Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CLASS II ANTIARRHYTHMIC DRUGS (β-ADRENERGIC BLOCKERS)
tachyarrhythmias. They are used either as sole agents or
in combination with other antiarrhythmic drugs.
They are also used to treat the cardiac effects of pheochromocytoma
in combination with prazosin.
Mechanism of action
Drugs that block β-adrenergic receptors do not produce
many of the specific cellular membrane changes observed
with other antiarrhythmic drugs. At doses that induce
β-adrenergic blockade, there is no change in resting
membrane potential, amplitude of the action potential
or velocity of depolarization. In the dog, however, atenolol
does prolong the refractory period. This change,
along with the inhibition of sympathetic input, reduces
the ability of induced premature beats to produce ventricular
tachycardia and fibrillation in experimental
dogs 7–30 days following induced myocardial infarction,
at a time when ventricular arrhythmias are caused
by re-entry.
With all β-blockers, no simple correlation between
dose or serum concentration and therapeutic effect
exists. The serum concentration required to produce a
beneficial effect depends on the prevailing sympathetic
tone and on β-adrenergic receptor density and sensitivity.
These variables vary widely from patient to
patient.
In addition, the pharmacokinetics of β-blockers can
differ substantially between patients. In humans, there
can be a 20-fold difference in plasma concentration
between patients receiving the same oral dose. In one
study in normal dogs, a five-fold difference between
dogs administered the same dose was reported. Because
hepatic blood flow is a major determinant of propranolol
clearance and half-life, this variability can be expected
to be even greater in cardiac patients where hepatic
blood flow is compromised. Consequently, the dose
required to produce a therapeutic effect varies substantially.
Because of this, the dosage must be titrated to an
effective endpoint in each patient.
Adverse effects
In patients subjected to chronic increases in circulating
catecholamine concentrations and increased sympathetic
nervous system activity (e.g. patients with heart
failure), β-adrenergic receptors decrease in number,
internalize into the cell membrane and become less efficient
at producing cAMP. These changes are commonly
lumped together and termed receptor downregulation.
In these patients, fewer receptors are available for drug
binding. However, many of these patients are very
dependent on stimulated β-receptors to maintain myocardial
contractility. Acute administration of mediumto-high
doses of a β-blocker to patients with compromised
myocardial function (e.g. patients with dilated cardiomyopathy)
dependent on β-receptor stimulation can
result in lethal decreases in contractility and heart
rate.
Propranolol
Clinical applications
Propranolol is indicated in canine and feline patients
with ventricular and supraventricular tachyarrhythmias.
It is commonly used with digoxin to slow the ventricular
rate in patients with atrial fibrillation. It is effective for
terminating and preventing the recurrence of supraventricular
tachycardia.
Propranolol can be effective as the sole agent for terminating
ventricular tachyarrhythmias but is generally
more effective when used in combination with other
antiarrhythmic agents. Propranolol is effective for
decreasing the sinus rate in patients with hyperthyroidism,
pheochromocytoma and heart failure. Few antiarrhythmic
drugs can be used in cats. Propranolol has
been used to treat both supraventricular and ventricular
tachyarrhythmias in cats with moderate success.
Mechanism of action
Propranolol is the prototype β-receptor blocking agent.
It reduces catecholamine-dependent automatic (normal
and abnormal) rhythms and slows conduction in
abnormal ventricular myocardium. Propranolol also
increases the refractory period and slows conduction
velocity in AV nodal tissues. This slows the ventricular
response to atrial fibrillation and flutter and effectively
abolishes supraventricular arrhythmias due to AV nodal
re-entry.
By reducing contractility, propranolol reduces
myocardial oxygen consumption, which may reduce
myocardial hypoxia and arrhythmia formation in
patients with subaortic stenosis. Propranolol also abolishes
supraventricular and ventricular tachyarrhythmias
due to pheochromocytoma and thyrotoxicosis.
Propranolol, like any β-blocker, produces dose-dependent
decreases in myocardial contractility. This does not
occur after an intravenous dose of 0.02 mg/kg in normal
dogs (this would be comparable to an oral dose of
0.2 mg/kg). An intravenous dose of 0.08 mg/kg (comparable
oral dose = 0.8 mg/kg) decreases dP/dt, an index
of myocardial contractility, by approximately 30%.
Propranolol has a profound effect on peripheral vascular
resistance in normal, conscious experimental dogs.
At an intravenous dose of 0.02 mg/kg, peripheral vascular
resistance increases to almost twice the baseline.
There is no further increase with a dose of 0.08 mg/kg.
These effects have not been studied in dogs with heart
failure but it is apparent that larger doses of propranolol
must be avoided in these patients. Propranolol appears
to have a greater effect on the sinus rate in normal dogs
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