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Chapter 7
Arrhythmias and chronic
heart failure
Useful terms for this topic
Arrhythmia: An abnormality in the normal pattern of
rhythmic excitation of the heart.
Bradycardia: Slower than normal heart rate, less than
60 beats/min.
Ectopic beats: Heart beats which originate from a
pacemaker outside the sinoatrial node.
Fibrillation: Uncoordinated muscle cell contraction
caused by chaotic electrical activity.
Heart block: When electrical excitation in the atria
does not lead to excitation of the ventricles; block can
be partial or complete.
Rate control: Restoring ventricular depolarizations to
a satisfactory rate.
Rhythm control: Restoring sinus rhythm.
Sinus rhythm: Orderly rhythmic activity originating in
the SA node.
Supraventricular arrhythmia: Origin of abnormal
activity is located above the ventricles.
Tachycardia: Faster than normal heart rate, greater
than 100 beats/min.
Ventricular arrhythmia: Origin of abnormal activity is
located in the ventricles.
If you get the feeling that your heart has ‘missed a beat’ or
you feel palpitations (an uncomfortable uttering), then
you have probably experienced an irregularity in your
heart beat. If it is not seriously disturbing and not
recurrent you will probably forget about it, with no further
consequences. However, if it is long-lasting or recurrent
you may take your pulse and nd it to be irregular; a visit
to your physician is then called for.
Further investigation, recording an electrocardiogram
(ECG), may reveal that the normally rhythmic pattern of
activity in your heart is not always orderly. is means
that you have an arrhythmia (also called dysrhythmia).
Most likely this will be uncoordinated electrical activity
in the atria, which may lead to a variety of diagnoses, the
most common of which is atrial brillation (AF). is is
a condition that can be treated with a somewhat
bewildering variety of possible drug interventions, as
well as non-drug treatments (e.g. electrical
cardioversion), designed to restore normal rhythm to
your heart. With clinical management, it is seldom
life-threatening; for some people it is resolved by
treatment, while others live satisfactorily with
continuing AF.
In Workbook 4 we encounter Den, a patient whose onset
of AF occurs after years of chronic heart failure. With a
failing heart, a satisfactory cardiac output cannot be
maintained—the patient is compromised. In Den’s case,
the combination of chronic heart failure and arrhythmia
leads to distressing symptoms. is combination is not
uncommon in elderly patients, and Den provides us with
an example of how we can use our understanding of
pharmacology to help them.
Before considering Den’s case, we will look at the causes
and dierent types of arrhythmias. We will note that in
addition to those originating in the upper chambers of
the heart (the atria, e.g. AF), which are not usually a
medical emergency, less common ventricular
arrhythmias such as ventricular brillation may be
catastrophic, and the cause of sudden death. We will,
however, concentrate on the cellular and molecular basis
of action of the drugs used in the treatment of the most
frequently encountered arrhythmia, AF. We will then
outline the nature of chronic heart failure, and the way in
which drugs act to alleviate the symptoms of this
common condition.
7.1 Arrhythmias 143
7.1 Arrhythmias
An arrhythmia is an abnormality in the normal pattern of
rhythmic excitation of the heart.
In Chapter 5 we introduced the normal pattern of origin
and conductance of electrical excitation of the heart (see
Chapter 5, Figure 5.2). We noted that the wave of
depolarization of cells that spreads throughout the atria
and ventricles starts at the top right-hand part of the heart,
with spontaneous rhythmic activity in the sinoatrial (SA)
node. e cells in this region have a slowly depolarizing
pacemaker slope which res an action potential once it
reaches threshold (see Chapter 5, Figure 5.3). Excitation
then spreads through the atria walls to reach the
atrioventricular boundary. Here, while the atria remain
depolarized and contracted, the excitation gathers at the
atrioventricular node (AV node), from where it passes very
rapidly through specialized conduction bres to
depolarize the ventricles, causing contraction and
ejection of blood. is conduction of excitation in the
heart is illustrated at the top of Box 7.1 in a simplied
version of the cardiac cycle, from diastole to systole.
7.1.1 The electrocardiogram
As dierent parts of the heart are depolarized, electrical
currents are created which are carried through the body
and are detectable by surface electrodes as an ECG. All
suspected arrhythmia patients will have their diagnosis
made on the basis of an ECG recording. Interpretation of
abnormal ECGs is beyond the scope of this text, but
Box 7.1 provides the basis for understanding how an ECG
relates to cardiac function.
Arrhythmias can occur because of abnormalities of either
formation or impulse propagation.
7.1.2 Arrhythmias arising from
abnormalities in impulse formation
1. Modulation of SA node activity. is is where the rate
of ring of impulses from the SA node is abnormal or
irregular. e most common arrhythmia of this sort is
sinus tachycardia, i.e. increased heart rate resulting
from a higher frequency of SA node ring, and detected
as a fast pulse. is is most likely to be due to enhanced
activity in the sympathetic nervous system, with
consequent excess stimulation of SA node 1adrenoceptors (Chapter 5). When associated with stress,
this fast heart rate will often not require drug treatment.
Excessive SA node activity may cause paroxysmal
supraventricular tachycardia, an episodic tachycardia
exhibiting abrupt onset and termination (paroxysmal
means ‘from time to time’). e condition can arise
from activity originating in the SA node, or alternatively
from distinct atrial sites (see below).
2. Ectopic pacemaker. Severe stress and excess stimulation
by noradrenaline or adrenaline of 1 adrenoceptors on
contracting cardiomyocytes can change their action
potential to create a pacemaker slope (Figure 7.1). is
can result in excitation originating in cells outside the SA
node, and can occur in either the atria or ventricles,
disrupting their normal function. Such changes can also
be brought about by ischaemic damage.
7.1.3 Arrhythmias arising from
abnormalities in impulse conduction
1. Re-entrant arrhythmias. Damage to a group of cells
in the wall of the heart can result in activity circulating
round the damage and re-exciting itself to create a
circuit (termed a circus movement). is can result in
a self-perpetuating excitation, which spreads out from
the area around the damage, disrupting normal
function. e original damage may be caused by
ischaemia, and is one way in which a myocardial
infarction (MI) can lead to arrhythmias. A
diagrammatic representation of how patches of
damaged tissue may give rise to re-entrant
arrhythmias is provided in Figure 7.2.
2. Heart block. In a normally functioning heart each
action potential from the SA node passes through the
atria and then excites the ventricles. Ischaemic damage
or the action of certain drugs may mean that some
atrial excitations are ‘lost’ at the AV node. is block
can occur to dierent degrees: partial block, when only
a proportion of atrial beats reach the ventricles, or
complete block, when no atrial excitations lead to
ventricular activity, and atria and ventricles beat
independently of one another. (is is possible because
all parts of the specialized cardiac conduction system
have pacemaker activity. Usually this is masked by
dominance of the higher rate set by the SA node. Where
this is lost, the rate at which the ventricles beat can be
set by a more distal site, e.g. AV node or His-Purkinje
system.) In some cases, for instance when atrial
excitations are very fast (e.g. in AF), a partial block may
Box 7.1
A
The cardiac cycle, conduction pathways, and the
electrocardiogram (ECG)
B
C
Aortic pressure
PR
segment
P
PR Interval
Diastole ends,
systole begins
QRS
complex
R
ST
segment
T
Q
S
QT Interval
Systole ends,
diastole begins
Left ventricular (LV)
pressure
D
LV volume
Figure a Electrical events during the cardiac cycle (A) reflected in an ECG recording (B), and concomitant
changes in aortic and left ventricular pressures (C) and left ventricular volume (D).
*
End-diastolic volume
End-systolic volume
Box 7.1 The cardiac cycle, conduction pathways, and the electrocardiogram (ECG)
(b)(a)
Panel A of Figure a illustrates (in green) the spread of
the wave of excitation, from its origin (SA node),
through the atrial muscle walls, collecting at the
atrioventricular (AV) node. is is followed by rapid
excitation of the ventricles through the specialized
conducting bres (bundle of His and Purkinje bres).
ese events are captured on an ECG; a typical
recording is shown in panel B. e P wave of the ECG
is caused by atrial depolarization. Ventricular
depolarization results in the QRS complex, and
ventricular repolarization leads to the T wave. During
the at PR segment, the atrial tissue is fully
depolarized and the ventricles are at rest; the reverse
is true of the ST segment. Panel C shows changes in
left ventricular pressure and aortic pressure during
diastole and systole, and panel D shows changes in the
volume of the left ventricle during the cardiac cycle.
e following points should be noted.
1) e pulse is created when the ventricles contract
and the pressure in the left ventricle rises until it
exceeds that in the aorta (panel C, blue line reaches
red line); the aortic valve ips open, and a volume
of blood is ejected from the left ventricle into the
aorta, sending a pulse of pressure through the
arteries.
2) Apart from taking your pulse and blood pressure,
the ECG provides the most convenient method of
monitoring the pattern of the cardiac cycle (panel
B). Irregularities in impulse propagation can be
detected, making the ECG a powerful tool for
diagnosing arrhythmias.
3) Diastolic and systolic blood pressures are created
by the rhythmic contractions of the left ventricle,
and correspond to low and high points in the blue
aortic pressure curve (Figure a, panel C).
4) When the left ventricle begins to contract there is a
short delay before the ventricular pressure reaches
the pressure in the aorta. During this time no blood
can ow out of the ventricle and its volume
therefore remains the same. is is known as
isovolumetric contraction (indicated by * in
panel D). Once the pressure in the ventricle
exceeds that in the aorta, the aortic valve opens,
and the ejection phase begins.
Normal action potential of a
non-automatic working myocyte
30
0
Excitation imposed
from outside cell
–90
No pacemaker
slope
Figure 7.1 Generation of a pacemaker slope in heart muscle cells may lead to ectopic
pacemaker activity.
(a) The action potential of a normal working ventricular myocyte. The initial segment is flat; there is no
pacemaker slope and the cell will not fire spontaneously. The membrane potential rises in response to
depolarization spreading from adjacent muscle cells. Voltage-sensitive Na+ channels open and Na+ flows into
the cell down its gradient; once threshold is reached, an action potential is fired. (b) If the muscle cell is
damaged or altered by, for example, ischaemia or excessive stimulation of 1-adrenoceptors, it may develop
a pacemaker slope. Now, the membrane potential spontaneously rises to threshold, to fire an action
potential in the absence of excitation from outside. This cell is said to have developed ‘automaticity’ and has
become a pacemaker, able to set abnormal excitations spreading through the cardiac tissue.
Time
With cardiac injury, ischaemia or severe
stress (excess catecholamines) the myocyte
may develop a pacemaker slope
Cell res at
threshold without
stimulation
Pacemaker slope
Time
146 Chapter 7 Arrhythmias and chronic heart failure
A
Action potentials carried by voltage-dependent sodium channels
Resting
B
(i)
C
(i) (ii) (iii)
Figure 7.2 Damage to heart tissue (e.g. following MI) may lead to
re-entrant arrhythmias.
Excitations (action potentials) are dependent on the opening of voltage-dependent
sodium channels on the muscle cell surface. When opened in response to a
depolarization of the membrane, to a less negative voltage inside the cell, Na+ enters
the cell, carrying the action potential forward. The channels then rapidly close, and for
a moment cannot be opened (they are refractory, panel A). This ensures the orderly
passage of an action potential in one direction through the walls of the heart—it
cannot go backwards (panels B(i) and C(i)). However, if a patch of tissue is damaged
and carries the action potential with a delay (panel B(ii)), or via a diversion around
dead tissue (panels C(ii) and (iii)), it may return to its origin after the refractory period is
over. It can now re-excite the same tissue, setting up self-perpetuating excitations. If
this process occurs in the left ventricle wall, orderly contraction may be disrupted,
resulting in a dangerous collapse of cardiac output.
Depolarization Closed
Normal
Open Refractory
Delay
Following myocardial
infarct
(ii)
Damaged
tissue
be articially introduced using drugs such as calcium
channel blockers and -blockers (see below).
7.1.4 Atrial fibrillation—a supraventricular
arrhythmia
Atrial brillation (AF) is the most common arrhythmia,
aecting around 1% of the overall population, and ~10%
of people over 75. It arises from abnormal impulse
conductance, and is characterized by extremely rapid
uncoordinated electrical activity in the atria arising from
multiple re-entry waves of depolarization. Atrial activity is
very irregular and at a very high rate (e.g. 350–600
impulses/minute). As a result contraction of the atria is
uncoordinated and ineectual. Conductance through the
AV node is variable, and the resulting contraction of the
ventricles is rapid and irregular (patients are described
clinically as having an irregularly irregular pulse). AF
approximately doubles the mortality rate, mainly as a
result of raised incidence of ischaemic stroke due to
cardiac thromboembolism (see below).
Electrical cardioversion is the application of debrillating
current to the chest to restore normal function. is is the
most common non-pharmacological treatment of AF. e
pharmacological approaches to therapy are discussed
below.
e following points are noteworthy:
1. e uncoordinated contractile activity characteristic of
AF results in inecient ejection of blood from the
7.2 Anti-arrhythmic drugs 147
atria, with pooling of blood. A static volume of blood
within the atria itself is potentially dangerous, since it
is prone to form a thrombus. is could be ejected as
an embolus, liable to block cerebral blood ow, and so
lead to a stroke (see Chapter 17). Patients with AF have
an approximate vefold increased risk of stroke; this
can be eectively managed with antithrombotic
therapy (see below).
2. Ventricular lling is not dependent on eective atrial
contraction. is is because in ventricular diastole the
pressure in the ventricles is lower than that in the
atria, even in the absence of atrial contraction. is
explains why AF, in which eective contraction of the
atria is lost, is not usually immediately lifethreatening.
3. Ventricular lling is, however, dependent on a suitably
long ventricular lling phase (i.e. ventricular diastole).
Clearly, if all the very fast atrial excitations were to
reach the ventricles there would be no ecient lling
phase, contractions would be uncoordinated and
ineective, and the patient would be at immediate
risk. is does not happen, because the AV node
cannot conduct at this rate, and so only some atrial
excitations reach the ventricles. Although still fast, the
ventricular rate of contraction is therefore much lower
than the atrial rate and a life-sustaining cardiac output
is maintained.
Recurrent AF may be usefully divided into three
categories, dependent on the duration and persistence of
the arrhythmia:
paroxysmal repeated episodes, normally
lasting no more than a few days,
terminating spontaneously
persistent recurrent episodes lasting over 7
days which do not terminate
spontaneously, requiring drug or
electroshock (electrical
cardioversion) therapy
permanent AF is present all the time, and is
not cured by medication or
cardioversion.
ese categories aect the approach to treatment, as set
out in Box 7.2. It should be recalled that AF can be treated
by both drug and non-drug approaches.
7.1.5 Ventricular tachyarrhythmias
While AF is the most common arrhythmia and dominates
prescribing for these types of conditions, the rarer
ventricular arrhythmias are important as a cause of sudden
death. ey are the most common arrhythmias associated
with cardiac arrest following MI. e structural damage
caused to the heart by MI can result in ventricular
tachycardia or brillation. In both cases ventricular rate is
too fast to allow adequate lling, and/or the uncoordinated
contractions are ineectual at ejecting blood, the cardiac
output collapses, and death may occur within minutes.
Management requires specialist care (see Chapter 6, Section
6.4, and Workbook 3). Immediate drug treatment is likely to
involve either lidocaine (lignocaine) or amiodarone.
7.2 Anti-arrhythmic drugs
We shall concentrate here on drugs used to treat AF, since
it is the most common of arrhythmias, and its
management illustrates the mode of action of most
anti-arrhythmic drugs. We will divide the drugs according
to the cellular basis of their action, and then consider their
use in the treatment of AF in the case of our ctional
patient Den.
Classication by mechanism of action, as proposed by
Vaughan Williams in 1970, gives four main classes:
Class I
Class II
Class III drugs that delay repolarization
Class IV
voltage-sensitive Na+ channel blockers
-adrenoceptor antagonists
Ca2+ channel blockers.
In addition to these four classes, two other drugs,
adenosine and digoxin, are described as ‘atypical’.
7.2.1 Class I: Use-dependent Na+
channel blockers
Taking a potent non-selective Na+ channel blocker is
likely to kill you (an example is the puer sh poison,
tetrodotoxin). However, a drug that binds selectively to
the refractory or open states of the Na+ channel
(Figure 7.3 and Chapter 16, Box 16.2) will result in a
reduction in activity; the greatest eect will occur in
those cells being excited at high frequency. e heart
will still be able to beat at normal frequencies. (In AF the
frequency of atrial excitations may be up to 600/
min—see below.) Here the term ‘use-dependent’
Box 7.2
Classification of atrial fibrillation (AF) and drug therapy—an introduction
Classication of AF is shown in Figure b.
Confirmed diagnosis of AF
Establish risk level for
Classication of AF -which type?
Paroxysmal* AF Persistent* AF Permanent* AF
Symptoms persist
Rhythm control
(restore normal rhythm
from sinoatrial node)
Rhythm control fails
thromboembolism
Rate control
(establish satisfactory rate of
ventricular activity despite
abnormal atrial activity)
e.g. flecainide,
amiodarone
*See main text for explanation of these types of AF.
Thromboembolism: Risk Stratification
This is the assessment of the risk of stroke following
thrombus formation in static blood in atria of a patient
with AF (patients without structural heart disease)
HIGH RISK
Previous
thromboembolic event
Age over 75 with risk
factors*
Warfarin
(INR target 2.5)
*Risk factors: e.g. diabetes, hypertension, or vascular disease.
Caution – warfarin itself is not without risk
MODERATE RISK
Age over 65 with no risk
factors
Age less than 75 with risk
factors*
Warfarin or
aspirin
e.g. propranolol,
verapamil, digoxin
LOW RISK
Age less than 65, no risk
factors
Aspirin
(low dose)
Figure b
Classification of AF as paroxysmal, persistent, or permanent will be overlaid with assessment of
risk so as to inform the decision over the strategy of its management (i.e. rate control versus
rhythm control) and the nature of antithrombotic therapy.
means a selective action at those channels opening
with high frequency.
As seen in Figure 7.2, panel A, voltage-sensitive Na+
channels are available for opening only in the resting state.
Preferential binding of a drug to channels in the other
states will lead to an accumulation of channels in these
states, with fewer available for opening. e usedependent drug does not bind to, and so does not block,
7.2 Anti-arrhythmic drugs 149
Na+ channel blockers
Resting Open Refractory
Figure 7.3 Use dependency in Class I anti-arrhythmic
drugs.
The voltage-sensitive Na+ channels, on which conductance of
cardiac excitation depends, exist in equilibrium between the three
states shown (see also Figure 7.2, panel A). These channels are
only available for opening in the resting state. If a drug binds
selectively to the other states (notably the refractory state) there
will be a depletion of channels available for opening. Such a drug
will have a greater effect in highly active channels; this is ‘use
dependency’. The activity in cells firing with high frequency will be
selectively reduced, whilst those firing slowly will be affected less.
resting channels, but does delay the return of refractory
channels to the resting state. So a second excitation
following very rapidly after a rst will nd more Na
+
channels unavailable to be opened. e eect of this is to:
a) slow conduction velocity
b) reduce spontaneous ring of cells (i.e. reduce
automaticity and ectopic pacemakers)
c) reduce high frequency depolarizations.
e Class I drugs are all use-dependent Na+ channel
blockers. ey are subdivided into three groups according
to their rate of association and dissociation from the
channel, which leads to dierent characteristics of the
block produced.
Class IA
e oldest Class I drugs produce a moderate degree of Na
+
channel block, intermediate between Classes IB and IC.
Notably, these drugs also prolong repolarization and so
lengthen the action potential (see Class III). Examples are
disopyramide, quinidine, and procainamide. ey are
now rarely used, owing to associated pro-arrhythmic and
non-cardiac side eects, many of which result from
antagonism of muscarinic cholinergic receptors. ese
side eects include ventricular tachycardia and brillation,
urinary retention, dry mouth, and constipation.
Class 1B
ese drugs have a strong preference for refractory
channels. Association and dissociation of the drug from
the channel is suciently rapid to allow normal rates of
ring (e.g. around 1 per second). Much faster rates are
blocked through an accumulation of channels in the
refractory state. e most notable example is lidocaine,
which has an important use in the prevention of
ventricular arrhythmias during, and immediately
following, MI. Its use, though, has now been largely
superseded by Class II drugs ( adrenoceptor antagonists;
see below) and amiodarone (Class III drugs; see below). It
is not used for supraventricular arrhythmias.
Class 1C
e slow association and dissociation of these drugs from
Na+ channels, and limited selectivity for refractory
channels, results in a reduction in all excitations, not just
those occurring at high frequency. is leads to reduced
heart rate, i.e. drugs have a negative chronotropic eect.
Class IC drugs also slow conductance of excitation through
the ventricles. e main example is flecainide, which is
useful for preventing onset of paroxysmal AF, treating
some ventricular arrhythmias, and suppressing ectopic
pacemakers. In common with the other Class I drugs,
ecainide is associated with pro-arrhythmic eects. ese
are greatest where structural damage to the myocardium
exists; it is not used post MI or in heart failure patients.
7.2.2 Class II: -adrenoceptor antagonists
ese drugs mainly reduce sympathetic nervous system
induced enhancement of pacemaker activity and
conductivity. ey are used to reduce mortality following
MI, when excessive sympathetic activity contributes to
ventricular tachycardias: 1-adrenoceptor-mediated
eects will be countered by -adrenoceptor antagonists
(-blockers). Conductance from the atria through to the
ventricles is enhanced by stimulation of 1adrenoceptors on the AV node; blocking these receptors
with Class II drugs increases AV delay, and so reduces
ventricular rate. is explains their usefulness in AF.
Examples include propranolol, acebutolol, and
atenolol. Propranolol is also prescribed for stress-
induced tachycardia (see Chapter 19, Section 19.4.1).
Sotalol is a -adrenoceptor antagonist with additional
Class III activity (see below) and is used for the
treatment of life-threatening arrhythmias, including
ventricular tachyarrhythmia. It is of interest to note that
for many of their uses, including as antihypertensives,
the long duration of action of most -adrenoceptor
antagonists is benecial. is is not, however, the case
150 Chapter 7 Arrhythmias and chronic heart failure
for all indications. Esmolol is an example of a
-adrenoceptor antagonist with a brief duration of
action used intravenously for the short-term control of
supraventricular arrhythmias, including AF and atrial
utter. ese drugs are described more fully in Chapter
5, where it is noted that due to their action at all -
adrenoceptors they are usually avoided for asthmatics.
Drugs with signicant action at 2-adrenoceptors should
also be avoided in diabetic patients (see Section 5.2.5).
7.2.3 Class III: Repolarization-delaying
drugs
During an action potential the polarity of the cell changes
from negative inside at rest (polarized) to positive inside
(depolarized). Before another action potential can occur
the cell must be repolarized (returned to negative inside).
A drug that prolongs the action potential by delaying
repolarization increases the gap between the upstroke of
action potentials; the frequency of ring is reduced. e
refractory period (the period following an action
potential before another can be generated) is prolonged;
this has a benecial eect in preventing the re-excitation
of cardiac tissue that occurs in re-entrant arrhythmias
(e.g. post MI). Repolarization delay may occur, for
example, if the potassium channels that normally open
and cause the membrane potential to fall back below
zero, are partially blocked. ere are two signicant Class
III anti-arrhythmic drugs, amiodarone and sotalol.
Amiodarone is a powerful tool to counter a wide range of
tachyarrhythmias, including AF. It is, however, limited by
serious toxic eects involving the lungs, thyroid gland
(due to its iodine content), liver, eyes, skin, and peripheral
nerves. It has an unpredictable and very long elimination
half-life (4–15 weeks) when given chronically, as it binds
extensively in tissues. It interacts with numerous drugs,
which importantly include digoxin, verapamil, and
diltiazem. It is used under careful supervision, and
usually only when other options have proved ineective
or are inappropriate. Sotalol combines Class III and Class
II activity and, like amiodarone, is useful in both
ventricular and supraventricular arrhythmias.
7.2.4 Class IV: Calcium channel
blocking drugs
We have previously encountered the three types of L-type
calcium channel blocker: dihydropyridines (e.g.
nifedipine), and the non-dihydropyridines verapamil and
diltiazem. As antihypertensives (Chapter 5), the
dihydropyridines, which preferentially block Ca
in arterial smooth muscle, are the most important drugs. In
the treatment of arrhythmias, however, verapamil, the most
cardioselective agent, is the main Class IV drug. It acts to
decrease the rate of action potential generation in the SA
node and to slow AV conduction (imposing partial heart
block). In addition, it is negatively inotropic by virtue of
reducing the inux of calcium into ventricular myocytes
during the calcium plateau of their action potential. It has
marked vasodilatatory eects. e main anti-arrhythmic
use of verapamil is in the prevention of supraventricular
tachycardia including AF (adenosine (see below) is used to
terminate existing supraventricular tachycardia) and in rate
control for AF. It has little eect on ventricular arrhythmias.
Adverse eects are covered in Chapter 5, Section 5.2.3. Of
note here are the potentially serious pro-arrhythmic eects
such as bradycardia, heart block, and cardiac failure.
2 +
channels
7.2.5 Atypical anti-arrhythmic drugs
Adenosine is an agonist at A1 receptors, Gi-coupled
receptors which lead to K+ channel opening, causing
hyperpolarization and reduction in pacemaker slopes.
A1–K+ channel coupling is present in the SA and AV nodes
and the atria (but not the ventricles). is means that
adenosine reduces ring of SA and AV nodes, resulting in
reduced heart rate and AV conductance. In addition,
hyperpolarization of atrial cells reduces excess
excitations. Overall, the result is supraventricular
anti-arrhythmic activity. Adenosine is administered by
intravenous injection, and has a rapid onset of action and
a very short half-life (seconds). is short duration of
action makes the drug a safer option than verapamil for
the rapid short-term control of paroxysmal
supraventricular tachycardias by inhibiting re-entry
excitations and slowing ventricular rate. But by interfering
with the SA and AV nodes, adenosine can induce
bradycardia, and even asystole (heart stops beating).
Adenosine is also used diagnostically to examine atrial
rhythm by slowing conduction through the AV node.
e metabolism of adenosine is unusual; it is taken up by
red blood cells via a specic nucleoside transporter, and
is metabolized by enzymes on the vascular endothelium.
e uptake is inhibited by the antiplatelet drug
dipyridamole (Section 4.2.2), which thereby prolongs the
action of adenosine.
7.3 Drugs and atrial fibrillation 151
Adenosine can induce bronchospasm, and so should be
avoided in asthmatic patients. Xanthines such as
theophylline, used as bronchodilators in asthma and
COPD (see Chapter 11), are adenosine receptor
antagonists; patients who have taken such drugs may
respond poorly to adenosine and require a higher dose.
Digoxin is the most commonly used among the group of
drugs called cardiac glycosides, naturally occurring
compounds found in foxgloves (Digitalis spp) and related
plants. It has clinical use in heart failure as well as
arrhythmias, and so is discussed further below. Digoxin
has two main mechanisms of action:
1 slowing AV conduction as a result of increased
parasympathetic (vagal) activity, accounting for its
anti-arrhythmic activity
7.3 Drugs and atrial fibrillation
Drug treatment in the management of AF has the
objective of rate control or rhythm control, with
prevention of thromboembolism.
2 inhibition of the Na+/K+ pump (Na+/K+ ATPase) in heart
cells (see use in heart failure below).
Slowing AV conduction makes digoxin eective in rate
control (see Section 7.3.2), in the management of AF, by
reducing the ventricular rate despite a continuing atrial
arrhythmia. Digoxin is therefore used to control persistent
AF, but not to terminate paroxysmal atrial brillations. It is
particularly useful in the treatment of AF in patients with
heart failure. Its side eects and other considerations,
such as its narrow therapeutic window, are discussed in
Section 7.5.3.
presents a danger of cardiovascular collapse. Rate control
aims to achieve an eective ventricular rate in the face of
continuing AF by employing AV node-blocking agents:
7.3.1 Rhythm control
e most rapid and eective means of bringing about an
orderly excitation from the SA node in AF is electrical
cardioversion. Restoration of sinus rhythm can also be
attempted chemically, using the following drug classes to
reduce excitability within the atria:
Class IA (e.g. quinidine)
Class IC (e.g. ecainide)
Class III repolarization-delaying drugs
(e.g. amiodarone).
Whilst sinus rhythm can be restored in most patients,
without further treatment it usually recurs.
use-dependent Na+
}
channel blockers
7.3.2 Rate control
With this strategy the atrial brillations remain, but
the number of ventricular excitations is kept down by
partially blocking transmission of excitation from the
atria to the ventricles through the AV node.
Remember that, although your heart can continue to
work even if the atria are not eectively pumping, if the
rate of contraction of the left ventricle is too high, it will
not be able to ll eciently and so eject blood. is
Class II -adrenoceptor antagonists
(e.g. propranolol)
Class IV Ca2 + channel blockers (e.g. verapamil)
Digoxin slows AV conduction.
7.3.3 Antithrombotic medication
Estimation of the degree of risk of thromboembolism
(risk stratication) is used to determine appropriate
antithrombotic therapy. is is introduced in Box 7.2. In
summary most, if not all, patients with AF will be oered
antithrombotic therapy, most commonly in the form of
daily low-dose aspirin or, where risk is greater, warfarin
(see Chapter 4).
7.3.4 ‘Pill-in-the-pocket’ approach
As an alternative, or in addition, to maintenance or
routine daily drugs, the ‘pill-in-the-pocket’ approach
provides a drug to be carried and taken as needed at the
onset of brillations. is approach has been adopted by
some prescribers for the management of sporadic atrial
brillations in the absence of structural heart disease,
using ecainide for example.