Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Pharmacokinetics
Procainamide has a short half-life of approximately 3 h
in the dog. The short half-life is problematic when
administering procainamide orally to a dog. To maintain
a serum concentration within the therapeutic range
generally requires administering the drug at least q.6 h
PO. The volume of distribution is approximately 2 L/kg.
The vast majority of the drug is metabolized in the liver.
Parenteral and oral routes of administration are used
but intravenous injections must be administered slowly
to prevent circulatory collapse from peripheral vasodilation
and decreased cardiac contractility.
Humans commonly have beneficial effects from procainamide
at lower doses and at a lower serum concentration
than commonly seen in dogs. One reason for this
may be because they metabolize procainamide to a
metabolite, N-acetyl procainamide (NAPA), which has
antiarrhythmic properties. Dogs cannot acetylate aromatic
and hydrazine amino groups and so are incapable
of producing NAPA.
Procainamide pharmacokinetics have not been studied
in the cat.
Adverse effects
● Theoretically, procainamide can produce cardiotoxicity
manifested as QRS and Q-T interval prolongation.
However, this is almost never observed
clinically.
● In humans, procainamide can have a proarrhythmic
effect in some patients. This has never been documented
in dogs, although it is suspected to occur.
● Toxic concentrations can depress myocardial contractility
and produce hypotension. This only occurs
with rapid intravenous administration.
● In humans, procainamide can cause systemic autoimmune
reactions. Experimental dogs (beagles) given
procainamide at 25–50 mg/kg q.6 h for 1–5 months
developed antinuclear antibodies (ANA). This has
not been reported in clinical patients, although the
authors have observed two possible immunemediated
abnormalities in dogs receiving procainamide.
One dog developed granulocytopenia that
resolved when procainamide administration was discontinued.
Another dog developed lymphadenopathy
and a positive ANA test that resolved after
procainamide administration was discontinued. Both
dogs had been on procainamide for several years
prior to these abnormalities occurring.
Special considerations
The intravenous preparation may become a light yellow
color; it can still be used. If the solution becomes amber,
however, the drug has deteriorated and the solution
should not be used.
Disopyramide
Clinical applications
Because procainamide is as effective as disopyramide
and is safer, disopyramide is almost never used in canine
or feline patients.
Mechanism of action
Disopyramide is an oral antiarrhythmic agent with
properties almost identical to those of quinidine and
procainamide.
Formulations and dose rates
Disopyramide phosphate is supplied in capsules. When used as an
antiarrhythmic in dogs, 7–30 mg/kg is administered q.4 h PO.
Pharmacokinetics
In the dog, disopyramide has a half-life of approximately
3 h, which makes effective dosing difficult. It is
rapidly absorbed and its bioavailability is 70%.
Adverse effects
● In experimental dogs, all doses of disopyramide
prolong the P-R interval. Doses of 15 and 30 mg/kg
q.8 h prolong the Q-T interval while the 30 mg/kg
q.8 h dose also prolongs the duration of the QRS
complex.
● Doses of 15 and 30 mg/kg q.8 h significantly decrease
the echocardiographic shortening fraction.
● Disopyramide is contraindicated in heart failure
patients because it decreases myocardial contractility
and increases peripheral vascular resistance, a potentially
lethal combination.
● Disopyramide is such a potent negative inotropic
agent that it is used in humans with HCM to reduce
systolic anterior motion of the mitral valve.
● Disopyramide possesses significant anticholinergic
properties that may produce toxic effects.
● It also decreases the serum glucose concentration in
a dose-dependent manner (approximately 15%
decrease at a dose of 30 mg/kg).
Mexiletine
Mexiletine is an analog of lidocaine that is not extensively
metabolized on its first pass through the liver. It
was first used as an antiarrhythmic agent in Europe in
1969.
Clinical applications
Mexiletine is indicated for chronic treatment of ventricular
tachyarrhythmias in dogs but reports of clinical
efficacy vary. One group of investigators reported
limited success in suppressing ventricular arrhythmias
with mexiletine in canine patients. In contrast, another
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