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23

Pharmacology of
Cardiac Rhythm
Ehrin J. Armstrong, April W. Armstrong, and David E. Clapham

INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . 401-402


ELECTRICAL PHYSIOLOGY OF THE HEART . . . . . . . . . . . . . 401
Pacemaker and Nonpacemaker Cells . . . . . . . . . . . . . . . . 401
Cardiac Action Potentials . . . . . . . . . . . . . . . . . . . . . . . . . 402
Determination of Firing Rate . . . . . . . . . . . . . . . . . . . . . . 406
PATHOPHYSIOLOGY OF ELECTRICAL DYSFUNCTION . . . . . . 406
Defects in Impulse Formation (SA Node) . . . . . . . . . . . . . 406
Altered Automaticity . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Triggered Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Defects in Impulse Conduction . . . . . . . . . . . . . . . . . . . . . 407
Re-entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Conduction Block . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Accessory Tract Pathways. . . . . . . . . . . . . . . . . . . . . . 408
PHARMACOLOGIC CLASSES AND AGENTS . . . . . . . . . . . . . 408
General Mechanisms of Action
of Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . . . . . . 408

Classes of Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . 409


Class I Antiarrhythmic Agents:
Fast Na Channel Blockers . . . . . . . . . . . . . . . . . . . . . 409
Class II Antiarrhythmic Agents:
-Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . 413
Class III Antiarrhythmic Agents:
Inhibitors of Repolarization . . . . . . . . . . . . . . . . . . . . . 413
Class IV Antiarrhythmic Agents:
Ca 2 Channel Blockers . . . . . . . . . . . . . . . . . . . . . . . . 415
Other Antiarrhythmic Agents . . . . . . . . . . . . . . . . . . . . 416
CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . 416
Suggested Reading. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

 INTRODUCTION

of cell depolarization and impulse conduction. Once initiated, a cardiac action potential is a spontaneous event that
proceeds based on the characteristic responses of ion channels to changes in membrane voltage. At the completion of
a cycle, the spontaneous depolarization of pacemaker cells
ensures that the process repeats without interruption.

The human heart is both a mechanical and an electrical organ.


To perfuse the body adequately with blood, the mechanical and
electrical components of the heart must work in precise concert
with each other. The mechanical component pumps the blood;
the electrical component controls the rhythm of the pump. When
the mechanical component fails despite a normal rhythm, heart
failure can result (see Chapter 25, Integrative Cardiovascular
Pharmacology: Hypertension, Ischemic Heart Disease, and
Heart Failure). When the electrical component goes awry (called
an arrhythmia), cardiac myocytes fail to contract in synchrony,
and effective pumping is compromised. Changes in the membrane potential of cardiac cells directly affect cardiac rhythm,
and most antiarrhythmic drugs act by modulating the activity of
ion channels in the plasma membrane. This chapter discusses
the ionic basis of electric rhythm formation and conduction in
the heart, the pathophysiology of electrical dysfunction, and the
pharmacologic agents used to restore a normal cardiac rhythm.

 ELECTRICAL PHYSIOLOGY OF THE HEART


Electrical activity in the heart, leading to rhythmic cardiac
contraction, is a manifestation of the hearts exquisite control

Pacemaker and Nonpacemaker Cells


The heart contains two types of cardiac myocytesthose
that can spontaneously initiate action potentials and those
that cannot. Cells possessing the ability to initiate spontaneous action potentials are termed pacemaker cells. All pacemaker cells possess automaticity, the ability to depolarize
above a threshold voltage in a rhythmic fashion. Automaticity results in the generation of spontaneous action potentials. Pacemaker cells are found in the sinoatrial node (SA
node), the atrioventricular node (AV node), and the ventricular conducting system (bundle of His, bundle branches, and
Purkinje fibers). Together, the pacemaker cells constitute
the specialized conducting system that governs the electrical activity of the heart. The second type of cardiac cells,
the nonpacemaker cells, includes the atrial and ventricular
myocytes. The nonpacemaker cells contract in response to
depolarization and are responsible for the majority of cardiac
401

CHAPTER 23 / Pharmacology of Cardiac Rhythm 403

160

ECa
+150 mV

120
80

Em (mV)

Depolarize

A SA node cell

myocyte remains near EK until the cell is stimulated by a


wave of depolarization that is initiated by nearby pacemaker
cells. The five phases of the ventricular myocyte action potential result from an intricately woven cascade of channel
openings and closings; the phases are numbered from 0 to 4
(Fig. 23-3 and Table 23-1).

ENa
+70 mV

40
+10
0

Repolarize

Phases of SA Node
Action Potential

-40

-55

-80
-120
0

100

200

300

400

500

Major Currents

Phase 4

If = Pacemaker current, relatively


nonselective. IK1 = Inward
rectifier, outward K+ current

Phase 0

ICa = Inward Ca2+ current

Phase 3

IK = Delayed rectifier,
outward K+ current

EK
-94 mV

Time (ms)

160

ECa
+150 mV

120
80

K+

K+
Na+

ENa
+70 mV

+45

40

Ca2+

A SA node action potential

Repolarize

-40
-80

-85

-120
0

100

200

300

400

500

EK
-94 mV

Time (ms)

Membrane potential (mV)

Em (mV)

Depolarize

B Ventricular muscle cell

40
20
0
ICa

-40
-60

Phase 0

IK

Phase 4

If

IK1
If
150

Time (ms)
B Ion currents of SA node action potential
4

Currents across
membrane (A/F)

SA node action potential, the kinetics of this depolarization


are modulated by voltage-gated Na channels that are also
expressed in the node. There are gradients of expression of
If channels and of the more selective voltage-gated Na and
Ca2 channels within the SA node, such that cells at the border of the node express relatively more voltage-gated Na
channels and cells in the center of the node express relatively
more If and voltage-gated Ca2 channels. The expression of
voltage-gated Na channels in the SA node is partly responsible for the effect of certain antiarrhythmics on the automaticity of SA nodal cells (see below).
Unlike SA nodal cells, ventricular myocytes do not depolarize spontaneously under physiologic conditions. As
a result, the membrane potential of the resting ventricular

Phase 3

FIGURE 23-1.

SA node and ventricular muscle cell action potentials.


The resting membrane potential of a sinoatrial (SA) node cell is approximately
55 mV, while that of a ventricular muscle cell is 85 mV. The shaded areas
represent the approximate depolarization required to trigger an action potential in
each cell type. Together, the cardiac action potentials last for approximately half a
second. SA node cells (A) depolarize to a peak of 10 mV, and ventricular muscle
cells (B) depolarize to a peak of 45 mV. Note that the ventricular action potential
has a much longer plateau phase. This long plateau ensures that ventricular myocytes have adequate time to contract before the onset of the next action potential.
The Nernst equilibrium potentials of the major ions (ECa, ENa, EK) are shown as
dashed horizontal lines. Em, membrane potential.

IK

-20

IK

IK1

IK1

0
-2

If

If
ICa

-4
-6

(Outward currents are +; inward currents are -)


0

150

Time (ms)

FIGURE 23-2. SA node action potential and ion currents. A. SA nodal cells
are depolarized slowly by the pacemaker current (If ) (phase 4), which consists of
an inward flow of sodium (mostly) and calcium ions. Depolarization to the threshold potential opens highly selective voltage-gated calcium channels, which drive
the membrane potential toward ECa (phase 0). As the calcium channels close and
potassium channels open (phase 3 ), the membrane potential repolarizes. B. The
flux of each ion species correlates roughly with each phase of the action potential.
Positive currents indicate an outward flow of ions (blue and purple ), while negative currents are inward (gray and black ).

PR

QT
R

5 mm =
0.5 mV
T

P
Q

S
ST

QRS
5 mm = 0.2 second

406 Principles of Cardiovascular Pharmacology

Determination of Firing Rate


The specialized conduction system of the heart consists of
the SA node, AV node, bundle of His, and Purkinje system.
These different populations of cells have different intrinsic rates of firing. Three factors determine the firing rate.
First, as the rate of spontaneous depolarization in phase 4
increases, the rate of firing increases because the threshold
potential (the minimum potential necessary to trigger an action potential) is reached more quickly at the end of phase 4.
Second, if the threshold potential becomes more negative,
the rate of firing increases because the threshold potential
is reached more quickly at the end of phase 4. Third, if the
maximum diastolic potential (the resting membrane potential) becomes more positive, the rate of firing increases because less time is needed to repolarize the membrane fully at
the end of phase 3.
Because the various populations of pacemaker cells possess different intrinsic rates of firing, the pacemaker population with the fastest firing rate sets the heart rate. The SA
node possesses the fastest intrinsic firing rate60100 times
per minuteand is the native pacemaker of the heart. The
cells of the atrioventricular (AV) node and bundle of His fire
intrinsically between 50 and 60 times per minute, and the
cells of the Purkinje system have the slowest intrinsic firing
rate3040 times per minute. The cells of the AV node, bundle of His, and Purkinje system are termed latent pacemakers, because their intrinsic rhythm is overridden by the faster
SA-node automaticity. In a mechanism termed overdrive
suppression, the SA node suppresses the intrinsic rhythm of
the other pacemaker populations and entrains them to fire at
the SA nodal firing rate.

 PATHOPHYSIOLOGY OF ELECTRICAL
DYSFUNCTION
Causes of electrical dysfunction in the heart can be divided
into defects in impulse formation and defects in impulse
conduction. In the former case, SA-node automaticity is interrupted or altered, leading to missed beats or ectopic beats,
respectively. In the latter case, impulse conduction is altered
(for example, in the case of re-entrant rhythms), and sustained arrhythmias can result.

Defects in Impulse Formation (SA Node)


As the native pacemaker of the heart, the SA node has a
pivotal role in normal impulse formation. Electrical events
that alter SA nodal function or disturb overdrive suppression
can lead to impaired impulse formation. Two mechanisms
commonly associated with defective impulse formation are
altered automaticity and triggered activity.
Altered Automaticity
Some mechanisms that alter automaticity of the SA node are
physiologic. In particular, the autonomic nervous system often
modulates automaticity of the SA node as part of a physiologic response. In sympathetic stimulation during exercise,
an increased concentration of catecholamines leads to greater
1-adrenergic receptor activation. Activation of 1 receptors
causes the opening of a greater number of pacemaker channels (If channels); a larger pacemaker current is then conducted
through these channels; and faster phase 4 depolarization results.
Sympathetic stimulation also causes the opening of a greater

number of Ca2 channels, and thereby shifts the threshold to


more negative potentials. Both of these mechanisms increase
heart rate. The parasympathetic vagus nerve affects the SA
node by a number of mechanisms that oppose the sympathetic
regulation of heart rate. Vagus nerve release of acetylcholine
initiates an intracellular signaling cascade that: (1) reduces the
pacemaker current by decreasing pacemaker channel opening;
(2) shifts the threshold to more positive potentials by reducing
Ca2 channel opening; and (3) makes the maximum diastolic
potential (analogous to the resting membrane potential in these
spontaneously firing cells) more negative by increasing K
channel opening. The SA node, atria, and AV node are highly
innervated and are thus more sensitive than the ventricular conducting system to the effects of vagal stimulation.
In pathologic conditions, automaticity can be altered when
latent pacemaker cells take over the SA nodes role as the
pacemaker of the heart. When the SA nodal firing rate becomes
pathologically slow or when conduction of the SA impulse is
impaired, an escape beat may occur as a latent pacemaker
initiates an impulse. A series of escape beats, known as an
escape rhythm, may result from prolonged SA nodal dysfunction. On the other hand, an ectopic beat occurs when latent pacemaker cells develop an intrinsic rate of firing that is
faster than the SA nodal rate, in some cases despite the presence of a normally functioning SA node. A series of ectopic
beats, termed an ectopic rhythm, can result from ischemia,
electrolyte abnormalities, or heightened sympathetic tone.
Direct tissue damage (such as can occur after a myocardial infarction) also results in altered automaticity. Tissue
injury can cause structural disruption of the cell membrane.
Disrupted membranes are unable to maintain ion gradients,
which are critical for maintaining appropriate membrane
potentials. If the resting membrane potential becomes sufficiently positive (more positive than 60 mV), nonpacemaker cells may begin to depolarize spontaneously. Another
mechanism by which tissue damage leads to altered automaticity is through the loss of gap junction connectivity. Direct
electrical connectivity is important for the effective delivery
of overdrive suppression from the SA node to the rest of the
cardiac myocytes. When connectivity is disrupted due to tissue injury, overdrive suppression is not efficiently relayed,
and the unsuppressed cells can initiate their own rhythm.
This abnormal rhythm can lead to cardiac arrhythmia.
Triggered Activity
Afterdepolarizations occur when a normal action potential
triggers extra abnormal depolarizations. That is, the first
(normal) action potential triggers additional oscillations of
membrane potential, which may lead to arrhythmia. There
are two types of afterdepolarizationsearly afterdepolarizations and delayed afterdepolarizations.
If the afterdepolarization occurs during the inciting action potential, it is termed an early afterdepolarization
(Fig. 23-5). Conditions that prolong the action potential
(e.g., drugs that prolong the QT interval, such as procainamide and ibutilide) tend to trigger early afterdepolarizations. Specifically, an early afterdepolarization can occur
during the plateau phase (phase 2) or the rapid repolarization phase (phase 3). During the plateau phase, because most
of the Na channels are inactivated, an inward Ca2 current is responsible for the early afterdepolarization. On the
other hand, during the rapid repolarization phase, partially
recovered Na channels can conduct an inward Na current

CHAPTER 23 / Pharmacology of Cardiac Rhythm 407

Defects in Impulse Conduction

Membrane potential (mV)

50

Early
afterdepolarization

Repetitive
afterdepolarization

0
Na+ channels
recover from
inactivation

-50

Triggered
arrhythmia

-100
0

0.2

0.6

0.4

0.8

Time (sec)

FIGURE 23-5.

Early afterdepolarization. Early afterdepolarizations generally occur during the repolarizing phase of the action potential, although they can
also occur during the plateau phase. Repetitive afterdepolarizations can trigger
an arrhythmia.

that contributes to the early afterdepolarization. If an early


afterdepolarization is sustained, it can lead to a type of ventricular arrhythmia termed torsades de pointes. Torsades de
pointes, French for twisting of the points, is characterized
by QRS complexes of varying amplitudes as they twist
along the baseline; this rhythm is a medical emergency that
can lead to death if not treated emergently with antiarrhythmics and/or defibrillation.
In contrast to early afterdepolarizations, delayed afterdepolarizations occur shortly after the completion of repolarization
(Fig. 23-6). The mechanism of delayed afterdepolarizations is
not well understood; it has been proposed that high intracellular Ca2 concentrations lead to an inward Na current, which,
in turn, triggers the delayed afterdepolarization.

The second type of electrical disturbance of the heart involves


defects in impulse conduction. Normal cardiac function requires unobstructed and timely propagation of an electrical
impulse through the cardiac myocytes. In pathologic conditions, altered impulse conduction can result from one or a
combination of three mechanisms: re-entry, conduction block,
and accessory tract pathways.
Re-entry
Normal cardiac conduction is initiated at the SA node and
propagated to the AV node, bundle of His, Purkinje system,
and myocardium in an orderly fashion. The cellular refractory period ensures that stimulated regions of the myocardium depolarize only once during propagation of an impulse.
Figure 23-7A depicts normal impulse conduction, in which
an impulse arriving at point a travels synchronously down
two parallel pathways, 1 and 2.
Re-entry of an electrical impulse occurs when a selfsustaining electrical circuit stimulates an area of the myocardium repeatedly and rapidly. Two conditions must be present
Cardiac
action
potential
A Normal conduction

a
1

Non-excitable area
2

Cardiac
action
potential
B Re-entrant circuit

Unidirectional
conduction block

50

Membrane potential (mV)

A delayed afterdepolarization
that reached threshold voltage

Re-entrant
conduction

Abnormally slow
retrograde
conduction

2 (damaged or partially

1
0

depolarized cells)

Slow upstroke
velocity

b
-50

Delayed
afterdepolarization

-100
0

0.2

0.4

0.6

0.8

Time (sec)

FIGURE 23-6. Delayed afterdepolarization. Delayed afterdepolarizations occur


shortly after repolarization. Although the mechanism has not been firmly elucidated, it
appears that intracellular Ca2 accumulation activates the Na/Ca2 exchanger, and
the resulting electrogenic influx of 3 Na for each extruded Ca2 depolarizes the cell.

FIGURE 23-7. Normal and re-entrant electrical pathways. A. In normal impulse conduction, an impulse traveling down a pathway arrives at point a, where it is
able to travel down two alternate pathways, 1 and 2. In the absence of re-entry, the
impulses continue on and depolarize different areas of the ventricle. B. A re-entrant
circuit can develop if one of the branch pathways is pathologically disrupted. When
the impulse arrives at point a, it can travel only down pathway 1 because pathway 2
is blocked unidirectionally (i.e., the effective refractory period of the cells in pathway 2
is prolonged to such an extent that anterograde conduction is prohibited). The impulse
conducts through pathway 1 and proceeds to point b. At this point, the cells in pathway 2 are no longer refractory, and the impulse conducts in a retrograde fashion up
pathway 2 toward point a. When the retrograde impulse arrives at point a, it can initiate
re-entry. Re-entry can result in a sustained pattern of rapid depolarizations that trigger
tachyarrhythmias. This mechanism can occur over small or large regions of the heart.

408 Principles of Cardiovascular Pharmacology

for a re-entrant electrical circuit to occur: (1) unidirectional


block (anterograde conduction is prohibited, but retrograde
conduction is permitted); and (2) slowed retrograde conduction velocity. Figure 23-7B shows a re-entrant electrical
circuit. As the impulse arrives at point a, it can travel only
down pathway 1 (the left branch), because pathway 2 (the
right branch) is blocked unidirectionally in the anterograde
direction. The impulse conducts through pathway 1 and
travels to point b. At this junction, the impulse travels in a
retrograde fashion up pathway 2 toward point a. The conduction time from point b to point a is slowed because of cell
damage or the presence of cells that are still in the refractory
state. By the time the impulse reaches point a, the cells in
pathway 1 have had adequate time to repolarize, and these
cells are stimulated to continue conducting the action potential toward point b. In this manner, tachyarrhythmias result
from the combination of unidirectional block and decreased
conduction velocity in the abnormal pathway.
Conduction Block
Conduction block occurs when an impulse fails to propagate
because of the presence of an area of inexcitable cardiac tissue. This area of inexcitable tissue could consist of normal
tissue that is still refractory, or it could represent tissue that
has been damaged by trauma, ischemia, or scarring. In either
case, the myocardium is unable to conduct an impulse. Because conduction block removes overdrive suppression by
the SA node, the cardiac myocytes are free to beat at their
intrinsically slower frequency. For this reason, conduction
block can be manifested clinically as bradycardia.
Accessory Tract Pathways
During the normal cardiac cycle, the SA node initiates an
impulse that travels quickly through the atrial myocardium
and arrives at the AV node. Impulse conduction then slows
through the AV node, allowing sufficient time for filling of
the ventricles with blood before ventricular contraction is

AV node

Bundle of His

SA node

Purkinje
fibers

Bypass tract
(Bundle of Kent)

FIGURE 23-8.

Bundle of Kent. The bundle of Kent is an accessory electrical


pathway that conducts impulses directly from the atria to the ventricles, bypassing the
AV node. Impulse conduction through this accessory tract is more rapid than conduction through the AV node, setting up the conditions for re-entrant tachyarrhythmias.

initiated. After the impulse travels through the AV node, it


again propagates quickly throughout the ventricles to trigger
ventricular contraction.
Some individuals possess accessory electrical pathways
that bypass the AV node. One common accessory pathway is
the bundle of Kent, a band of myocardium that conducts impulses directly from the atria to the ventricles, bypassing the
AV node (Fig. 23-8). In these individuals, an impulse originating in the SA node is conducted through the bundle of Kent
to the ventricles more rapidly than the same impulse would
be conducted through the AV node. Because the bundle of
Kent is an accessory pathway, the ventricular tissue receives
impulses from both the normal conduction pathway and the
accessory pathway. As a result, electrocardiograms from these
individuals typically exhibit a wider-than-normal QRS complex and an earlier-than-normal ventricular upstroke. More
importantly, because the two conduction tracts have different
conduction velocities, the presence of an accessory tract can
set up the conditions for a re-entrant loop, and thereby predispose the individual to tachyarrhythmias.

 PHARMACOLOGIC CLASSES
AND AGENTS
Ion currents across the plasma membrane induce changes in the
membrane potential of cells. Changes in the membrane potential of cardiac pacemaker cells underlie the timely contraction
of cardiac myocytes. Defects in impulse formation and altered
impulse conduction can lead to disturbances in cardiac rhythm.
Antiarrhythmic agents are used to restore normal cardiac
rhythm by targeting proarrhythmic regions of the heart.

General Mechanisms of Action


of Antiarrhythmic Agents
Although there are many different antiarrhythmic agents, there
are surprisingly few mechanisms of antiarrhythmic action.
In general, drugs that affect cardiac rhythm act by altering:
(1) the maximum diastolic potential in pacemaker cells (and/
or the resting membrane potential in ventricular cells); (2) the
rate of phase 4 depolarization; (3) the threshold potential; or
(4) the action potential duration. The specific effect of a particular channel blocker follows directly from the role of the
current carried by that channel in the cardiac action potential.
For example, Na and Ca2 channel blockers typically alter
the threshold potential, while K channel blockers tend to prolong action potential duration. These drugs generally block the
pore from inside the cell; they can access their sites of action
by either traversing the pore of the channel or diffusing across
the lipid bilayer within which the channel is embedded.
State-dependent ion channel block is an important concept in antiarrhythmic drug action. Ion channels are capable of
switching among various conformational states, and changes
in the permeability of the membrane to a particular ion are
mediated by conformational changes in the channels that pass
that ion. Antiarrhythmic drugs often have different affinities
for different conformational states of the ion channel; that
is, these drugs bind to one conformation of the channel with
higher affinity than they do to other conformations of the channel. This type of binding is referred to as state-dependent.
Na channel blockers serve as an excellent example to
illustrate the concept of state-dependent ion channel block.
The Na channel undergoes three major state changes

410 Principles of Cardiovascular Pharmacology

(Fig. 23-9). The block of Na channels leaves fewer channels available to open in response to membrane depolarization, thereby raising the threshold for action potential firing
and slowing the rate of depolarization. Both of these effects
extend the duration of phase 4, and thereby decrease heart
rate. Furthermore, the shift in threshold potential means that,
in patients with implanted defibrillators who are treated with
Na channel blockers, a higher voltage is needed to defibrillate the heart. Therefore, it is important to take into account
the effect of Na channel blockers when choosing appropriate settings for implanted defibrillators.
In addition to decreasing SA-node automaticity, Na
channel blockers act on ventricular myocytes to decrease reentry. This is achieved mainly by decreasing the upstroke
velocity of phase 0 and, for some Na channel blockers,
by prolonging repolarization (Fig. 23-10). By decreasing

Membrane potential (mV)

60

Class IA Antiarrhythmics

30

0
-30

Increased
threshold
Normal threshold

-60
Decreased slope of
phase 4 depolarization

-90
0

100

200

300

400

500

600

700

Time (ms)

B
60

Membrane potential (mV)

phase 0 upstroke velocity, Na channel blockers decrease the


conduction velocity through cardiac tissue. Ideally, conduction velocity is reduced to such an extent that the propagating wavefront is extinguished before it is able to restimulate
myocytes in a re-entrant pathway. However, if conduction
velocity is not sufficiently decreased, and the impulse is
not extinguished, then the slowed impulse can support reentry as it reaches cells that are no longer refractory (see
above), and thereby precipitate an arrhythmia. In addition to
decreasing phase 0 upstroke velocity, class IA Na channel
blockers prolong repolarization. Prolonged repolarization
increases the effective refractory period, so that cells in a reentrant circuit cannot be depolarized by the re-entrant action
potential. In summary, Na channel blockers decrease the
likelihood of re-entry, and thereby prevent arrhythmia, by:
(1) decreasing conduction velocity, and (2) increasing the
refractory period of ventricular myocytes.
Although the three subclasses of class I antiarrhythmics
(class IA, IB, and IC) have similar effects on the action potential in the SA node, there are important differences in
their effects on the ventricular action potential.

30

0
-30
Normal threshold

-60
Addition of
ACh or adenosine

Decreased slope
of phase 4
depolarization

-90
Hyperpolarization

100

200

300

400

500

600

700

Time (ms)

FIGURE 23-9. Effects of class I antiarrhythmics and natural agonists on


the SA-node action potential. A. The normal SA-node action potential is shown
as a solid curve. Class I antiarrhythmics (Na channel blockers) alter SA-node
automaticity by affecting two aspects of the SA nodal action potential: (1) the
threshold is shifted to more positive potentials; and (2) the slope of phase 4
depolarization is decreased. B. Acetylcholine and adenosine slow the SA nodal
firing rate by opening K channels that hyperpolarize the cell and decrease the
slope of phase 4 depolarization.

Class IA antiarrhythmics exert a moderate block on Na


channels and prolong the repolarization of both SA nodal
cells and ventricular myocytes. By blocking Na channels, these agents decrease the phase 0 upstroke velocity,
which decreases conduction velocity through the myocardium. Class IA antiarrhythmics also block K channels, and
thereby reduce the outward K current responsible for repolarization of the membrane. This prolongation of repolarization increases the effective refractory period of the cells.
Together, the decreased conduction velocity and increased
effective refractory period decrease re-entry.
Quinidine is often considered the prototypical drug
among the class IA antiarrhythmics, but it is becoming less
frequently used due to its adverse effects. In addition to the
pharmacologic actions described above for all class IA antiarrhythmics, quinidine exerts an anticholinergic (vagolytic) effect, most likely by blocking the K channels that are opened
upon vagal stimulation of M2 muscarinic receptors in the AV
node (see Fig. 23-9B, Fig. 9-1). The anticholinergic effect
is significant clinically because it can increase conduction
velocity through the AV node. Increased AV nodal conduction can have potentially detrimental effects in patients with
atrial flutter. Such patients manifest an average atrial firing
rate of 280300 beats per minute. Because some of these impulses reach the AV node while it is still refractory, not all of
the impulses are transmitted to the ventricles. Therefore, the
atria fire much faster than the ventriclesthere is typically
a 2:1 or 4:1 ratio of atrial to ventricular firing rates. When
quinidine is administered to patients with atrial flutter, the
atrial firing rate decreases because of quinidines pharmacologic action in slowing conduction velocity through the
myocardium. At the same time, however, AV nodal conduction velocity increases because of the vagolytic effects of the
drug. The increase in AV nodal conduction velocity abolishes
the 2:1 or 4:1 ratio of atrial to ventricular firing rates, and a
1:1 ratio of atrial to ventricular firing rates is often established. For example, with an atrial flutter rate of 300 and 2:1
AV block, the ventricles are driven at a rate of 150, which
most individuals can tolerate. If the flutter rate is slowed to
200 and AV conduction is enhanced to 1:1, however, the

CHAPTER 23 / Pharmacology of Cardiac Rhythm 411

Membrane potential (mV)

Mild Na+
channel block

Moderate
Na+ channel
block

Class IA

No change in
repolarization

Shortened
repolarization

Prolonged
repolarization

Marked Na+
channel block

Class IB

Class IC

Time

Effects of class IA, IB, and IC antiarrhythmics on the ventricular action potential. Class I antiarrhythmics (Na channel blockers) act on ventricular myocytes to decrease re-entry. All subclasses of the class I antiarrhythmics block the Na channel to some degree: class IA agents exhibit moderate Na channel
block, class IB agents rapidly bind to (block) and dissociate from (unblock) Na channels, and class IC agents produce marked Na channel block. Class IA, IB, and IC
agents also differ in the degree to which they affect the duration of the ventricular action potential.

FIGURE 23-10.

ventricles are driven at a rate of 200, which is usually too fast


for effective ventricular pumping. For this reason, an agent
that slows AV nodal conductionsuch as a -adrenergic antagonist or verapamil (a Ca channel blocker)should be
used in conjunction with quinidine to prevent an excessively
rapid ventricular response in patients with atrial flutter.
The most common adverse effects of quinidine are diarrhea, nausea, headache, and dizziness. These effects make it
difficult for patients to tolerate chronic therapy with quinidine. Quinidine is contraindicated in patients with QT prolongation and in patients who are taking medications that
predispose to QT prolongation, because of the increased risk
of torsades de pointes. Relative contraindications to quinidine use include sick sinus syndrome, bundle branch block,
myasthenia gravis (because of quinidines anticholinergic
action), and liver failure.
Quinidine is administered orally and metabolized by cytochrome P450 enzymes in the liver. Quinidine increases
plasma levels of digoxin (an inotropic agent), most likely
by competing for the P450 enzymes that are responsible for
digoxin metabolism. Because digoxin has a narrow therapeutic index (see Chapter 24, Pharmacology of Cardiac
Contractility), quinidine-induced digoxin toxicity occurs
in a significant fraction of patients. The plasma potassium
level must be carefully monitored in patients treated with
quinidine, because hypokalemia decreases quinidine efficacy, exacerbates QT prolongation, and, most importantly,
predisposes to torsades de pointes. It is hypothesized that
torsades de pointes is the mechanism most likely responsible
for quinidine-induced syncope. Because of quinidines numerous adverse effects and contraindications, this drug has
largely been replaced by class III agentssuch as ibutilide
and amiodaronefor the pharmacologic conversion of atrial
flutter or atrial fibrillation to normal sinus rhythm.
Procainamide is a class IA antiarrhythmic agent that is
effective in the treatment of many types of supraventricular
and ventricular arrhythmias. Procainamide is often used in the
pharmacologic conversion of new-onset atrial fibrillation to
normal sinus rhythm, although with less efficacy than intravenous ibutilide. Procainamide can be used safely to decrease
the likelihood of re-entrant arrhythmias in the setting of acute

myocardial infarction, even in the presence of decreased cardiac output. Procainamide can also be administered by slow
intravenous infusion to treat acute ventricular tachycardia.
Unlike quinidine, procainamide has few anticholinergic
effects and does not alter plasma levels of digoxin. Procainamide can cause peripheral vasodilation via inhibition
of neurotransmission at sympathetic ganglia. With chronic
therapy, almost all patients develop a lupus-like syndrome
and positive antinuclear antibodies; the precise mechanism of this reaction is not known, but it remits if the drug
is discontinued. Procainamide is acetylated in the liver to
N-acetyl-procainamide (NAPA); this active metabolite produces the pure class III antiarrhythmic effects of prolonging
the refractory period and lengthening the QT interval. NAPA
does not appear to cause the lupus-like adverse effects of
procainamide.
Disopyramide is similar to quinidine in its electrophysiologic and antiarrhythmic effects; the difference between
the two drugs lies in their adverse effects. Disopyramide
causes fewer gastrointestinal problems but has even more
profound anticholinergic effects than quinidine, producing
such adverse effects as urinary retention and dry mouth. The
profound anticholinergic effects of disopyramide appear to
be related to the drugs action as an antagonist at muscarinic
acetylcholine receptors. Disopyramide is contraindicated
in patients with obstructive uropathy or glaucoma. Disopyramide is also contraindicated in patients with conduction
block between the atria and ventricles and in patients with
sinus-node dysfunction. Disopyramide has the prominent
but unexplained effect that it depresses cardiac contractility, which has led to its use in the treatment of hypertrophic
obstructive cardiomyopathy and neurocardiogenic syncope.
Because of its negative inotropic effects, disopyramide is
absolutely contraindicated in patients with decompensated
heart failure. Oral disopyramide is approved only for the
treatment of life-threatening ventricular arrhythmias; oral or
intravenous disopyramide is sometimes used to convert supraventricular tachycardia to normal sinus rhythm. The current trend in the treatment of life-threatening arrhythmias,
however, is away from class I antiarrhythmic agents and toward class III agents and electrical devices.

412 Principles of Cardiovascular Pharmacology

Class IB Antiarrhythmics

Class IB antiarrhythmics include lidocaine, mexiletine, and


phenytoin. Lidocaine is the prototypical class IB agent.
These drugs alter the ventricular action potential by blocking Na channels and sometimes by shortening repolarization; the latter effect may be mediated by the drugs ability to
block the few Na channels that inactivate late during phase
2 of the cardiac action potential (Fig. 23-10). In comparison to class IA antiarrhythmics, which preferentially bind
to open Na channels, class IB drugs bind to both open and
inactivated Na channels. Therefore, the more time Na
channels spend in the open or inactivated state, the more
blockade the class IB antiarrhythmics can exert. The major
distinguishing characteristic of the class IB antiarrhythmics
is their fast dissociation from Na channels. Because Na
channels recover quickly from class IB blockade, these
drugs are most effective in blocking depolarized or rapidly
driven tissues, where there is a higher likelihood of the Na
channels being in the open or inactivated state. Thus, class
IB antiarrhythmics exhibit use-dependent block in diseased
myocardium, where the cells have a tendency to fire more
frequently; these antiarrhythmics have relatively little effect
on normal cardiac tissue.
Myocardial ischemia provides an example of the therapeutic utility of the use-dependent block exerted by class IB antiarrhythmics. The increase in extracellular H concentration
in ischemic tissue activates membrane pumps that cause an
increase in the extracellular K concentration. This increase
in extracellular K shifts EK to a more depolarized (more
positive) value; for example, EK may shift from 94 mV to
85 mV. The altered electrochemical K gradient provides
a smaller driving force for K ions to flow out of cells, and
depolarization of the membrane leads to a higher likelihood
of action potential firing. Because ischemic cardiac myocytes
tend to fire more frequently, the Na channels spend more
time in the open or inactivated state, serving as a better target
for blockade by class IB antiarrhythmics.
Lidocaine is commonly used to treat ventricular arrhythmias in emergency situations. This drug is not effective in treating supraventricular arrhythmias. In hemodynamically stable
patients, lidocaine is reserved for treatment of ventricular tachyarrhythmias or frequent premature ventricular contractions
(PVCs) that are bothersome or hemodynamically significant.
Lidocaine has a short plasma half-life (approximately
20 minutes), and it is metabolically de-ethylated in the liver.
Its metabolism is governed by two factors, liver blood flow
and liver cytochrome P450 activity. For patients whose liver
blood flow is decreased by old age or heart failure, or whose
P450 enzymes are acutely inhibited, for example, by cimetidine (see Chapter 4, Drug Metabolism), a lower dose of lidocaine should be considered. For patients whose P450 enzymes
are induced by drugs such as barbiturates, phenytoin, or rifampin, the dose of lidocaine should be increased.
Because lidocaine shortens repolarization, possibly by
blocking the few Na channels that inactivate late during
phase 2 of the cardiac action potential, it does not prolong
the QT interval. Therefore, the drug is safe for use in patients
with long QT syndrome. However, because lidocaine also
blocks Na channels in the central nervous system (CNS),
it can produce CNS adverse effects such as confusion,
dizziness, and seizures. In addition to its use as an acute intravenous therapy for ventricular arrhythmias, lidocaine is
used as a local anesthetic (see Chapter 11).

Mexiletine, an analogue of lidocaine, is available in oral


formulation. While the efficacy of mexiletine is similar to
that of quinidine, mexiletine does not prolong the QT interval
and it lacks vagolytic effects. In addition, little hemodynamic
depression has been reported with the use of mexiletine. The
primary indication for mexiletine is life-threatening ventricular arrhythmia. In practice, however, mexiletine is often used
as an adjunct to other antiarrhythmic agents. For example,
mexiletine is used in combination with amiodarone in patients with implantable cardioverter-defibrillators (ICDs) and
in patients with recurrent ventricular tachycardia. Mexiletine
is also used in combination with quinidine or sotalol to increase antiarrhythmic efficacy while reducing adverse effects.
There are no data supporting reduced mortality with the use of
mexiletine or any of the other class IB antiarrhythmic agents.
Major adverse effects of mexiletine include dose-related
nausea and tremor, which can be ameliorated when the medication is taken with food. Mexiletine undergoes hepatic metabolism, and its plasma levels may be altered by inducers of
hepatic P450 enzymes such as phenytoin and rifampin.
While phenytoin is usually considered an antiepileptic
medication, its effects on the myocardium also allow it to
be classified as a class IB antiarrhythmic agent. The pharmacologic properties of phenytoin are discussed in detail
in Chapter 15, Pharmacology of Abnormal Electrical Neurotransmission in the Central Nervous System. Although
the use of phenytoin as an antiarrhythmic agent is limited,
it has been found to be effective in ventricular tachycardia
of young children. Specifically, phenytoin has been used in
the treatment of congenital prolonged QT syndrome when
therapy with -adrenergic antagonists alone has failed; it
is also used to treat ventricular tachycardia after congenital
heart surgery. Phenytoin maintains AV conduction in digoxin-toxic arrhythmias, and it is especially useful in the rare
patient who has concurrent epilepsy and cardiac arrhythmia.
Phenytoin is an inducer of hepatic enzymes including P450
3A4, and thus affects plasma levels of other antiarrhythmic
agents such as mexiletine, lidocaine, and quinidine.
Class IC Antiarrhythmics

Class IC antiarrhythmics are the most potent Na channel


blockers, and they have little or no effect on action potential
duration (Fig. 23-10). By markedly decreasing the rate of
phase 0 upstroke of ventricular cells, these drugs suppress
premature ventricular contractions. Class IC antiarrhythmics
also prevent paroxysmal supraventricular tachycardia and
atrial fibrillation. However, these drugs have marked depressive effects on cardiac function and, thus, must be used with
discretion. In addition, the CAST (Cardiac Arrhythmia Suppression Trial) and other studies have brought attention to
the proarrhythmic effects of these agents.
Flecainide is the prototypical class IC drug; other
members of this class include encainide, moricizine, and
propafenone. Flecainide illustrates the principle that antiarrhythmic agents can also cause arrhythmia. When flecainide is administered to patients with preexisting ventricular
tachyarrhythmias and to those with a history of myocardial
infarction, it can worsen the arrhythmia even at normal
doses. Currently, flecainide is approved for use only in lifethreatening situations; for example, when paroxysmal supraventricular or ventricular arrhythmia is unresponsive to
other measures. Flecainide is eliminated very slowly from
the body; it has a plasma half-life of 1230 hours. Because

CHAPTER 23 / Pharmacology of Cardiac Rhythm 413

of its marked blockade of Na channels and its suppressive


effects on cardiac function, flecainide use is associated with
adverse effects that include sinus-node dysfunction, a marked
decrease in conduction velocity, and conduction block.
Class II Antiarrhythmic Agents: -Adrenergic Antagonists
Class II antiarrhythmic agents are -adrenergic antagonists (also called -blockers). These agents act by inhibiting sympathetic input to the pacing regions of the heart.
(-Adrenergic antagonists are more extensively discussed in
Chapter 10, Adrenergic Pharmacology.) Although the heart
is capable of beating on its own without innervation from the
autonomic nervous system, both sympathetic and parasympathetic fibers innervate the SA node and the AV node, and
thereby alter the rate of automaticity. Sympathetic stimulation releases norepinephrine, which binds to 1-adrenergic
receptors in the nodal tissues. (1-Adrenergic receptors are
the adrenergic subtype preferentially expressed in cardiac
tissue.) Activation of 1-adrenergic receptors in the SA node
triggers an increase in the pacemaker current (If), which increases the rate of phase 4 depolarization and, consequently,
leads to more frequent firing of the node. Stimulation of
1-adrenergic receptors in the AV node increases Ca2 and
K currents, thereby increasing the conduction velocity and
decreasing the refractory period of the node.
1-Antagonists block the sympathetic stimulation of 1adrenergic receptors in the SA and AV nodes (Fig. 23-11).
The AV node is more sensitive than the SA node to the
effects of 1-antagonists. 1-Antagonists affect the action
potentials of SA and AV nodal cells by: (1) decreasing the
rate of phase 4 depolarization; and (2) prolonging repolarization. Decreasing the rate of phase 4 depolarization results in
decreased automaticity, and this, in turn, reduces myocardial
oxygen demand. Prolonged repolarization at the AV node increases the effective refractory period, which decreases the
incidence of re-entry.

Membrane potential (mV)

60
Prolonged
repolarization
at AV node

Tonic
-adrenergic
levels

30

0
-30
Threshold

-60
Decreased slope of phase 4 depolarization
(Block of adrenergic tone)

-90
0

100

200

300

400

500

600

700

Time (ms)

FIGURE 23-11. Effects of class II antiarrhythmics on pacemaker cell


action potentials. Class II antiarrhythmics (-antagonists) reverse the tonic
sympathetic stimulation of cardiac 1-adrenergic receptors. By blocking the
adrenergic effects on the SA and AV nodal action potentials, these agents decrease the slope of phase 4 depolarization (especially important at the SA node)
and prolong repolarization (especially important at the AV node). These agents are
useful in the treatment of supraventricular and ventricular arrhythmias that are
precipitated by sympathetic stimulation.

1-Antagonists are the most frequently used agents in the


treatment of supraventricular and ventricular arrhythmias precipitated by sympathetic stimulation. 1-Adrenergic antagonists have been shown to reduce mortality after myocardial
infarction, even in patients with relative contraindications
to this therapy such as severe diabetes mellitus or asthma.
Because of their wide spectrum of clinical application and established safety record, -adrenergic antagonists are the most
useful antiarrhythmic agents currently available.
There are several generations of -antagonists, each
characterized by slightly different pharmacologic properties.
First-generation -antagonists, such as propranolol, are
nonselective -adrenergic antagonists that antagonize both
1-adrenergic and 2-adrenergic receptors. They are widely
used to treat tachyarrhythmias caused by catecholamine
stimulation during exercise or emotional stress. Because
propranolol does not prolong repolarization in ventricular
tissue, it can be used in patients with long QT syndrome.
Second-generation agents, including atenolol, metoprolol,
acebutolol, and bisoprolol, are relatively selective for
1-adrenergic receptors when administered in low doses.
Third-generation -antagonists cause vasodilation in addition to 1-receptor antagonism. Labetalol and carvedilol
induce vasodilation by antagonizing -adrenergic receptormediated vasoconstriction; pindolol is a partial agonist at the
2-adrenergic receptor; and nebivolol stimulates endothelial
production of nitric oxide.
The different generations of -antagonists produce varying degrees of adverse effects. Three general mechanisms
are responsible for the adverse effects of -blockers. First,
antagonism at 2-adrenergic receptors causes smooth muscle spasm, leading to bronchospasm, cold extremities, and
impotence. These effects are more commonly caused by the
nonselective first-generation -antagonists. Second, exaggeration of the therapeutic effects of 1-receptor antagonism
can lead to excessive negative inotropic effects, heart block,
and bradycardia. Third, drug penetration into the CNS can
produce insomnia and depression.
Class III Antiarrhythmic Agents: Inhibitors of Repolarization
Class III antiarrhythmic agents block K channels. Two types
of currents determine the duration of the plateau phase of the
cardiac action potential: inward, depolarizing Ca2 currents
and outward, hyperpolarizing K currents. During a normal
action potential, the hyperpolarizing K currents eventually dominate, returning the membrane potential to more
hyperpolarized values. Larger hyperpolarizing K currents
shorten plateau duration, returning the membrane potential
to its resting value more rapidly, while smaller hyperpolarizing K currents lengthen plateau duration and delay return
of the membrane potential to its resting value.
When K channels are blocked, a smaller hyperpolarizing

K current is generated. Therefore, K channel blockers cause
a longer plateau and prolong repolarization (Fig. 23-12). The
ability of K channel blockers to lengthen plateau duration is
responsible for both their pharmacologic uses and their adverse
effects. On the beneficial side, prolongation of the plateau duration increases the effective refractory period, which, in turn,
decreases the incidence of re-entry. On the toxic side, prolongation of the plateau duration increases the likelihood of developing early afterdepolarizations and torsades de pointes. With
the exception of amiodarone, K channel blockers also exhibit
the undesirable property of reverse use-dependency: action

Membrane potential (mV)

50
Block of repolarizing
K+ channels
Balance of Ca2+
(depolarizing)
and K+
(hyperpolarizing)
currents

-50

Prolonged
repolarization

-100
0

0.2

0.4

Time (sec)

0.6

0.8

Membrane potential (mV)

60
Slow rise of
action potential

30

0
-30
Threshold

-60

-90
0

100

200

300

400

Time (ms)

500

600

700

CHAPTER 23 / Pharmacology of Cardiac Rhythm 417

models are used for the majority of ion channel research;


comparatively little is known about the clinical pharmacology of ion channels expressed in humans. With the mouse
and human genomes now completely sequenced, researchers will be able to investigate the possibility that newly
identified gene products can serve as selective targets for
new therapeutic agents. The identification of ion channel
gene expression in the various tissues of the human heart
(SA node, AV node, atrial conduction pathways, endocardium, ventricular conduction pathways, etc.), both during development and in response to injury, may provide
new targets that are not now known. Many of the genes
are likely to encode channels that form heteromultimers,
and there are likely to be many genetic variants within the
population. This enormous complexity will likely represent
a boon to drug development because it will allow more tailored strategies to be employed. For example, current research in atrial fibrillation has focused on the development
of antiarrhythmics selective for ion channels that are expressed selectively in the atria. In parallel, the development
of implantable computers, stimulators, and defibrillators

will constitute an alternative strategy to prevent or terminate arrhythmias.

Suggested Reading
Ackerman MJ, Clapham DE. Ion channelsbasic science and clinical disease. N Engl J Med 1997;336:15751586. (Broad review of ion channels.)
Delacretaz E. Clinical practice. Supraventricular tachycardia. N Engl J Med
2006;354:10391051. (Discussion of the clinical uses of antiarrhythmic
agents in treating supraventricular tachycardia.)
Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on
cardiovascular events in patients with atrial fibrillation. N Engl J Med
2009;360:668678. (Trial of dronedarone suggesting safety in patients with
atrial fibrillation.)
McBride BF. The emerging role of antiarrhythmic compounds with atrial
selectivity in the management of atrial fibrillation. J Clin Pharmacol
2009;49:258267. (Future directions in drug development for treatment of
atrial fibrillation.)
Nash DT, Nash SBD. Ranolazine for chronic stable angina. Lancet 2008;
372:13351341. (Recent review of ranolazine.)
Rudy Y, Silva JR. Computational biology in the study of cardiac ion channels
and cell electrophysiology. Quarterly Rev Biophys 2006;39:57116. (Summarizes the known cardiac ion channels in models of cardiac action potentials.)