Pharmacological Treatment Of Arrhythmias
Most anti-arrhythmic drugs, whatever their
specific mechanisms, have two actions that reduce abnormal electrical activity,
but cause tolerably small effects on normal myocardium.
·
They suppress
abnormal (ectopic) pacemakers more than they do the sinoatrial node.
·
They increase
the ratio of the effective refractory period to action potential duration (ERP:
APD).
Anti-arrhythmic drugs are divided into
four classes, based on their mechanisms (Figure 51). However, most
anti-arrhythmic drugs have properties of more than one class, often because
drug metabolites have their own separate anti-arrhythmic effects or because the
drugs exist as 50/50 mixtures of two stereoisomers with different actions. This
classification system, introduced by Vaughan Williams and Singh, also excludes
several drugs, and is not useful for matching specific drugs to particular
arrhythmias. A more clinically relevant classification scheme is shown in Table
51.1.
Clinical trials have shown that class
I agents do not enhance survival, and in fact are deleterious if used for some
purposes (e.g. prevention of ventricular ectopic
beats). Conversely, the class III agent amiodarone modestly increases survival,
and class II agents (β-blockers) can suppress a wide spectrum of arrhythmias
and increase survival in conditions such as chronic heart failure and ischaemic
heart disease which frequently lead to lethal arrhythmias. However, because radiofrequency
catheter ablation can effectively cure many superventricular tachyarrhythmias
and implantable defibrillators are more effective than drugs in reducing the incidence of lethal ventricular arrhythmias,
the emphasis of arrhythmia management is shifting towards device-based therapy.
Class I drugs act mainly by blocking
Na+ channels, thus slowing and depressing impulse conduction. This suppresses
re-entrant circuits which depend on an area of impaired conduction, as further
Na+ channel blockade here may block conduction completely, which terminates the
arrhythmia. Class I drugs can also suppress automaticity by raising the
membrane potential thresh-old required for delayed afterpolarizations to
trigger action potentials (APs).
Because they have a higher affinity
for Na+ channels when they are open or inactivated, these drugs bind to Na+
channels during each AP and then progressively dissociate following repolarization.
Dissociation is slowed in cells in which the resting potential is decreased,
and this deepens channel blockade in tissue that is depolarized due to
ischaemia.
Three subclasses of class I drugs are
designated based their differential effects on the AP in canine Purkinje
fibres. Once bound, each subclass of drug dissociates from the Na+
channel at different rates. Class IB drugs (lidocaine, mexiletine)
dissociate from the channel very rapidly and almost completely between APs.
They therefore have little effect in normal myocardium because the steady-state
level of drug bound to the channel is minimal. However, in tissue that is
depolarized or firing at a high frequency, dissociation between impulses is
decreased, promoting channel blockade and depression of conduction. These drugs
have there-fore been used to treating ventricular tachycardia (VT) associated
with MI, which mainly originates in myocardium depolarized by ischaemia.
Conversely, class IC drugs (flecainide, propafenone) dis-sociate
very slowly, remaining bound to channels between APs even at low frequencies of
stimulation. This strongly depresses conduction in both normal and depolarized
myocardium, thus reducing cardiac contractility. The intermediate dissociation
rate of class IA drugs (procainamide, disopyramide) causes a
lengthening of the ERP,
which gives them class III activity (see below).
Class I drugs cause many side effects,
not the least of which are several types of arrhythmia. This pro-arrhythmic effect
is unsurprising, given that depression of conduction and prolongation of the AP
can induce arrhythmia development (Chapter 48).
At present, class 1B lidocaine and
procainamide are sometimes used to terminate episodes of VT. Class 1C drugs
(e.g. flecainide, propafenone) are used mainly in the prophylaxis of certain
supraventricular tachycardias, particularly AF, and act by suppressing the
arrhythmia at its source. This approach to treating SVT is termed rhythm
control. An alternative approach, rate control, uses drugs that slow
or block the conduction of impulses through the AVN, thereby slowing the ventricles
and unmasking the underlying atrial rhythm. Drugs used for this purpose include
class II and IV agents, as well as adenosine and digoxin.
β-Blockers such as propranolol and
atenolol form the second class of anti-arrhythmics (Figure 51, lower
right). They are used for rate control in SVT, and work by reducing the
conduction of the atrial impulse through the AVN, because this is promoted by
sympathetic stimulation. They can also be useful in ameliorating VT because
sympathetic drive to the heart is arrhythmogenic, particularly if there is
ischemia or structural heart disease (Chapter 48).
Class III drugs
Class III drugs are K+ channel
blockers that increase APD and therefore prolong ERP. Re-entry occurs when an
impulse is locally delayed, and then re-enters and re-excites adjacent
myocardium (see Chapter 48). Drugs that prolong ERP can prevent this re-excitation because the adjacent myocardium is still refractory (inexcitable) at
the time when the delayed impulse reaches it.
The class III agent amiodarone is
effective against both SVT and VT, probably because it also has class IA, II
and IV actions. Although amiodarone modestly reduces mortality after MI and in
congestive heart failure, its long-term use is recommended only if other anti-arrhythmic
drugs fail, because it has many cumulative adverse effects and must be
discontinued in about one-third of patients. Hazards include pulmonary
fibrosis, hypo and hyperthy roidism, liver dysfunction, photosensitivity and
peripheral neuropathy. Amiodarone also has a very unpredictable and long
(4–15 weeks) plasma half-life, which complicates its oral administration. Dronedarone
is a new class III drug, used to prevent recurrence of AF, which is
structurally similar to amiodarone and also has class I and IV activity.
Compared with amiodarone, it has fewer side effects and a much better
pharmacokinetic profile (t1/2 of 1 day) but is less effective. It
cannot be used in patients with severe heart failure, and may in rare cases
cause liver failure. Sotalol is a mixed class II and III drug used for
both VT and SVT. Although it causes far fewer extra-cardiac side effects than
amiodarone, it is more likely to cause torsades de pointes (see Chapter 50). Dofetilide,
ibutilide and azimilide are drugs that are seen as ‘pure’ class
III agents in that they are relatively selective for the voltage-gated K+
channels involved in repolarization. These drugs are used to terminate atrial
flutter and fibrillation. Ibutilide is used to premedicate patients due for cardioversion
because it enhances myocardial sensitivity. These agents can also cause
torsades de pointes, although azimilide is less apt to do so. Vernakalant is
a new class III drug used to terminate episodes of AF. It acts selectively on
the atria, and seems to cause torsades de pointes less often than other class
III drugs.
Class IV drugs, adenosine and
digoxin
Class IV drugs (verapamil, diltiazem)
are used to treat SVT, and exert their anti-arrhythmic effects on the AVN by
blocking L-type Ca2+ channels, which mediate the AVN
action potential. Their blockade therefore slows AVN depolarization and
conduction, and also increases its refractory period. These effects suppress
AVN re-entrant rhythms and can slow the ventricular rate in atrial flutter and
fibrillation by preventing a proportion of atrial impulses from being conducted
through the AVN. Negative inotropy can occur due to L-type channel inhibition,
especially if left ventricular function is impaired. Negative inotropic and
chronotropic effects are exacerbated by coadministration of β-blockers. These
drugs are also sometimes effective in treating focal ventricular tachycardias,
because these may be triggered by DADs (see Chapters 48 and 50). Adenosine,
an endogenous nucleoside (see Chapter 23), acts on A1-receptors in
the AVN, suppressing the Ca2+ current and enhancing K+
currents. This depresses AVN conduction enough to break the circuit causing the
tachyarrhythmia. Adenosine, given as a bolus injection, is the drug of choice
for rapidly terminating SVT. It commonly causes transient facial flushing,
bronchospasm and a sense of impending doom. Digoxin slows AV conduction
by stimulating the vagus and is used to treat AF and other SVTs, especially in
patients with heart failure (see Chapter 47).
