4. Anti-Arrhythmic Drugs Flashcards
The Cardiac Action Potential Phase 4
‘pacemaker potential’: in non-conducting tissue (atrial and ventricular
myocytes, and Purkinje tissue), the negative resting membrane potential (RMP) of
around −90 mV is maintained by high outward conductance of K+ (gK+) through
open K+ channels
fast Na+ channels and slow (L-type) Ca2+ channels are closed.
In non-conducting tissue therefore the pacemaker potential is unimportant.
In nodal and conducting tissue,
however, there occurs a gradual depolarization owing to greater inward Na+
(gNa+) and Ca2+ (gCa2+) conductance during late diastole
The negative membrane
potential in early diastole also activates a cation channel that is permeable to both
Na+ and K+ and which generates the inward If current
Phase 0 –
rapid depolarization:
at the threshold level of around −65 mV the
fast sodium channels open with a large transient increase in gNa+.
(This is triggered in non-conducting tissue by an action potential [AP] in an adjacent cell.)
The sudden influx in Na+ generates a fast-response AP
(meanwhile, the potassium channels close
and K+ efflux ceases).
Phase 1
– this is the period of rapid partial repolarization mediated by a short-lived
hyperpolarizing efflux of K+:
the sodium channels close and inward gNa+ drops
Phase 2
this is the plateau phase which lengthens the cardiac AP
(in contrast to the much shorter APs generated in nerves and skeletal muscle)
and which is produced mainly by the large influx of Ca2+ ions through slow
(long-lasting L-type) calcium channels
which open at a membrane potential of around −40mV.
During phase 2, cardiac fibres are absolutely refractory to repeated depolarization.
(This is the effective refractory period [ERP], which protects the heart from multiple compounded
APs.)
Phase 3
repolarization: this is caused by a large increase in gK+ (efflux) and the
inactivation of the Ca2+ channels (influx).
The Na+/K+ pump re-establishes the resting membrane potential.
Phase 3 is a relative refractory period during which a
stimulus may generate an AP large enough to be propagated,
but it will be conducted more slowly than usual.
Vaughan–Williams classification of anti-arrhythmic drugs
It does not account for drugs that have more than one site of action
(such as amiodarone),
it fails to find a satisfactory classification for compounds such as adenosine and digoxin, and it is based on the
assumption that all the agents are channel blockers,
when in fact some drugs activate either receptors or ion channels
Class I:
drugs block sodium channels by binding to sites in the α-subunit,
and reduce the maximum rate of depolarization during phase 0 of the cardiac AP.
All share the same underlying mechanism of action but are further subdivided
into classes Ia, Ib and Ic according to the specific characteristics of the Na+
channel block that they produce.
Ia, disopyramide; Ib,
lidocaine; and Ic, flecainide.
Class II:
includes (some) β-adrenoceptor antagonists, including propranolol,
atenolol, metoprolol and esmolol. These drugs increase the refractory period of
the atrioventricular node and so may prevent recurrent supraventricular tachycardia,
including paroxysmal atrial fibrillation (AF).
Class III:
this group includes drugs such as amiodarone and sotalol,
which are now known to have more than one action.
(The original definition encompassed drugs that prolonged the cardiac AP.)
Their main mechanism of action is outward K+ channel blockade
which prolongs repolarization.
This extends the Q–T interval,
and, rarely, these drugs can precipitate torsade de pointes.
Amiodarone (5 mg kg−1 iv) is useful both for supraventricular and ventricular arrhythmias.
Sotalol is racemic, the S-enantiomer is a β-blocker, and both R and S forms prolong the AP.
Other class III agents include ibutilide and dofetilide (used to convert atrial
fibrillation).
Class IV
: these drugs block voltage-sensitive Ca2+ channels, thereby slowing
conduction through the SA and AV nodes.
Examples include verapamil, which is preferentially selective for cardiac tissues,
and diltiazem.
The drugs are ineffective in treating ventricular tachycardias,
and verapamil given intravenously for this purpose has been fatal.
Magnesium sulphate (MgSO4) is a natural Ca2+ antagonist
(an increase in intracellular Mg2+ inhibits Ca2+ influx through Ca2+ channels).
It is effective at abolishing ventricular tachyarrhythmias,
particularly torsade de pointes,
and those induced by adrenaline, digitalis and
bupivacaine
Class V:
this added category includes those drugs that do not fit readily into the
other four classesg
Adenosine
acts at the A1 receptor
(which is linked to the muscarinic K+ channel).
By enhancing K+ efflux,
adenosine hyperpolarizes cells and slows AV conduction.
It has a very short duration of action (20–30 seconds) and, in a dose of 3–6 mg intravenously (repeated as needed),
provides effective chemical cardioversion of supraventricular tachycardia (SVT).
Digoxin
and other cardiac glycosides increase contractile force
and decrease AV node conduction,
mainly via their inhibitory effect on the membrane Na+/K+- ATPase,
and an increase in intracellular Ca2+.
Digoxin’s long-term effect may be caused mainly by the increase in vagal tone.
Sinus bradycardia:
the commonest acute cause is an increase in vagal tone,
either unmasked by anaesthetic agents with no intrinsic vagolytic activity,
or provoked by surgical stimuli such as traction on the peritoneum
or the extraocular muscles.
Vagal activation at the SA node increases gK+ (outwards)
reduces slow channel gNa+ and gCa2+ (inwards),
decreases the slope of the pacemaker potential and suppresses the If current.
Hyperkalaemia may stop pacemaker activity by increasing gK+ (outward).
Sinus tachycardia:
this is not an arrhythmia, but is included for completeness.
Sympathetic stimulation increases heart rate by decreasing gK+.
It also increases slow inward gCa2+ and gNa+ and enhances the If current
Drug effects:
Calcium-channel blockers, as their name suggests,
inhibit slow inward Ca2+ currents during phases 4 and 0,
some, such as diltiazem, can slow the heart rate.
Digoxin enhances parasympathetic activity
(and slows conduction through the AV node).
β-adrenoceptor antagonists prevent the normal inhibition of vagal tone
mediated by sympathetic activity
(which normally increases heart rate by decreasing gK+ outwards and increasing slow gCa2+ and gNa+ inwards, thereby increasing the slope of the pacemaker potential during phase 4).
Hyperkalaemia
Hypokalaemia
Hyperkalaemia:
this hyperpolarizes the cell, induces bradycardia and can even stop SA nodal firing completely.
Hypokalaemia: this increases the rate of phase 4 depolarization by decreasing gK+
and thereby increases the rate.
Hypoxia:
Hypoxia: this is the most ominous cause of bradycardia. The lack of cellular oxygen
can lead to complete cessation of pacemaker activity
Ectopic pacemaker activity (ventricular premature beats
non-conducting cells do not usually depolarize
until activated by the pacemaker impulses
Under some circumstances, however,
they do have a rising phase 4 which means that they can
generate an AP spontaneously and themselves act as pacemakers
This occurs because of an increased inward movement of Ca2+
which reduces the membrane potential to threshold (−65 mV).
Increased intracellular Ca2+ results particularly
from myocardial ischaemia but is also associated with adrenergic stress and high dose
cardiac glycosides.
Ischaemia also closes fast Na+ channels and inhibits the
Na+/K+ pump (which requires ATP [and oxygen] to maintain a low intracellular Na+
against its concentration gradient).
Re-entry (pre-excitation) tachycardia:
these pre-excitation rhythms arise when a wave of depolarization
that can travel down different conducting pathways encounters a block
The impulse continues down the normal path, but should the
paths then rejoin, the depolarization can travel retrogradely up the blocked
segment only to depolarize the normal conducting pathway prematurely
The cycle repeats itself and thus gives rise to a tachyarrhythmia (typically
supraventricular). Re-entrant circuits can be congenital (as in the accessory
pathways of the Wolff–Parkinson–White syndrome) or acquired, following
myocardial damage.
Atrial fibrillation (AF
The commonest cause is
myocardial ischaemia, but there are numerous others including sepsis, autonomic
stimulation, hypomagnesaemia, hypokalaemia, hyperthyroidism, alcohol excess
and mitral valve disease
Atrial fibrillation appears mainly to be a re-entry
abnormality in which multiple propagating waves of depolarization are
initiated by ectopic foci (most of which almost certainly originate from the
pulmonary veins).
Management of Intraoperative Atrial Fibrillation
If this is severe then the immediate treatment is DC cardioversion.
Otherwise the pharmacological options are as follows.
β-adrenoceptor blockers slow ventricular rate pending more considered
treatment
All β-blockers should be avoided if the
patient is on concomitant calcium channel blockers, and used with caution in
patients with heart failure.
Amiodarone
Amiodarone: this is a valuable treatment for a range of acute arrhythmias including
AF. The initial dose is 5 mg kg–1 (given by infusion in glucose 5%), followed by a
stabilizing infusion of 900 mg over 24 hours.
Flecainide
Flecainide: a dose of 2 mg kg–1 (to a maximum of 150 mg) may be enough to
chemically cardiovert new onset AF, and will also help stabilize sinus rhythm that has
been restored by DC cardioversion.
Digoxin
Digoxin:
this is used for medium- and long-term rate control rather than as an acute
therapy.
A loading dose (in the presence of normal serum K+) of 500 μg given by
infusion over 20–30 minutes can be repeated at 6–8 hours before maintenance
treatment is initiated.
Digoxin has a narrow therapeutic index and measurement of
blood levels may be necessary.
