Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
taken up by and concentrated in adrenergic nerve terminals.
This initially results in noradrenaline (norepinephrine)
release and a brief sympathomimetic effect.
This is followed by an inhibition of noradrenaline
release.
Bretylium’s major effect on cardiac tissues is to
prolong the action potential and refractory period of
atrial and ventricular myocardium and Purkinje fibers.
In so doing, it increases the fibrillation threshold. Bretylium
produces a biphasic effect on impulse initiation
and conduction and on hemodynamics. Sinus rate, myocardial
contractility and blood pressure increase transiently
for 10–15 min. These variables then tend to
decrease as sympathetic tone decreases. These antiadrenergic
effects prolong atrioventricular conduction
time in dogs.
Formulations and dose rates
Bretylium tosylate is supplied as a solution for intravenous administration.
Because the oral route results in erratic absorption, bretylium is
only administered intravenously.
DOGS
• 2–6 mg/kg IV. This dose increases the fi brillation threshold to
5–18 times the baseline
• In experimental dogs, this dose is effective at preventing
ventricular fi brillation and tachycardia when administered every
12 h chronically. This, however, is not a practical means of
treating canine patients
• When bretylium is administered to dogs during cardiopulmonary
resuscitation, the antifi brillatory effects are not immediate.
Lidocaine produces a more rapid but less pronounced
antifi brillatory effect. A combination of lidocaine (2 mg/kg) and
bretylium (5 mg/kg) may have a more benefi cial effect than
either drug alone
Pharmacokinetics
In the dog, bretylium has a biological half-life of
approximately 16 h. However, plasma concentration
declines rapidly after intravenous administration of
15 mg/kg from approximately 20 µg/mL at 6 min to less
than 2 µg/mL after 1 h. The drug is cleared from the
body through renal elimination. The antifibrillatory
action correlates with myocardial concentration, which
increases slowly after intravenous administration to
reach a peak 1.5–6 h after dosing.
Adverse effects
● Toxicity is rare, although hypotension can occur.
Blood pressure should be monitored and dopamine
or noradrenaline (norepinephrine) administered if
systolic blood pressure falls below 75 mmHg.
● Transient hypertension and arrhythmia exacer -
bation may occur after the initial dose because of
noradrenaline (norepinephrine) release from nerve
terminals.
Sotalol
Sotalol is a class III antiarrhythmic with important β-
blocking properties but should not be substituted for a
pure β-blocker. The information provided on this drug
in this chapter is based on studies in experimental
animals, on reports of its use in human medicine, on
limited clinical experience and on anecdotal reports
from individuals who have used the drug. Sotalol is
potentially a very useful drug in small animal veterinary
medicine but this potential has not yet been fully
explored.
Clinical applications
In human medicine, sotalol is effective for treating
various arrhythmias. It is not as successful as quinidine
at converting primary atrial fibrillation to sinus rhythm.
It is, however, as effective as quinidine at preventing
recurrence of atrial fibrillation after electrical cardioversion.
Sotalol is effective at terminating supraventricular
tachycardia due to AV nodal re-entry or pre-excitation
in humans. In human patients with ventricular tachycardia,
sotalol may be one of the more effective agents
for terminating or slowing the tachycardia. It also
appears to be efficacious for preventing sudden death.
These effects, however, are not profound and have
required large clinical trials to reach statistical
significance.
A major indication in veterinary medicine is boxer
dogs with severe ventricular tachyarrhythmias and
syncope. Sotalol is very effective at suppressing the
arrhythmias and stopping the syncopal events in this
breed. The authors have limited experience with sotalol
for the treatment of supraventricular arrhythmias and
ventricular arrhythmias in other breeds.
Mechanism of action
Sotalol is a potent and nonselective β-adrenergic blocking
drug that also prolongs the action potential duration
and increases the refractory period of both atrial and
ventricular myocardium (class III effect). In human
medicine it is useful for treating a variety of arrhythmias
and for increasing the fibrillation threshold.
Sotalol is marketed as the racemic mixture of its
stereo isomers, D- and L-sotalol. The D-isomer has less
than one-50th the β-blocking activity of the L-isomer.
The L-isomer’s potency is similar to that of propranolol.
The D- and L-isomers both prolong action potential
duration and refractoriness. The increase in action
440