Clinical Pharmacology and Therapeutics

SELECTED ANTI-DYSRHYTHMIC DRUGS 225
Drug interactions
Amiodarone potentiates warfarin by inhibiting its metabolism.
It can precipitate digoxin toxicity (the digoxin dose
should be reduced by 50% when amiodarone is added) and
can cause severe bradycardia if used with β-adrenoceptor
antagonists or verapamil.
SOTALOL
Use
Sotalol has uses similar to amiodarone, but a different spectrum
of adverse effects. The plasma K concentration should
be monitored during chronic use and corrected if it is low in
order to reduce the risk of torsades de pointes (see below).
Mechanism of action
Sotalol is unique among β-adrenoceptor antagonists in
possessing substantial class III activity. It is a racemate, the
D-isomer possessing exclusively class III activity. A clinical
trial of D-sotalol (the ‘SWORD’ study) indicated that it reduces
survival in patients with ventricular ectopic activity. The racemate
is preferred.
Adverse effects and contraindications
Since it prolongs the cardiac action potential (detected on the
ECG as a prolonged QT interval) it can cause ventricular
tachycardia of the torsades de pointes variety, like amiodarone.
Hypokalaemia predisposes to this effect. The betablocking
activity of sotalol contraindicates its use in patients
with obstructive airways disease, unstable heart failure,
peripheral vascular disease or heart block.
Drug interactions
Diuretics predispose to torsades de pointes by causing electrolyte
disturbance (hypokalaemia/hypomagnesaemia).
Similarly, other drugs that prolong the QT interval should be
avoided. These include class Ia anti-dysrhythmic drugs
(quinidine, disopyramide), which slow cardiac repolarization
as well as depolarization, and several important psychotropic
drugs, including tricyclic antidepressants and
phenothiazines. Histamine H 1 -antagonists (terfenadine,
astemizole) should be avoided for the same reason.
VERAPAMIL
Use
Verapamil is used as an anti-dysrhythmic:
• prophylactically to reduce the risk of recurrent SVT, by
mouth;
• to reduce the ventricular rate in patients with atrial
fibrillation who are not adequately controlled by digoxin
alone (but beware interaction causing digoxin toxicity,
see below);
• to terminate SVT in patients who are not
haemodynamically compromised. In this setting it is given
intravenously over five minutes. Adenosine is generally
preferred, but verapamil may be useful in patients in
whom adenosine is contraindicated (e.g. asthmatics).
Mechanism of action
Verapamil blocks L-type voltage-dependent Ca 2 channels. It
is a class IV drug and has greater effects on cardiac conducting
tissue than other Ca 2 antagonists. In common with other calcium
antagonists, it relaxes the smooth muscle of peripheral
arterioles and veins, and of coronary arteries. It is a negative
inotrope, as cytoplasmic Ca 2 is crucial for cardiac contraction.
As an anti-dysrhythmic drug, its major effect is to slow
intracardiac conduction, particularly through the AV node.
This reduces the ventricular response in atrial fibrillation and
flutter, and abolishes most re-entry nodal tachycardias. Mild
resting bradycardia is common, together with prolongation of
the PR interval.
Adverse effects and contraindications
1. Cardiovascular effects: Verapamil is contraindicated in
cardiac failure because of the negative inotropic effect. It is
also contraindicated in sick sinus syndrome or intracardiac
conduction block. It can cause hypotension, AV block or
other bradydysrhythmias. It is contraindicated in WPW
syndrome complicated by supraventricular tachycardia,
atrial flutter or atrial fibrillation, as it can increase the rate
of conduction through the accessory pathway. Verapamil
is ineffective in ventricular dysrhythmias and its negative
inotropic effect makes its inadvertent use in such
dysrhythmias extremely hazardous.
2. Gastrointestinal tract: About one-third of patients
experience constipation, although this can usually be
prevented or managed successfully with advice about
increased dietary intake of fibre and use of laxatives, if
necessary.
3. Other adverse effects: Headache, dizziness and facial
flushing are related to vasodilatation (compare with
similar or worse symptoms caused by other calciumchannel
blockers). Drug rashes, pain in the gums and a
metallic taste in the mouth are uncommon.
Drug interactions
The important pharmacodynamic interaction of verapamil
with β-adrenoceptor antagonists, which occurs especially
when one or other member of the pair is administered intravenously,
contraindicates their combined use by this route.
Verapamil reduces digoxin excretion and the dose of
digoxin should therefore be halved when these drugs are
combined. For the same reason, verapamil is contraindicated
in patients with digoxin toxicity, especially as these drugs also
have a potentially fatal additive effect on the AV node.
ADENOSINE
Use
Adenosine is used to terminate SVT. In addition to its use in
regular narrow complex tachycardia, it is useful diagnostically
in patients with regular broad complex tachycardia
which is suspected of being SVT with aberrant conduction. If
adenosine terminates the tachycardia, this implies that the AV
node is indeed involved. However, if this diagnosis is wrong