

+30

mV

0
0
–30

B

3

Threshold
4

–60

Ca2+ In
Na+ + Ca2+ In
Less K+ out

Ca2+ In

4

More K+ out
No Na+ In

Figure 40-2.  A, Ion channels responsible for the sinoatrial/atrioventricular (SA/AV) node action potential. This diagram shows the
action of the various ion channels responsible for the SA/AV node
action potential (slow response tissues) over the time it takes for
a complete cycle of depolarization and repolarization. B, Ion flux
­responsible for the SA/AV node action potential. This diagram
shows the influx and efflux of various ions responsible for the SA/AV
node action potential (slow response tissues) over a single complete
cycle of depolarization and repolarization; this corresponds to the
action of their respective ion channels seen in A.

previously described. These slow response tissue action potentials are divided into three phases instead of five (Fig. 40-2, A
and B). Phase 4 is the spontaneous depolarization (pacemaker
potential) phase that triggers the action potential once the membrane potential reaches threshold (between −40 and −30 mV).
Phase 0 is the depolarization phase of the action potential. This
is followed by phase 3 repolarization. Once the cell is completely repolarized at about −60 mV, the cycle is spontaneously
repeated.
Phase 4—Spontaneous Depolarization
(Pacemaker Potential)
The unique firing of pacemaker cells is attributable to their
capacity to slowly and spontaneously depolarize. The resting potential of a pacemaker cell (−60mV to −70mV) is caused
by ongoing efflux of potassium ions. Potassium permeability
decreases with time, contributing to the slow depolarization.
Additionally a slow inward flow of sodium, called the “funny
490

Phase 0—Depolarization
The predominant ion activity during this phase is dependent
on the influx of calcium through L-type calcium channels as
opposed to sodium influx in fast response tissues. In fact INa
channels are largely absent from these cells.
The upstroke (Vmax) and therefore the conduction velocity in
a pacemaker cell is significantly slower than in the fast response
tissue cells, with the AV node action potential demonstrating a
faster Vmax than that of the SA node.5

Autonomic Innervation
Both sympathetic and parasympathetic nerve fibers are abundantly found in both the SA and AV nodes; however, parasympathetic nerve fibers are only minimally located in fast response
tissue. Therefore, parasympathetic tone fluctuations are notable in the SA and AV nodes with minimal or no effect on fast
response tissue.
Increased sympathetic tone results in enhanced automaticity,
increased conduction velocity (Vmax), and decreased refractoriness. These effects combine to produce an increased number of
action potentials that are propagated faster. Increased parasympathetic (vagal) tone has the opposite effect, with diminished
automaticity and conduction velocity but increased refractoriness. These observations have an important impact on clinical
arrhythmias and their management.
It is helpful to keep in mind the various roles of ion channels
on the different stages of the action potential, in both fast and
slow response cells, to achieve an understanding of the potential
key effects of antiarrhythmic agents. In addition, the VaughanWilliams classification of antiarrhythmic drugs is based upon
which ion channels they affect.

Classification
Vaughan-Williams
This is currently the most widely used classification of antiarrhythmic drugs (Table 40-1). This classification was initially
introduced by Vaughan Williams6,7 and was based on the electrophysiologic effects of antiarrhythmics. It was later modified
by Harrison8 with the recognition that drugs in the same class
have different potencies and that the same drug may exert multiple class effects.
Amiodarone has effects across all classes, blocking Na+ channels in depolarized tissues, but is also capable of affecting Ca2+
and K+ channels and adrenergic receptors. This makes it an
extremely versatile drug capable of affecting a wide variety of
arrhythmias. Sotalol has a significant β-blocker effect in addition to its class III action. Ibutilide can also enhance the slow
delayed sodium current. Although moricizine has diverse effects


Antiarrhythmic Electrophysiology and Pharmacotherapy
Table 40–1.  Vaughan-Williams Classification of Antiarrhythmics and Their Mechanism of Action
Class

Mechanism

I

Na+

Drugs

A

Slows conduction velocity (Vmax) and prolongs action potential. Results in decreased
conductivity and increased refractoriness.

Quinidine, procainamide,
­disopyramide

B

Minimal effect on conduction velocity (Vmax) and shortens action potential duration.
Results in decreased refractoriness.

Lidocaine, mexiletine

C

Significant slowing of conduction velocity (Vmax), minimal effect on action potential
duration. Results in decreased conductivity and no change in refractoriness.

Flecainide, propafenone,
­moricizine

II

β-blockers
Decrease sympathetic tone affecting SA and AV nodes

Atenolol, esmolol, propranolol

III

K+ channel blockers
No effect on conduction velocity with significant increase in action potential duration.
Results in no change in conductivity but marked increase in refractoriness.

Amiodarone, sotalol, dofetilide,
ibutilide, azimilide

IV

Ca2+ channel blockers
Affect SA and AV node by direct cell membrane effects

Verapamil, diltiazem
(non-dihydropyridine)

V

Other mechanisms
Affect SA and AV nodes by increasing vagal tone

Digoxin, adenosine

channel blockers

across different classes, this drug is not currently used because it
has been demonstrated to increase mortality.
Class I Antiarrhythmics and Use Dependence
Class I drugs are all Na+ channel blockers with varying potency
and are classified based on their effect on the action potential
upstroke or Vmax and therefore their ability to alter conduction
velocity. They can prolong it, shorten it, or have no net effect (Fig.
40-3). Their different potency is due to variable rates of binding
and dissociation from the channel receptor.9 Class IC are the
most potent Na+ channel blockers because they have the slowest binding and dissociation from the receptor; class IA are the
least potent (fastest binding and dissociation); and class IB are
moderately potent. Faster heart rates allow less time for drugreceptor dissociation, resulting in an increased total number
of blocked receptors and more effective antiarrhythmic action.
This is known as “use dependence” and is most noted with class
IC agents.10 These effects can result in prolonged conduction
velocity and manifest by widening of the QRS complex on the
surface electrocardiogram (ECG), especially during tachycardia.
Class III Antiarrhythmics and Reverse Use Dependence
Class III antiarrhythmic agents extend the plateau phase of
the action potential by blocking K+ channels. They effectively
prolong repolarization and the action potential duration with
a resultant increase in refractoriness without a change in conductivity (Fig. 40-4). This manifests as prolongation of the Q–T
interval on the surface ECG. These effects are most pronounced
during slow heart rates. This is known as “reverse use dependence” and thus, longer Q–T intervals are noted at slower heart
rates.11 This provides the potential for dangerous arrhythmias
such as torsades de pointes.12 This is known as proarrhythmia
and is one of the most serious, life-threatening side effects associated with antiarrhythmic drug use. Amiodarone, however,
appears to be the exception, with proarrhythmia being reported
only uncommonly.13

IA

IC
IB

• Class IA: Procainamide
– ERP
• Class IB: Lidocaine
– ERP
• Class IC: Flecainide
– ERP Unchanged
Figure 40-3.  Effect of class I antiarrhythmics on the His-Purkinje
action potential. All class I antiarrhythmics retard the slope of
phase 0 of the action potential resulting in a decrease of Vmax and
a ­decrease in the conduction velocity of the cardiac cell. Class IC
agents slow the upstroke of the action potential (Vmax) the most,
resulting in prolongation of the action potential. This prolongation causes a marked decrease in conductivity, but has little overall
­effect on the effective refractory period. Class IC agents do not alter
refractoriness significantly. Class IA agents slow the upstroke (Vmax)
moderately, prolonging the action potential, decreasing conduction
velocity, and increasing refractoriness. Class IB agents have a very
small effect on the Vmax, shortening the action potential, which
results in an overall decrease in refractoriness.

Class II Antiarrhythmics
These drugs act by competitive inhibition of the β-adrenergic
receptor, and largely affect the SA and AV node. Yet they also
have mild Na+ channel inhibitory effects. There is a preponderance of data demonstrating the antiarrhythmic properties
of β-blockers. β-blockers have played an increasingly important role in increasing survival in patients with coronary heart
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40


Pharmacologic Agents in the CICU

K+ blockade

to any of the other ion-based antiarrhythmics. These include
drugs such as digoxin and adenosine and will be discussed individually later in the chapter because of their potential utility in
the critical care setting

Sicilian Gambit
ERP
Figure 40-4.  Lengthening of effective refractory period on class III
antiarrhythmics. All class III agents cause a blockade of K+ channels.
As a result, the rate of outward flux of K+ is slowed down during
phases 2 and 3, which causes a prolongation of the time it takes
a cardiac cell to return to the resting membrane potential. This
prolongs the effective refractory period of the cardiac cell, resulting
in an increased time before it is ready for the subsequent depolarization.

­ isease and congestive heart failure, along with adjunctive therd
apy to implantable cardiac defibrillators (ICDs) by decreasing
the incidence of sudden cardiac death (SCD). Although not all of
the beneficial effects of β-blockers are understood it is likely that
they essentially work by reversing or preventing the proarrhythmic actions of sympathetic activity.14 These include increased
automaticity because of enhanced phase 4 depolarization in the
SA and AV nodes, increased membrane excitability in phase 2
and 3 of the His-Purkinje action potential, increased Vmax, and
increased delayed afterpotentials, which can lead to increased
triggered activity type arrhythmias. They are therefore most
effective in tissue under intense adrenergic stimulation (e.g., in
ischemia) and it is not surprising that their effects are most obvious in patients having acute myocardial infarction and decompensated heart failure.
Class IV
The non-dihydropyridine calcium channel blockers (verapamil
and diltiazem) are the only ones that exhibit significant electrophysiologic and antiarrhythmic properties. These are mediated
through their ability to block the slow calcium channel. Their
antiarrhythmic properties are exerted through two main effects.
Their most prominent activity is to block the slow calcium channel in the action potential of the SA and AV node, effectively
slowing phase 4 spontaneous depolarization. This results in a
variable slowing of the heart rate (similar to β-blocker–induced
adrenergic blockade)15 and slowing conduction through the AV
node, manifested by bradycardia and prolongation of the P-R
interval on the surface ECG.
The other action is their ability to shorten the plateau phase of
the action potential of ventricular myocytes, therefore inhibiting early afterdepolarizations (EADs).16 EADs are due to fluxes
in calcium and appear to occur mostly under conditions that
prolong the action potential (e.g., hypoxia, drug induced), giving
rise to torsades de pointes. Therefore, calcium channel blockers may play an active role in the prevention of these types of
arrhythmias.
Atypical Agents (Class V)
Although there is no designated class V in the Vaughan-­Williams
classification of antiarrhythmics, it is unofficially used to place
atypical agents whose antiarrhythmic properties do not belong
492

Although the merits of the Vaughan-Williams classification are
its simplicity and wide recognition, providing a useful mode
for communication regarding the use of antiarrhythmics, it
does not take into account several complexities. These include
drugs’ ability to exert effects that cross into different classes,
having variable potencies within the same class, and causing
other effects such as changes in metabolism, autonomic stimulation, or hemodynamics. The Sicilian gambit17 (Table 40-2)
was introduced as a method of rationalizing the approach to
the use of antiarrhythmics. Although not widely known and
far more complex in its original format, it is included here
for its emphasis on approaching antiarrhythmic drug choice
based on the mechanism of each individual arrhythmia and
the perceived “vulnerable parameter” that can be affected to
­terminate it.
Pharmacology
Pharmacologic concerns of drug therapy can be divided into two
main disciplines. The first is pharmacokinetics, which describes
the process of drug delivery to its target site. It encompasses
the processes of drug absorption, distribution, metabolism, and
elimination. This can be summarized in the relationship between
drug dose and plasma concentration over time. This should not
be confused with pharmacodynamics, which describes targetspecific drug interaction, and the resultant downstream whole
body effects. This can be thought of as the relationship between
drug concentration and magnitude of drug effect.
Obviously, both of these processes can then be impacted by
various factors such as drug absorption, bioavailability, volume
of distribution, drug clearance, elimination, and half-life. Due to
the complexity of drug transport and activity, genetic variability,
and the heterogeneous and often abnormal metabolic milieu of
the critically ill patient, significant interpatient variability can be
expected in their response to the same drugs.
Drug Absorption
This is the process by which orally administered drugs are
taken up from the gastrointestinal tract and enter into the
systemic circulation. Bioavailability describes the percentage
of drug that reaches the circulation unchanged, as compared
with ­intravenous drug administration, which represents 100%
­bioavailability.
In general, bioavailability can be altered by two main factors.
The first considers the successful gut uptake of the drug, which
can be affected by various factors such as drug dissolution rates,
different formulations, gastric pH levels, and bacterial flora. The
second main factor is presystemic (first pass) clearance through
the liver, where drugs may undergo metabolism, alteration, or
excretion by hepatocytes into the bile, thereby affecting bioavailability.
With rare exceptions, most drugs administered in the critical care setting are administered in the intravenous form and
therefore many of the issues surrounding drug absorption do
not apply in this circumstance.


Antiarrhythmic Electrophysiology and Pharmacotherapy
Table 40–2.  Sicilian Gambit (Modified)*
Mechanism

Arrhythmia

Vulnerable Parameter (Effect)

Drugs (Effect)

Enhanced automaticity

Inappropriate sinus tachycardia
Some idiopathic ventricular
tachycardias

Decrease phase 4 depolarization

β-blockers
Na+ channel blockers

Abnormal automaticity

Atrial tachycardia

Maximum diastolic potential
­(hyperpolarization)
Phase 4 depolarization (decrease)

Muscarinic receptor agonists

Automaticity

Accelerated idioventricular
rhythms

Ca2+ or Na+ channel blockers

Triggered Activity
Early afterdepolarization
(EAD)

Torsades de pointes

Shorten action potential duration
Suppress EAD

β-blockers
Ca2+ channel blocker; Mg2+;
β-blockers

Delayed afterdepolarization
(DAD)

Digitalis-induced arrhythmias

Calcium overload (unload)
DAD suppression
Calcium overload (unload)
DAD suppression

Ca2+ channel blockers
Na+ channel blockers
β-blockers
Ca2+ channel blockers

Right ventricular outflow tract
ventricular tachycardia
Na+ Channel-Dependent Re-entry
Long excitable gap

Typical atrial flutter
AV reciprocating tachycardia
Monomorphic VT

Depress conduction and excitability
Depress conduction and excitability
Depress conduction and excitability

Class IA, IC Na+ channel ­blockers
Class IA, IC Na+ channel ­blockers
Na+ channel blockers

Short excitable gap

Atypical atrial flutter
Atrial fibrillation
AV reciprocating tachycardia
Polymorphic and uniform
­ventricular tachycardia
Bundle branch reentry

Prolong refractory period
Prolong refractory period
Prolong refractory period
Prolong refractory period

K+ channel blockers
K+ channel blockers
Amiodarone, sotalol
Class IA Na+ channel blockers

Prolong refractory period

Class IA Na+ channel blockers;
amiodarone

Depress conduction and excitability

Ca2+ channel blockers

Depress conduction and excitability
Depress conduction and excitability

Ca2+ channel blockers
Ca2+ channel blockers

Ca2+ Channel-Dependent Re-entry
Atrioventricular nodal
­re­entrant tachycardia
AV reciprocating tachycardia
Verapamil-sensitive ventricular
tachycardia

*Classification of drug actions on arrhythmias based on their ability to modify a vulnerable parameter of the arrhythmia.
Adapted from the Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian gambit: a new approach to the classification of arrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991;84(4):1831-1851.

Distribution
A drug is distributed to the best perfused tissues first, termed
the central compartment, such as the heart, lungs, and brain.
Subsequently, it reaches less perfused tissues such as the skin
and muscle—the peripheral compartment. Some drugs such
as amiodarone have very slow distribution to tissues such as
adipose, termed the deep compartment, which prevent it from
reaching a steady state until these tissues are saturated.
The volume of distribution (Vd) of a particular drug refers to
a theoretical space or volume into which the drug is ­distributed
and can be used to describe the relationship between drug
dose and plasma concentration. This can in turn be affected
by changes in the actual plasma volume reflected by tissue

­ erfusion, as can be noted in cases of congestive heart failure
p
or shock. Alternatively, tissue affinity, fraction of drug bound to
proteins (only the free portion of a drug produces the desired
effect) and degree of lipid or water solubility can all play a role in
altering the volume of distribution.
A classic example is lidocaine administration in heart failure
patients. The Vd may be reduced by 40%18 because of decreased
perfusion and therefore unless lidocaine bolus doses are reduced
in these patients, lidocaine toxicity can result.
Most antiarrhythmics are bound to α1-glycoprotein. This
protein's concentration increases with acute and critical illness
(such as shock, trauma, or severe bacterial infection). The result
may be decreased effectiveness of the antiarrhythmic agent
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Pharmacologic Agents in the CICU

despite an unchanged plasma concentration, as the fraction of
unbound (free) active drug is smaller.
Metabolism and Elimination
Most antiarrhythmics are metabolized hepatically by the
cytochrome P450 system, and many undergo extensive first
pass metabolism. This accounts for the large ratio of oral to
­intravenous doses of such medicines as verapamil, metoprolol, or propafenone. Others such as lidocaine are so completely
­eliminated by the first pass effect that oral dosage is useless.19
Metabolism of the parent drug produces metabolites that may
or may not be active. Furthermore, these metabolites may have
similar or different effects than the parent drug. Classic examples include amiodarone metabolism to desethylamiodarone,
which accounts for a persistent drug effect beyond the drug's
half-life. Procainamide, however, a class Ia agent, is metabolized
to N-acetylprocainamide (NAPA), which has a predominant
class III effect.
A drug's half-life describes the time required to reduce a
plasma drug concentration by 50%. This may be secondary to
either drug metabolism and elimination or redistribution. It typically requires five half-lives to eliminate a drug from the plasma
completely and five half lives to achieve a steady state. Since only
three doses are required to achieve greater than 90% steady state
plasma concentrations, drug loading doses should only be used
when such an interval is clinically unacceptable such as in lifethreatening arrhythmias in critically ill patients. In such situations, a loading dose may be given to achieve desirable plasma
concentration levels much faster.20

Antiarrhythmics of Clinical
Relevance in the CCU
Although detailed accounts of every antiarrhythmic are available
elsewhere, the focus of this review is to discuss the antiarrhythmics that have the most clinical relevance to the management of
the critically ill patient in the acute care setting. Older medications no longer in current use and those that cannot be administered intravenously or are contraindicated in critical illness are
not discussed (Table 40-3).
Class IA
Of the drugs in this class, procainamide is the only agent with a
potential role in the modern critical care setting.
Procainamide
Procainamide is a Na+ channel blocker that results in reduced
Vmax associated with decreased conduction velocity and prolongation of the His-Purkinje action potential, and therefore
the effective refractory period.21 Its effect on prolongation of
the action potential is mediated through its active metabolite
N-acetylprocainamide (NAPA), which is a class III antiarrhythmic agent. In addition it can suppress automaticity in slow
response tissues (SA and AV nodes)22 and triggered activity in
normal Purkinje fibers.23
Clinical Effects
The surface ECG may reflect prolongation of the P-R interval and QRS intervals without significant effect on the RR
interval.24 Widening of the QRS is increased at faster heart
494

rates or high plasma concentrations.25 Widening of the QRS
to greater than 25% has been recommended as a useful end
point of procainamide's myocardial effect.26 In addition, prolongation of the Q–T interval can be seen and may herald
proarrhythmia.
Indications
Intravenous procainamide continues to be the drug of choice
for the acute treatment of atrial fibrillation in Wolf-ParkinsonWhite syndrome. However, ibutilide, as an alternative, has also
been shown to be effective for this.27 Procainamide's effect is
achieved through suppression of both antegrade and retrograde
conduction across accessory pathways, which reflects its ability
to increase refractoriness and decrease conduction velocity in
cardiac tissue.
Procainamide has been recommended above amiodarone and
lidocaine (level of evidence IIA) for acute resuscitation of hemodynamically stable wide complex tachycardia in patients with
normal cardiac function.28-29 Amiodarone, however, has been
advocated as an alternative. This is because of the fact that both
agents are effective in the treatment of ventricular and supraventricular tachycardias.
A versatile drug, procainamide can be administered in both
an oral and intravenous form. Prolonged oral use of procainamide, however, is not advocated because it is more poorly
tolerated than other currently available alternatives and is contraindicated in renal failure. Furthermore, the EVSEM trial
demonstrated procainamide and other class I agents to be less
effective in the treatment of ventricular tachyarrhythmias than
sotalol and amiodarone.30
Dosage and Administration
In the acute setting, it is administered with a loading dose of
15 to 18 mg/kg over 20 to 30 minutes, but this dose should
be reduced to 12 mg/kg in significant renal or cardiac impairment. Blood pressure and continuous ECG monitoring is
mandatory to detect acute hypotension, QRS, and Q–Tc prolongation. Alternatively, it can be administered intravenously
at a dose of 100 to 200 mg over 5 minutes to a maximum dose
of 1000 mg. ACLS guidelines suggest infusing 20 mg/min until
arrhythmia is controlled, hypotension occurs, QRS complex
widens by 50% of its original width, or a total of 17 mg/kg is
given. Maintenance intravenous infusion is administered at a
dose of 1 to 4 mg/min.
Pharmacokinetics
Procainamide is acetylated in the liver by N-acetyltransferase to
N-acetylprocainamide (NAPA), an electrophysiologically active
product with antiarrhythmic class III properties. This product
has a plasma half-life of 4 to 15 hours and is renally cleared. Rate
of acetylation varies individually and variation in renal clearance
makes monitoring of both procainamide and NAPA levels mandatory (sum of <80 μM) to prevent proarrhythmia, especially
torsades de pointes.
Side Effects
Procainamide is associated with a host of side effects that include
blood dyscrasia with potentially life-threatening pancytopenia
and agranulocytosis, which may be mediated by either allergic,
hypersensitive, or immunologic mechanisms. This can occur
days to weeks after drug initiation, and necessitates ­immediate


Antiarrhythmic Electrophysiology and Pharmacotherapy
Table 40–3.  Commonly Used Antiarrhythmic Agents in the ICU
Usual Dosage Ranges
Intravenous (mg)

Oral (mg)

Pregnancy Class

Half-Life
(hr)

Bioavailability (%)

Metabolism

250-1000
q4-6h

3-5

70-85

Kidneys

C

N/A

1-2

N/A

Liver

B

10-200 q6-8h

3-6

35-65

Liver

C

800-1600
qd for
7-14 days

200-600 qd

56 day

25

Liver

D

N/A

N/A

N/A

6

Kidneys

C

2 to 5 μg/kg
infusion

N/A

N/A

0.125-0.5
q12h

7-13

90

Kidneys

C

Verapamil

5-10 mg over
1-2 min

0.005 mg/kg/
min

80-120 q6-8h

3-8

10-35

Liver

C

Adenosine

6-18 mg
(­rapidly)

N/A

N/A

N/A

Digoxin

0.5-1.0 mg

0.125-0.25 qd

0.5-1.0

0.125-0.25 qd

Drug

Loading

Maintenance

Loading

Maintenance

Procainamide

12-18 mg/kg
at 0.2-0.5
mg/kg/min

1-4 mg/min

500-1000

Lidocaine

1-3 mg/kg at
20-50 mg/
min

1-4 mg/min

N/A

Propranolol

0.25-0.5 mg
q 5 min to
≤ 0.20 mg/
kg

Amiodarone

15 mg/min
for 10 min,
1 mg/min
for 6 hr,
0.5 mg/min
thereafter

0.5-1 mg/min

Ibutilide

1 mg over
10 min

Dofetilide

discontinuation of the drug. Cardiac side effects include left
ventricular dysfunction, hypotension, and proarrhythmia with
Q–T prolongation and torsades de pointes. Other nonspecific
systemic side effects include gastrointestinal disturbances with
nausea and vomiting, induced systemic lupus erythematosus
syndrome, pyrexia, headache, and psychosis.
Class IB
Both lidocaine and mexiletine are included in this classification; however, mexiletine is only available in an oral form,
which limits its use in the critical care setting. It may be
helpful in suppressing automatic or re-entrant ventricular
arrhythmias but this is only as an adjunct to other primary
antiarrhythmics.
Lidocaine
Lidocaine is a Na+ channel blocker of intermediate potency
and results in a decrease in Vmax and therefore decreased conduction velocity. In contrast to class IA or IC antiarrhythmics,
lidocaine causes a shortening of the action potential duration
probably through an increase in IK1 activity.31 It also depresses
automatic activity by decreasing the slope of phase 4 diastolic
depolarization. These effects are limited to Purkinje fibers

C
36-48

60-80

Kidneys

C

and little or no effect is seen on atrial myocardium or on slow
response tissues (SA and AV nodes).32 Interestingly, published
data from prior trials demonstrated an increased incidence of
asystole and bradycardia with lidocaine use33; however, this has
been debated.
Clinical Effects
Lidocaine is typically very well tolerated hemodynamically. Only
rarely, with very high doses, is blood pressure and cardiac output depressed due to reduced contractility and ejection fraction.
At therapeutic doses, there are no detectable changes on the
ECG.34
Indications
The role of lidocaine use and its potential benefits in acute
myocardial infarction has been the source of heated debate
as far back as the 1960s. Although earlier studies pointed to
a decreased incidence of primary ventricular fibrillation and
therefore reduced mortality, they were limited by lack of randomization and small sample sizes. Subsequent studies using
prophylactic lidocaine in acute myocardial infarction demonstrated a decreased incidence of ventricular fibrillation but
no significant decrease in all-cause mortality.35-36 Subsequent
495

40


Pharmacologic Agents in the CICU

Dosage and Administration
A loading dose of 1.5 mg/kg is administered over 2 to 3 minutes, followed by a maintenance infusion rate of 1 to 4 mg/
min. Since the bolus dose has a half-life of 15 minutes and
the maintenance infusion requires 2 to 3 hours to achieve a
steady state, repeated boluses may be required to achieve the
desired effect.44 A reduced dose is necessary in liver impairment or heart failure. Lidocaine can also be injected intramuscularly at a dose of 4 to 5 mg/kg, achieving therapeutic
concentrations more reliably via the deltoid than the gluteal
muscle.44
Pharmacokinetics
Lidocaine undergoes extensive first pass metabolism and is
therefore only administered in an intravenous form. It has a
short half-life of 3 hours and is metabolized to metabolites with
weak class I antiarrhythmic properties: glycinexylidide and
monoethylglycinexylidide. It is highly bound to α1-acid glycoprotein, which may be increased in heart failure, making the free
active drug less readily available. On the other hand, reduced
clearance and volume of distribution in heart failure result in
higher levels of the active drug, requiring a dosage reduction.
Therapeutic plasma lidocaine levels range between 1.5 to 5.0 μg/
mL and should be monitored.
Side Effects
The most common side effects are related to central nervous
system toxicity,45 with various mental status changes that are
usually mild and resolve with dose reduction. These are most
frequently seen in the elderly, patients with heart failure, and
those with liver impairment. Tremors are an early bedside sign
of toxicity. High plasma levels have been shown to provoke generalized seizures.46 Primary cardiovascular side effects include
sinus slowing, asystole, hypotension, and shock. These occur
with overdosing or with the overly rapid administration of
­lidocaine.
496

MORTALITY REDUCTION WITH HR
Reduction in HR (bpm)

meta-analyses also demonstrated a decreased incidence of
ventricular ­fibrillation but not overall mortality.33,37-39 These
findings were further compounded by an increasing body of evidence ­associating ­prophylactic antiarrhythmics with increased
mortality, including the IMPACT study.40 Mexiletine is often
considered to be an “oral” form of lidocaine. As a result, prophylactic lidocaine use in acute myocardial infarction is no longer
­recommended.41
Currently, ACLS guidelines only recommend the use of lidocaine in the setting of shock-refractory ventricular fibrillation or
pulseless ventricular tachycardia, and it is still not the preferred
agent, coming in after amiodarone.28 There is good evidence
that other agents are more effective.42
Lidocaine can be used in hemodynamically stable patients
with recurrent polymorphic ventricular tachycardia and prolonged Q–Tc at baseline (torsades de pointes), since amiodarone
and other Q–T prolonging agents should be avoided. However,
evidence suggests that administration of magnesium, rapid rate
ventricular pacing to 100 to 120 beats per minute, and isoproterenol infusion are more effective.43
Lidocaine can be used as adjunctive therapy in patients having acute ischemic ventricular tachycardia or ventricular fibrillation, after reversing the acute ischemic cause, and if refractory
to β-blocker and amiodarone therapy.

5

Pindolol
Propranolol
Carvedilol
Bisoprolol
Metoprolol
Timolol

20
0

5

10

15

20

Reduction in mortality (%)
Figure 40-5.  Relationship between the highest reductions in
mortality in patients receiving β-blocker therapy with the greatest
reductions in heart rate (HR). (Adapted from Kjekshus JK: Importance of heart rate in determining beta-blocker efficacy in acute
and long-term acute myocardial infarction intervention trials. Am J
Cardiol 1986;57:43F-49F.)

Class IC
This class of antiarrhythmics is not used in the modern day critical care setting. This is primarily due to the results of both of the
CAST and CAST II trials.1,2 Both trials were ended prematurely
after investigators noted a significant increase in arrhythmic
deaths in patients treated with encainide, flecainide, and moricizine versus a placebo for suppression of premature ventricular
contractions following myocardial infarction.
Class II
β-blockers have had a major impact on the treatment of cardiac
arrhythmias. They are the only antiarrhythmics with a proven
mortality benefit in the treatment of patients with acute myocardial infarction, coronary artery disease, and congestive heart
failure. Although there are many different β-blockers, they are
generally considered to possess a class effect with most of them
providing equal benefit when titrated to equivalent therapeutic
dosage. They may be generally classified into those with selective
β1 (cardiac) and those with β2 (noncardiac) activity. Some have
both. In addition, carvedilol also possesses α1-blocking activity
and is seen as primarily beneficial in patients with congestive
heart failure.
Some β-blockers such as pindolol also exert an intrinsic sympathomimetic action, which results in moderate activation of
the β-receptor. This can ultimately result in an attenuated bradycardic effect or even a tachycardic response. This may have an
adverse effect in patients with ischemic heart disease, and in fact
the best mortality benefit has been demonstrated in β-blockers
with the most bradycardic effects (Fig. 40-5).
The electrophysiologic effects of β-blockers are numerous but
are thought to be predominantly due to blockade of the deleterious effects of adrenergic stimulation. These deleterious effects
include abnormal automaticity due to enhanced phase 4 spontaneous depolarization, delayed after depolarizations (DADs) and
triggered activity, and re-entrant excitation.47 β-blockers have a
profound effect on both the SA and AV nodes because of their
dense adrenergic innervations, whereas they have a minimal to
moderate effect on atrial, ventricular, and accessory pathway tissues unless these tissues are ischemic.
They also exert a membrane-stabilizing effect, which
depresses excitability, delays conduction velocity, and prolongs
refractoriness. In addition, β-blockers have been shown to


Antiarrhythmic Electrophysiology and Pharmacotherapy
Table 40–4.  Commonly Used β-blockers in the Critical Care Setting
Drug
Atenolol

β1 Potency

β1 Selectivity

1.0

++

IV Dosage

Half-Life

Elimination

Other Properties

5 mg every 10 min up to 10 mg

6-9 hr

Renal

None

Metoprolol

1.0

++

5 mg every 2-5 min up to 15 mg

3-4 hr

Hepatic

None

Esmolol

0.02

++

500 μg/kg loading dose then
50-300 μg/kg/min

9 min

Blood esterases

None

Propranolol

1.0

0

1 mg/min up to 5 mg

3-4 hr

Hepatic

Membrane
­stabilizing action

Labetalol

0.3

0

20 mg IV push then 40-80 mg
every 10 min up to 300 mg,
or infusion at 2 mg/min up to
300 mg

3-4 hr

Hepatic

α-Blocker

increase the ventricular fibrillation threshold, making ventricular
tachycardia less likely to degenerate into ventricular fibrillation.
This is probably the reason for the reduced incidence of sudden cardiac death noted in congestive heart failure trials using
β-blockers.48,49,50
Indications
β-blockers can be used for a wide variety of cardiac arrhythmias.
These include supraventricular arrhythmias such as sinus tachycardia without an underlying reversible cause such as that seen
in inappropriate sinus tachycardia or temporarily in hyperthyroidism until the primary disorder is addressed.51 They are also
useful in slowing the ventricular response in arrhythmias such
as atrial fibrillation, atrial flutter, or atrial tachycardia.51 They
should not be used with the aim of converting these rhythms
to sinus rhythm because they are ineffective, given their modest effects on nonischemic atrial and ventricular muscle tissue.
Their activity is most effective on adrenergically innervated tissue, such as the SA and AV nodes.
Ventricular arrhythmias in the peri-infarct or post–coronary
artery bypass surgery period, likely related to ischemic tissues, respond well to β-blocker therapy. They are also effective
in suppression of adrenergically mediated or exercise induced
ventricular arrhythmias such as right ventricular outflow tract
tachycardias. β-blockers have also been shown to be effective
in reducing sudden cardiac death in patients with long QT syndrome.
Dosage, Administration, and Pharmacokinetics
Multiple β-blockers are currently available for intravenous
administration to critically ill patients. Listed here are the most
commonly available of these drugs, appropriate doses, and
routes of elimination (Table 40-4).
Side Effects
There is concern about exacerbating heart failure in patients
with borderline compensation, as sympathetic drive may play an
important role in maintaining cardiac output. Despite this concern, the evidence is that β-blockers are beneficial in heart failure patients and this effect of exacerbating heart failure was only
observed in 6% of patients treated with carvedilol.52 Although
increased dizziness and hypotension may occur, the absolute
increase of these side effects was small and did not necessitate
drug discontinuation in studies.53 Significant bradyarrhythmias

have been noted in patients with SA node dysfunction or preexisting AV node disease and may require back-up pacing if
drug administration is necessary for the treatment of concomitant tachyarrhythmias.
Noncardiac adverse effects include exacerbation of bronchospastic disease, but this is typically observed with nonselective
β-blockers. β1 selective agents do not confer complete protection and should be used cautiously in these patients initially.
The same applies to the use of β-blockers in patients with severe
peripheral vascular disease because the drugs may exacerbate
their symptoms; however, this is less noted with β1 selective
agents.54
Retarded response to hypoglycemia due to blockade of epinephrine has been observed; however, data suggest that this is
less serious with β1 selective agents.55 Although fatigue, depression, and sexual dysfunction are often-cited side effects, a systematic review of randomized trials found only small increases
in these effects.56
Class III
This class includes amiodarone, ibutilide, sotalol, dofetilide,
azimilide, and bretylium. It is important to note that while
classified as a class III agent, amiodarone has multiple actions
across different classes. Since neither intravenous sotalol or
azimilide have been approved by the Food and Drug Administration in the United States, they are unavailable for use in this
country. In the presence of amiodarone and ibutilide availability, there is little use for dofetilide in the critical care setting.
Bretylium is not currently used in modern medicine; therefore
a discussion of the first two drugs only will be addressed in this
chapter.
Amiodarone
Amiodarone is considered by some to be the most effective antiarrhythmic agent currently available. It is available in both intravenous form and oral tablets. Its wide range of effects across
different antiarrhythmic classes makes it suitable for both acute
therapy and long-term management of a host of arrhythmias
with different mechanisms. These range from automatic to reentrant supraventricular and ventricular arrhythmias. It has
a very low incidence of proarrhythmia,57-5 making it ideal for
administration in acute critical illness or for outpatient initiation. Its Achilles heel is its wide range of side effects that become
more common with long-term therapy.
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40


Pharmacologic Agents in the CICU

Initially developed in Belgium as an anti-anginal agent in
1962, it was later approved by the FDA for the treatment of ventricular arrhythmias in 1985. It is classified as a class III antiarrhythmic agent because of its effect of prolonging the action
potential duration and increasing the refractory period of atrial
and ventricular tissue.60 It has this effect by virtue of its ability
to block IKr, but also IKs with chronic use. In addition, it inhibits Na+ and Ca2+ currents, which are class I and IV properties,
respectively.60 Its class I properties can result in widening of
the QRS complex. It also has weak class II (β-blocker) activity
and α1-blocking action with resultant bradycardia and vasodilation, which may mediate its anti-ischemic effects. Finally,
it decreases peripheral conversion of T4 to T3 and impairs T3
binding to myocytes, resulting in hypothyroid metabolism in
cardiac cells.61
The degree of amiodarone's various properties and antiarrhythmic effects varies depending on whether it is given in an
intravenous or oral preparation. Compared with the intravenous form, the oral preparation of amiodarone results in a more
significant increase in action potential duration of atrial and
ventricular tissues, slowing of phase 4 depolarization and automaticity, ventricular refractoriness, prolongation of the Q–Tc
interval, and blockade of T4 to T3 conversion.62
Clinical Effects
As a result of the various effects of amiodarone, the ECG may
reflect slowing of the sinus rate, prolongation of the P-R interval
and earlier Wenckebach block due to increased AV node refractoriness. In addition, widening of the QRS may also be noted.
Q–Tc prolongation is also observed but is generally well tolerated and rarely causes proarrhythmia.
Due to its ability to prolong the action potential and increase
refractoriness, it affects a re-entrant circuit of arrhythmia by
prolonging the wave length and decreasing the excitable gap.
This results in the leading edge of the re-entrant circuit colliding
with the wake of the tail edge of the circuit, thereby extinguishing the re-entrant circuit and terminating the arrhythmia. As
with other class III agents, it exhibits reverse use dependence
properties with less efficacy noted at higher heart rates and
more Q–Tc prolongation and proarrhythmia noted at slower
heart rates.
In addition to its bradycardic effect, amiodarone results in a
drop in blood pressure probably secondary to its β-blocker, calcium channel blocker, and α1-blocking actions. This can result
in increased cardiac output secondary to a reduction in afterload.63,64 In addition, its smooth muscle relaxation effect results
in coronary artery vasodilation, thereby potentially decreasing
coronary ischemia, which may also contribute to its antiarrhythmic properties. It does not depress left ventricular function,65
thereby avoiding heart failure exacerbations. For these reasons,
it is safe and approved for use in patients with left ventricular
dysfunction.
Indications
Amiodarone is a unique antiarrhythmic agent because of its
multiple class effects. It is effective in the acute treatment of
both ventricular and atrial arrhythmias; however it is currently
approved by the FDA for the treatment of life-threatening ventricular arrhythmias only.
The most recent ACLS guidelines recommend amiodarone for
the treatment of ventricular fibrillation or pulseless ventricular
498

tachycardia after cardioversion shocks. It is also recommended
for treatment of stable monomorphic ventricular tachycardia or
stable polymorphic ventricular tachycardia with a normal Q–T
interval on the baseline ECG.28
Part of the controversy surrounding the use of amiodarone
has been the conflicting results of different antiarrhythmic trials.
For the secondary prevention of sudden cardiac death, the CASCADE trial demonstrated amiodarone to be more effective than
conventional therapy.66 On the other hand, both the EMIAT and
CAMIAT studies for the primary prevention of sudden cardiac
death demonstrated amiodarone reduced cardiac death compared with a placebo but had no effect on all-cause mortality.67,68
The GESICA trial concluded that amiodarone significantly
reduced mortality in a population of mostly nonischemic cardiomyopathy,69 but this was contradicted by the CHF-STAT study
that had more ischemic cardiomyopathy patients and showed
no mortality difference.70 The more recent SCDHeFT trial had
both ischemic and nonischemic cardiomyopathy patients and
showed amiodarone was no more effective than a placebo in the
primary prevention of sudden cardiac death.71
Amiodarone is very effective for the treatment of atrial
arrhythmias, especially atrial fibrillation. In the CTAF study,
amiodarone was more effective at maintaining sinus rhythm
than sotalol or propafenone.72 This was also echoed by findings
from the SAFE-T trial, which compared amiodarone to sotalol
or a placebo.73 The ability to use amiodarone in critically ill
patients for rate control, maintaining sinus rhythm, and improving hemodynamics, makes its use even more applicable to the
acute care setting. Similar to β-blocker therapy, multiple studies
have shown amiodarone to be effective in decreasing the incidence of postoperative atrial fibrillation following cardiac surgery, possibly resulting in shorter hospital stays, cost reduction,
and decreased morbidity.74
Dosage and Administration
In the critical care setting, intravenous administration is the
most relevant route of administration. Whether for recurrent
hemodynamically unstable ventricular tachycardia or for atrial
fibrillation with a rapid ventricular response, a loading dose of
150 mg given over 10 minutes is recommended. This is followed
by an intravenous infusion at a rate of 1 mg/min for 6 hours
and then 0.5 mg/min, delivering a total of 1050 mg in 24 hours.
Central venous access catheter delivery is preferable since concentrations above 2 mg/mL can result in significant peripheral
vein phlebitis.
Oral administration of amiodarone is associated with a
delayed onset of action of approximately 2 to 3 days because of
its highly lipophilic nature, resulting in a very large volume of
distribution. This is also the reason for its prolonged half-life,
which can be up to 25 to 100 days.
Pharmacokinetics
Amiodarone undergoes deiodinization and is metabolized in the
liver to desethylamiodarone, an active metabolite with properties similar to the parent drug but a much longer elimination
half-life. It is subsequently excreted via hepatic and gastrointestinal routes. Dose adjustment is necessary in patients with
hepatic impairment and routine hepatic liver function monitoring is required. Renal metabolism or elimination does not
occur at all and amiodarone is not removed by either peritoneal or hemodialysis. Consequently no dosage adjustment is


Antiarrhythmic Electrophysiology and Pharmacotherapy

required in patients with renal insufficiency or in those receiving
­hemodialysis.
Intravenous amiodarone can achieve peak drug levels in as
little as 30 minutes to a few hours following administration.
With oral long-term administration it may take several weeks
or months to achieve a steady state. This is due to amiodarone's
highly lipophilic nature causing it to have a large volume of distribution. Consequently, complete saturation of peripheral tissues, such as adipose, muscle, liver, and spleen, needs to occur
before achieving a steady state.
Side Effects
In the acute care setting, amiodarone is typically given to critically ill patients with significant arrhythmias. Hemodynamic
and arrhythmia monitoring is the rule in such patients to detect
potential side effects such as significant hypotension with intravenous administration of the drug. Regular Q–Tc monitoring is
important to detect rare episodes of torsades de pointes (1% to
2% incidence). Telemetry allows the detection of bradyarrhythmias because of decreased automaticity or AV node refractoriness, although this is less common with the intravenous form of
amiodarone.
Long-term oral therapy with amiodarone is associated with
a host of potential side effects. These include cardiac bradyarrhythmias, pulmonary fibrosis, hepatic dysfunction and cirrhosis, hyperthyroidism and hypothyroidism, skin discoloration,
optic neuritis, CNS dysfunction, peripheral neuropathy, and
many others. This underscores the need for routine physical
examinations and biannual blood tests.
Ibutilide
Ibutilide is a class III agent that is available only in an intravenous
formulation because of extensive first pass metabolism making
an oral formulation ineffective.75 It blocks IKr during phase 3 of
the action potential with a resultant increase in action potential
duration and refractoriness of both atrial and ventricular tissue.
This is manifested by Q–Tc prolongation and the potential risk
for proarrhythmia. It also blocks a slow sodium current during
the repolarization phase of the action potential. Like other class
III agents, it exhibits reverse use dependence with longer Q–Tc
prolongation at slower heart rates.
Clinical Effects
Ibutilide has minimal effects on heart rate and its major effect
on the surface ECG is prolongation of the Q–Tc. It is very
well tolerated hemodynamically and is not associated with
hypotension.
Indications
Ibutilide is indicated for the acute conversion of atrial fibrillation or atrial flutter to sinus rhythm. Although electrical cardioversion is far more successful, ibutilide can be used to achieve
chemical cardioversion without necessitating anesthesia typically required for electrical cardioversion. It is most successful in
treating atrial fibrillation or atrial flutter of relatively short duration.75 It can also be given to facilitate electrical cardioversion
in patients that are difficult to cardiovert electrically and have
required multiple shocks or exhibit early recurrence of atrial
fibrillation after electrical cardioversion.76 In addition, ibutilide
has been shown to be as effective as procainamide in terminating atrial fibrillation with WPW syndrome.77

Dosage and Administration
Due to its potential for proarrhythmia, ibutilide should be
administered with continuous telemetry. Electrolytes should be
optimized (especially serum magnesium and potassium levels),
and an external defibrillator should be available in case of polymorphic ventricular tachycardia.
The typical dose is 1 mg to be infused over 10 minutes,
which can be repeated again in 10 minutes if the first dose
was ineffective and if there is no significant lengthening of the
Q–Tc. In patients less than 60 kg, the recommended dose is
0.01 mg/kg. If marked prolongation of the Q–Tc is noted during
administration of the infusion, or if cardioversion occurs, the
infusion should be stopped. Continuous telemetry monitoring is
mandatory for at least 4 hours and preferably 6 hours following
the end of the infusion.
Pharmacokinetics
Available only in an intravenous form, it is metabolized hepatically into many metabolites, although only one has a weak antiarrhythmic effect. These metabolites are renally excreted. The
half-life ranges between 2 to 12 hours and can be quite prolonged in hepatic dysfunction.
Side Effects
The most common side effect of this intravenous agent is proarrhythmia. Torsades de pointes has been observed in various
studies with an incidence that varied between 3.6% and 8.3%,
with episodes requiring emergency cardioversion occurring
in 1.7% to 2.4%.78,79 The risk of developing proarrhythmia was
highest in patients with heart failure.
Class IV
Only the nonhydropyridine agents in this group of medications,
verapamil and diltiazem, appear to exert electrophysiologically
significant cardiac effects. Their effects are mediated through their
ability to block the slow calcium channel in slow response cardiac
tissue (SA and AV nodes), resulting in slow phase 4 depolarization and decreased conduction velocities. This property makes
them ideal for slowing the ventricular response in atrial arrhythmias, such as atrial fibrillation or atrial flutter. In addition they
seem to have antiadrenergic properties very similar to those seen
with β-blockers, which also contributes to slowing of the heart
rate. Although they typically do not affect ventricular tissue, they
have been noted to affect calcium flux across the cell membrane
in conditions of metabolic disturbance. This milieu is thought to
be responsible for the occurrence of early after depolarizations
(EADs), which are the arrhythmic mechanism of torsades de
pointes. This property seems directly related to their ability to
shorten the plateau phase of the ventricular action potential.
Clinical Effects
Calcium channel blockers cause slowing of phase 4 depolarization in the SA and AV node, in addition to increasing refractoriness of the AV node. Both the sinus and the ventricular response
rate slow down. Sinus slowing and P-R interval prolongation are
noted on the surface ECG. Typically there are no other changes
in the duration of the QRS complex and Q–T interval. They
exhibit use dependence properties with increasing efficacy at
higher heart rates.
Calcium channel blockers can also induce peripheral vasodilation through their smooth muscle relaxation properties. This
499

40


Pharmacologic Agents in the CICU

is noted slightly more with diltiazem than it is with verapamil
and may result in hypotension. They also exert a mild negative
inotropic effect, making them unsuitable in the management of
hemodynamically unstable patients or patients with heart failure exacerbations having supraventricular tachycardias.
Indications
The most common indication for using calcium channel blockers is for the treatment of supraventricular tachycardia. Intravenous verapamil or diltiazem are probably equally effective.
They are also commonly used for slowing the ventricular rates
in atrial fibrillation or atrial flutter.
Although they are typically not used in the treatment of ventricular tachycardias, they do have a role in the treatment of
certain ventricular tachycardia entities, such as right ventricularoutflow tract tachycardia or rare tachycardias, such as verapamilsensitive ventricular tachycardia or familial catecholaminergic
polymorphic ventricular tachycardia.
Dosage and Administration
Both verapamil and diltiazem can be administered intravenously with equal efficacy when rapid control of ventricular
rate in atrial arrhythmias, or termination of paroxysmal supraventricular tachycardia, is desirable.80 The verapamil loading
dose is 5 to 20 mg administered over 2 minutes and lasts for
up to 6 hours. A maintenance intravenous infusion at a rate of
0.005 mg/kg/min can be administered in patients who cannot
take the oral form. Short acting or extended release tablets are
available and the daily dose ranges between 240 mg to 480 mg
daily. Diltiazem can be loaded with a 20 mg bolus administered
over 2 minutes, and a maintenance infusion of 5 to 15 mg can
then be used if required. Repeated boluses can be given, if necessary, 15 ­minutes ­following the initial bolus. Extended release
oral tablets are available starting at a dose of 180 mg up to a
maximum of 540 mg daily.
Pharmacokinetics
Both verapamil and diltiazem undergo extensive first pass effect,
with only 35% to 40% bioavailability noted with the oral formulations. Both are metabolized in the liver but diltiazem is only
partially excreted by the kidney (35%), and the rest is excreted
through the gastrointestinal tract. Verapamil on the other hand
is mostly excreted by the kidney.
Side Effects
Both drugs are generally well tolerated orally with only mild
effects noted as a result of mild hypotension, such as facial
flushing or dizziness. Intravenous administration can cause
significant hypotension. Diltiazem does not appear to have the
same drug interaction noted with verapamil, which interacts
with amiodarone and dofetilide, resulting in excessive sinus rate
slowing and possible sinus arrest. Both drugs can potentiate the
hypotensive effects of β-blockers and increase the degree of AV
node refractoriness in patients receiving digoxin.
Atypical Antiarrhythmics
Digoxin
Digoxin is the most readily available form of digitalis and is
derived from the foxglove plant. The use of this cardiac glycoside has been documented for hundreds of years. It is listed as
an atypical antiarrhythmic agent because its electrophysiologic
500

effects do not conform to any of the other previously described
antiarrhythmic classes.
Digoxin has direct actions such as decreasing automaticity of
the SA node and increasing the refractoriness of the AV node.
Its most prominent effects, however, are its indirect effects of
increasing parasympathetic activity and inhibiting sympathetic
activity.81 This explains why it has little or no effect in transplanted hearts and has decreased efficacy in critically ill patients
with elevated levels of sympathetic activity commonly encountered in the critical care setting.
In the atria it shortens the plateau phase, which results in
decreased refractoriness with resultant increased atrial depolarization rates. It can also decrease the refractory period of
accessory pathways. This combination of effects makes it contraindicated in patients with Wolff-Parkinson-White syndrome
because it may facilitate an accelerated ventricular response to
atrial fibrillation in these patients, which may precipitate ventricular fibrillation.
Clinical Effects
At therapeutic doses there are typically no obvious ECG effects.
Sinus rate, P-R, and QRS intervals are usually unchanged.
Patients with significant sinus rate slowing are those with preexisting sinus node dysfunction. A well-known positive inotropic agent, this property has been attributed to digoxin's ability to
inhibit Na+-K+ ATPase, which results in increased intracellular
calcium that affects excitation-contraction coupling favorably.
This may also be the basis for some of the drug's proarrhythmic
effect. This positive inotropic activity can result in diuresis in
patients treated with digoxin. Although digoxin may improve
the symptoms of heart failure and decrease hospitalizations,
it has been shown not to decrease mortality in heart failure
patients.82
Indications
The most common indication for digoxin is to slow the ventricular rate of atrial fibrillation or atrial flutter. In this modern era,
however, it should not be used as first-line therapy for this indication. An understanding of the electrophysiologic effects of this
medication reveals why it is not ideally suited for treatment of
patients in the acute care setting. Furthermore, better and more
reliable rate control can be achieved with other medications,
such as β-blockers or calcium channel blockers, which can be
more tightly titrated and are readily available. Infrequently,
digoxin can be used as adjunctive therapy in patients with atrial
fibrillation and rapid ventricular response refractory to a combination of β-blocker and calcium channel blocker therapy. Also,
in patients who are hemodynamically intolerant of β-blocker
therapy or calcium channel blocker therapy due to hypotension,
digoxin may be useful because it generally does not cause significant hypotension.
Dosage and Administration
When rapid therapeutic serum levels are required, digoxin
can be loaded with a dose of 0.5 to 1.0 mg intravenously to be
divided over 18 to 24 hours, with a resultant peak effect in 2
to 4 hours. Typically the first administered dose is 0.5 mg followed by 2 doses of 0.25 mg. Daily maintenance doses are 0.125
to 0.25 mg orally, but the equivalent intravenous dosage should
be reduced by 20% to 25%. These doses should be reduced in the
elderly and in patients with renal insufficiency. Digoxin serum


Antiarrhythmic Electrophysiology and Pharmacotherapy

levels can be helpful initially to ascertain that a therapeutic level
has been achieved after loading. Serum concentrations of 0.8 to
2.0 ng/mL are the goal. A serum concentration higher than 2.0
indicates toxicity and the potential for proarrhythmia.
Pharmacokinetics
Oral administration results in absorption by the stomach and
small intestine with resultant bioavailability of 60% to 80%.
Although digoxin is metabolized in the liver, it is excreted by
the kidney almost unchanged. It has a 36 to 48 hour half-life, but
this may be longer in patients with renal insufficiency. Digoxin
levels are not significantly altered by hemodialysis because it is
extensively protein-bound.
Side Effects
Digoxin has significant drug-to-drug interactions with a host
of medications but notably with amiodarone and verapamil
because both decrease its metabolism and can result in elevated
levels of digoxin. Digoxin toxicity is more likely to occur in the
presence of renal failure, advanced age, and electrolyte abnormalities such as hypomagnesemia and hypokalemia. The latter
does so by decreasing renal tubular secretion of digoxin and
increasing tissue binding of the drug. Elevated levels of calcium
can predispose to increased delayed afterdepolarizations, which
is one of the main proarrhythmic mechanisms of digoxin, in
addition to increased sympathetic activity with enhanced automaticity.
Noncardiac manifestations of digoxin toxicity include
anorexia, nausea, and vomiting. Gastrointestinal symptoms are
typically early signs of toxicity. Central nervous system symptoms include headaches and visual disturbances, such as halo
vision, scotoma, and altered color perception.
Cardiac toxicity is typically in the form of various arrhythmias.
Almost any type of arrhythmia has been reported with digoxin
toxicity; however, classical examples include atrial tachycardia
with advanced AV block and accelerated junctional rhythms, in
addition to bidirectional ventricular tachycardias.
Treatment of toxicity usually involves stopping the medication
in patients who are hemodynamically stable along with correction of electrolyte abnormalities. Administering calcium should
be avoided as this can precipitate life-threatening arrhythmias
by further increasing potassium levels in a setting of ­preexisting
hyperkalemia secondary to digoxin toxicity. In patients who are
unstable as a result of their arrhythmias, digoxin immune FAB
antibody can be administered to bind digoxin, which can be
lifesaving.83 Cardioversion should be avoided in digoxin toxicity and if absolutely necessary, should be done at low energy as
this may precipitate ventricular fibrillation because of the preexisting myocardial increased excitability.
Adenosine
Adenosine is an endogenous nucleoside found throughout the
whole body. It has become the drug of choice for aiding in the
diagnosis of supraventricular tachycardias and terminating both
AV reciprocating tachycardia and AV nodal re-entrant tachycardia.
It plays an important role as a biochemical intermediate
and regulator of cellular metabolism. Its actions are mediated
through its interaction with A1 and A2 receptors, in addition to G proteins, to exert effects on potassium and calcium
­channels.

Adenosine primarily activates the IKAdo outward potassium
current, which is absent in ventricular tissue but present in atrial
tissue,84 causing shortening of the action potential in the atria.
It inhibits the “funny” channel (If ), which results in decreased
sodium influx in SA and AV node tissue. This decreases automaticity in these tissues and therefore has a negative chronotropic
effect. Its indirect actions include inhibition of intracellular
cAMP generation, which in turn decreases the catecholamine
driven inward calcium current and transient inward current.
These essentially anti-adrenergic effects may play a role in its
antiarrhythmic properties. It also has the ability to decrease the
sinus node rate by decreasing sinus node and atrial automaticity,
in addition to decreasing both sinus node and AV node conduction properties.
Indications
Adenosine is indicated for the rapid termination of supraventricular re-entrant tachycardias. It affects the antegrade slow pathway more readily than the retrograde fast pathway in patients
with dual pathway physiology. Similarly, it affects the antegrade
fast pathway limb of bypass mediated tachycardias more than
the retrograde bypass limb of the tachycardia. This means that
administration of adenosine can terminate both types of these
re-entrant supraventricular tachycardias, which are AV node
dependent, by affecting the antegrade limb of the tachycardia.
Typically the last cardiac activation noted is atrial activity manifested by a nonconducted P wave at the break of the tachycardia
before resumption of normal sinus rhythm. This may be difficult
to see, however, as sometimes the P wave is obscured by the
preceding QRS complex.
In atrial tachycardias or atrial flutter, the typical response
to an adenosine bolus is the occurrence of complete AV node
block, which can be profound sometimes, without termination
of the atrial arrhythmia itself. The atrial arrhythmia may now
be seen more clearly because of the absence of QRS complexes.
The caveat is that approximately 10% of atrial tachycardias are
adenosine sensitive and can terminate with administration of
adenosine resulting in a misleading diagnosis of the mechanism
of the arrhythmia.
Adenosine is also useful in terminating a type of idiopathic
ventricular tachycardia that typically has left bundle inferior axis
morphology and occurs in structurally normal hearts.85 These
tachycardias originate from the right ventricular outflow tract
and are adrenergically driven. They are thought to be due to
delayed afterdepolarizations caused by cAMP-mediated triggered activity.
Although adenosine can be given to differentiate hemodynamically stable wide complex tachycardia into supraventricular tachycardia with aberrancy and ventricular tachycardia, this
can be misleading and is no substitute for expert electrocardiographic consultation.
Dosage and Administration
Intravenous boluses are given at a dose of 12 mg in a peripheral vein but should start at 6 mg when administered via a central venous catheter. Tachycardia termination is typically seen
within 15 to 30 seconds of administering the bolus. If the initial
dose is ineffective at terminating the arrhythmia or producing
transient complete AV block, it can be repeated at the same dose
or at a higher dose up to 18 mg. Its half-life of 6 seconds allows
such rapid clearance of the drug that it can be readministered
501

40


Pharmacologic Agents in the CICU

within 30 seconds without accumulation of the drug. Hypotension is not typically noted as the drug has usually been cleared
before it reaches the systemic circulation.
Pharmacokinetics
Adenosine undergoes immediate and rapid clearance in the
bloodstream secondary to cellular uptake and enzymatic degradation. Although its half-life is difficult to determine, it has
been estimated to be between 0.5 to 6 seconds.86 Therefore, it
is best suited for rapid bolus administration for termination of
arrhythmias or potentially to aid in the diagnosis for arrhythmias as opposed to ongoing therapy for arrhythmias.
Side Effects
Adenosine's short half-life makes side effects very mild and
transient. Most patients report facial flushing, which is related
to transient vasodilation, and chest pain. It can also precipitate
bronchospasm, resulting in dyspnea, and should be used with
caution in patients with significant bronchial airway disease.
Frequent premature atrial or ventricular contractions have been
observed in addition to precipitation of atrial fibrillation in up to
15% of patients.87

Conclusion
Antiarrhythmics have an important role in the treatment of a
wide variety of arrhythmias that are associated with significant
morbidity and mortality. It is important to remember, however,
that these drugs are also associated with a host of side effects
and limitations. Novel antiarrhythmics are constantly being
evaluated in search of the holy grail of combined high efficacy
and high safety in the treatment of cardiac arrhythmias. In the
meantime, we will have to continue to rely on currently available
medicines and use them in a targeted way to derive the greatest
therapeutic benefit coupled with the highest safety in the management of critically ill patients.

References
  1. E
 cht DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients
receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl J Med 1991;324(12):781-788.
  2. The Cardiac Arrhythmia Suppression Trial II Investigators: Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J
Med 1992;327(4):227-233.
  3. Waldo AL, Camm AJ, deRuyter H, et al: Effect of d-sotalol on mortality in
patients with left ventricular dysfunction after recent and remote myocardial
infarction. The SWORD investigators. Survival with oral d-sotalol. Lancet
1996;348(9019):7-12.
  4. I n Rhoads RA, Bell DR (eds): Medical Physiology: Principles for Clinical Medicine, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2008,
p 224.
  5. Podrid PJ: Electrophysiology of the slow channel. In Podrid PJ, Kowey PR
(eds): Cardiac Arrhythmia: Mechanisms, Diagnosis, and Management. Baltimore, Williams & Wilkins, 1995, pp 34-35.
  6. Singh BN, Vaughan Williams EM: A third class of antiarrhythmic action: effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ1999 and AH3474. Br J Pharmacol
1970;39:675-687.
  7. Singh BN: Vaughan Williams EM: A fourth class of antidysrhythmic action?
Effect of verapamil on ouabain toxicity, on atrial and ventricular intracellular potentials, and on other features of cardiac function. Cardiovasc Res
1972;109:119.
  8. Harrison DC: Is there a rational basis for the modified classification of antiarrhythmic drugs? Am Heart J 1974;87:367-377.
  9. Snyders DJ, Hondeghem LM, Bennett PB: Mechanisms of drug-channel interaction. In Fozzard HA, Haber E, Jennings A et al (eds): The Heart and
Cardiovascular System. New York, Raven Press, 1991, pp 2165.

502

10. H
 ondeghem LM, Katzung BG: Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs.
Annu Rev Pharmacol Toxicol 1984;24:387.
11. Hondeghem LM, Snyders DJ: Class III antiarrhythmic agents have a lot of
potential but a long way to go. Reduced effectiveness and dangers of reverse
use dependence. Circulation 1990;81:686.
12. Roden DM, Hoffman BF: Action potential prolongation and induction of
abnormal automaticity by low quinidine concentrations in canine Purkinje
fibers. Circ Res 1985;56:857-867.
13. Jackman WM, Friday KJ, Anderson JL, et al: The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988;31:115-172.
14. Podrid PJ, Fuchs T, Candinas R: Role of the sympathetic nervous system in
the genesis of ventricular arrhythmia. Circulation 1990;82:I103.
15. Ferguson JD, DiMarco JP: Contemporary management of paroxysmal supraventricular tachycardia. Circulation 2003;107:1096-1099.
16. Hiromasa S, Coto H, Li ZY, et al: Dextrorotatory isomer of sotalol: electrophysiologic effects and interaction with verapamil. Am Heart J 1988;116(6 Pt
1):1552-1557.
17. Task Force of the Working Group on Arrhythmias of the European Society of
Cardiology: The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms.
Circulation 1991;84(4):1831-1851.
18. Thomson PD, Melmon KL, Richardson JA, et al: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann
Intern Med 1973;78:499-508.
19. Kowey PR, Reiffel JA: Pharmacokinetics, antiarrhythmic drugs, proarrhythmia. EPSAP II. 2000;6:4-5.
20. Siddoway LA: Pharmacological principles of antiarrhythmic drugs. In Podrid
PJ, Kowey PR (eds): Cardiac Arrhythmia: Mechanisms, Diagnosis, and Management. Baltimore, Williams & Wilkins, 1995, pp 362-363.
21. Rosen MR, Gelband H, Hoffman BF: Canine electrocardiographic and
cardiac electrophysiologic changes induced by procainamide. Circulation
1972;46:528-536.
22. Rosen MR, Merker C, Gelband H, et al: Effects of procainamide on the
electrophysiologic properties of the canine ventricular conducting system.
J Pharmacol Exp Ther 1973;185:438-446.
23. Arnsdorf MF: The effect of antiarrhythmic drugs on triggered sustained rhythmic activity in cardiac Purkinje fibers. J Pharmacol Exp Ther
1977;201:689-700.
24. Josephson ME, Caracta AR, Ricciutti MA, et al: Electrophysiologic properties of procainamide in man. Am J Cardiol 1976;33:596-603.
25. Morady F, DiCarlo LA, Baerman JM, et al: Rate dependant effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction. J Am Coll Cardiol 1985;6:179-185.
26. Giardina EV, Lipka LJ: Class IA antiarrhythmic agents: quinidine, procainamide, disopyramide. In Podrid PJ, Kowey PR (eds): Cardiac Arrhythmia:
Mechanisms, Diagnosis, and Management. Baltimore, Williams & Wilkins,
1995, p 377.
27. Varriale P, Sedighi A, Mirzaietehrane M: Ibutilide for termination of atrial
fibrillation in the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 1999;22(8):1267-1269.
28. Guidelines 2000 for cardiopulmonary resuscitation and emergency
­cardiovascular care. Part 6: advanced cardiovascular life support: Section 7: algorithm approach to ACLS emergencies. Circulation 2000;102:
I-136-I-165.
29. American Heart Association: 2005 American Heart Association guidelines
for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112(Suppl 24):IV1-IV203. Epub November 28, 2005.
30. Mason JW: A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias.
Electrophysiologic study versus electrocardiographic monitoring investigators. N Engl J Med 1993;329(7):445-451.
31. Arnsdorf MF, Bigger JT Jr: Effect of lidocaine hydrochloride on membrane conductance in mammalian cardiac Purkinje fibers. J Clin Invest
1972;51(9):2252-2263.
32. Roos JC, Dunning AJ: Effects of lidocaine on impulse formation and conduction defects in man. Am Heart J 1975;89(6):686-699.
33. MacMahon S, Collins R, Peto R, et al: Effects of prophylactic lidocaine in
suspected acute myocardial infarction: an overview of results from the randomized, controlled trials. JAMA 1988;260:1910-1916.
34. Schmitt CG, Kadish AH, Marchlinski FE, et al: Effects of lidocaine and procainamide on normal and abnormal intraventricular electrograms during
sinus rhythm. Circulation 1988;77(5):1030-1037.
35. Lie KI, Wellens HJ, van Capelle FJ, et al: Lidocaine in the prevention of primary ventricular fibrillation: a double blind, randomized study of 212 consecutive patients. N Engl J Med 1974;291:1324-1326.
36. Lie KI, Liem KL, Louridtz WJ, et al: Efficacy of lidocaine in preventing primary ventricular fibrillation within 1 hour after a 300 mg intramuscular injection. Am J Cardiol 1978;42:486-488.
37. DeSilva RA, Lown B, Hennekens CH, et al: Lignocaine prophylaxis in
acute myocardial infarction: an evaluation of randomized trials. Lancet
1981;2(8251):855-858.


Antiarrhythmic Electrophysiology and Pharmacotherapy
38. H
 ine LK, Laird N, Hewitt P, et al: Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med
1989;149(12):2694-2698.
39. Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug
therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 1993;270:1589-1595.
40. IMPACT Research Group: International mexiletine, placebo antiarrhythmic
coronary trial. I. Report on arrhythmia and other findings. J Am Coll Cardiol
1984;4:1148-1163.
41. Ryan TJ, Anderson JL, Antman EM, et al: ACC/AHA guidelines for the
management of patients with acute myocardial infarction. J Am Coll Cardiol
1996;28:1328-1428.
42. Marill KA, Greenbeg GM, Kay D, et al: Analysis of the treatment of
spontaneous sustained stable ventricular tachycardia. Acad Emerg Med
1997;12:1122-1128.
43. ACC, AHA: ESC: ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac
death–executive summary: a report of the American College of Cardiology/
American Heart Association task force and the European Society of Cardiology
committee for practice guidelines. J Am Coll Cardiol 2006;48(5):1064-1108.
44. Campbell RW: Class IB antiarrhythmic agents. In Podrid PJ, Kowey PR (eds):
Cardiac Arrhythmia: Mechanisms, Diagnosis, and Management. Baltimore,
Williams & Wilkins, 1995, pp 391-392.
45. Rademaker AW, Kellen J, Tam YK, et al: Character of adverse effects of
prophylactic lidocaine in the coronary care unit. Clin Pharmacol Ther
1986;40(1):71-80.
46. DeToledo JC: Lidocaine and seizures. Ther Drug Monit 2000;22(3):320-322.
47. Opie LH, Lubbe WF: Catecholamine-mediated arrhythmias in acute myocardial infarction. Experimental evidence and role of beta-adrenoceptor
blockade. S Afr Med J 1979;56(22):871-880.
48. MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart
failure (MERIT-HF). Lancet 1999;353:2001-2007.
49. CIBIS-II Investigators and Committees: The cardiac insufficiency bisoprolol
study II (CIBIS-II): a randomized trial. Lancet 1999;353:9-13.
50. Packer M, Coats A, Fowler M, et al: Effect of carvedilol on survival in severe
chronic heart failure. N Engl J Med 2001;344:1651-1658.
51. Frishman WH: β-Adrenergic blockers. Med Clin North Am 1988;72(1):
37-81.
52. Packer M, Bristow MR, Cohn JN, et al: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. carvedilol heart
failure study group. N Engl J Med 1996;334(21):1349-1355.
53. Ko DT, Hebert PR, Coffey CS, et al: Adverse effects of beta-blocker therapy
for patients with heart failure: a quantitative overview of randomized trials.
Arch Intern Med 2004;164(13):1389-1394.
54. Frohlich ED, Tarazi RC, Dustan HP: Peripheral arterial insufficiency. A
complication of beta-adrenergic blocking therapy. JAMA 1969;208(13):
2471-2472.
55. Shorr RI, Ray WA, Daugherty JR, et al: Antihypertensives and the risk of
serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA
1997;278(1):40-43.
56. Ko DT, Hebert PR, Coffey CS, et al: Beta-blocker therapy and symptoms of
depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-357.
57. Goldschlager N, Epstein AE, Naccarelli GV, et al: A practical guide for
clinicians who treat patients with amiodarone: 2007. Heart Rhythm
2007;4(9):1250–1259. Epub Jul 20, 2007.
58. Vorperian VR, Havighurst TC, Miller S, et al: Adverse effects of low dose
amiodarone: a meta-analysis. J Am Coll Cardiol 1997;30(3):791-798.
59. Hohnloser SH: Klingenheben T, Singh BN: Amiodarone-associated proarrhythmic effects. A review with special reference to torsades de pointes
tachycardia. Ann Intern Med 1994;121(7):529-535.
60. Kodama I, Kamiya K, Toyama J: Cellular electropharmacology of amiodarone. Cardiovasc Res 1997;35(1):13-29.
61. Singh BN: Amiodarone: historical development and pharmacologic profile.
Am Heart J 1983;106(4 Pt 2):788-797.
62. Desai AD, Chun S, Sung RJ: The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997;127(4):294-303.
63. Côté P, Bourassa MG, Delaye J, et al: Effects of amiodarone on cardiac and
coronary hemodynamics and on myocardial metabolism in patients with
coronary artery disease. Circulation 1979;59(6):1165-1172.
64. Kosinski EJ, Albin JB, Young E, et al: Hemodynamic effects of intravenous
amiodarone. J Am Coll Cardiol 1984;4(3):565-570.

65. S
 chwartz A, Shen E, Morady F, et al: Hemodynamic effects of intravenous
amiodarone in patients with depressed left ventricular function and recurrent ventricular tachycardia. Am Heart J 1983;106(4 Pt 2):848-856.
66. The CASCADE: Investigators: Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study). Am J Cardiol
1993;72(3):280-287.
67. Julian DG, Camm AJ, Frangin G, et al: Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European myocardial infarct amiodarone trial investigators. Lancet 1997;349(9053):667–674. Erratum in Lancet
1997;349(9059):1180. Lancet 1997;349(9067):1776.
68. Cairns JA, Connolly SJ, Roberts R, et al: Randomised trial of outcome after
myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian amiodarone myocardial infarction arrhythmia trial investigators. Lancet 1997;349(9053):675–682. Erratum
in Lancet 1997;349(9067):1776.
69. Doval HC, Nul DR, Grancelli HO, et al: Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de estudio de la sobrevida
en la insuficiencia cardiaca en Argentina (GESICA). Lancet 1994;344(8921):
493-498.
70. Singh SN, Fletcher RD, Fisher SG, et al: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival
trial of antiarrhythmic therapy in congestive heart failure. N Engl J Med
1995;333(2):77-82.
71. Bardy GH, Lee KL, Mark DB, et al: Amiodarone or an implantable
cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;
352(3):225–237. Erratum in N Engl J Med 2005;352(20):2146.
72. Roy D, Talajic M, Dorian P, et al: Amiodarone to prevent recurrence of atrial
fibrillation. Canadian trial of atrial fibrillation investigators. N Engl J Med
2000;342(13):913-920.
73. Singh BN, Singh SN, Reda DJ, et al: Amiodarone versus sotalol for atrial
fibrillation. N Engl J Med 2005;352(18):1861-1872.
74. Aasbo JD, Lawrence AT, Krishnan K, et al: Amiodarone prophylaxis reduces
major cardiovascular morbidity and length of stay after cardiac surgery: a
meta-analysis. Ann Intern Med 2005;143(5):327-336.
75. Murray KT: Ibutilide. Circulation 1998;97(5):493-497.
76. Oral H, Souza JJ, Michaud GF, et al: Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. N Engl J Med
1999;340(24):1849-1854.
77. Varriale P, Sedighi A, Mirzaietehrane M: Ibutilide for termination of atrial
fibrillation in the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 1999;22(8):1267-1269.
78. Ellenbogen KA, Stambler BS, Wood MA, et al: Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-­
response study. J Am Coll Cardiol 1996;28:130.
79. Stambler BS, Wood MA, Ellenbogen KA, et al: Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or
fibrillation. Circulation 1996;94:1613.
80. Dougherty AH, Jackman WM, Naccarelli GV, et al: Acute conversion of paroxysmal supraventricular tachycardia with intravenous diltiazem. IV diltiazem study group. Am J Cardiol 1992;70(6):587-592.
81. Eichhorn EJ, Gheorghiade M: Digoxin. Prog Cardiovasc Dis 2002;44(4):
251-266.
82. The Digitalis Investigation Group: The effect of digoxin on mortality and
morbidity in patients with heart failure. N Engl J Med 1997;336(8):525-533.
83. Ward SB, Sjostrom L, Ujhelyi MR: Comparison of the pharmacokinetics and in vivo bioaffinity of DigiTAb versus Digibind. Ther Drug Monit
2000;22(5):599-607.
84. Kurachi Y, Nakajima T, Sugimoto T: On the mechanism of activation of
muscarinic K+ channels by adenosine in isolated atrial cells: involvement of
GTP-binding proteins. Pflugers Arch 1986;407(3):264-274.
85. Lerman BB, Stein KM, Markowitz SM: Adenosine-sensitive ventricular tachycardia: a conceptual approach. J Cardiovasc Electrophysiol
1996;7(6):559-569.
86. Mangrum JM, DiMarco JP: Acute and chronic pharmacologic management
of supraventricular tachyarrhythmias. In Antman EM (ed): Cardiovascular
Therapeutics. 2nd ed. Philadelphia, WB Saunders, 2002, pp 423-444.
87. Glatter KA, Cheng J, Dorostkar P, et al: Electrophysiologic effects of
adenosine in patients with supraventricular tachycardia. Circulation
1999;99(8):1034-1040.

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