Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CLASS III ANTIARRHYTHMIC DRUGS
3.2 days in the dog. It is very lipophilic and accumulates
to up to 300 times the plasma concentration in adipose
tissue. Once drug administration is discontinued, amiodarone
is cleared rapidly from all tissues except adipose
tissue.
Myocardial concentration of the drug is approximately
15 times that of plasma. The long half-life of the
drug means that it takes a long time to produce a significant
effect once administration starts. It also takes a
long time for the drug effect to dissipate once administration
is discontinued. For example, the time to reach
one-half of the peak value ultimately achieved for the
increase in left ventricular refractory period in dogs is
2.5 days. The time to come down to one-half the peak
value after drug administration is discontinued is 21
days in dogs. Because of the long time to onset, loading
doses of amiodarone are commonly administered in
human medicine. In humans it may take 1–3 weeks to
observe onset of action, even with loading doses. Antiarrhythmic
effects are present for weeks to months after
discontinuing the drug in humans.
Adverse effects
● Numerous side effects of amiodarone have been
reported in the human literature. In humans who
receive more than 400 mg/d of amiodarone (400 mg
is approximately 6 mg/kg/d), 75% experience adverse
reactions and 7–18% discontinue the drug because
of side effects. Most of the adverse sequelae occur
after 6 months of drug use.
● Adverse reactions in humans consist of neurological
problems (20–40%), gastrointestinal disturbances
(25%), visual disturbances including corneal microdeposits
(4–9%), dermatological reactions including
photosensitivity and blue discoloration of the skin
(5%), cardiovascular reactions including congestive
heart failure and bradycardia (3%), abnormal
liver function tests (4–9%), pulmonary inflammation
and fibrosis (4–9%) and hypothyroidism and
hyperthyroidism.
● Pulmonary fibrosis is the most common severe
sequela of amiodarone administration in humans.
Pulmonary fibrosis, heart failure and elevation of
liver enzymes necessitate discontinuing the drug in
humans. Pulmonary toxicity appears to be multifaceted
but inhibition of phospholipase A with resultant
phospholipidosis is one mechanism responsible for
producing pulmonary lesions.
● Amiodarone’s side effect profile in dogs is poorly
documented.
– In two studies elevated liver enzymes and neutropenia
were reported in some dogs. The liver
enzymes returned to normal following discontinuation
of the medication in most dogs.
– Gastrointestinal disturbances have also been
reported.
– The authors can find no studies of chronic toxicity
of amiodarone in dogs.
– Comparable lung changes to those seen in humans
are induced in rats and mice.
– Dyslipidic lesions can be produced in the gastrointestinal
tract of dogs by amiodarone administration
but only at very high doses (>50 mg/kg/d
for 30 d).
– It is also known that amiodarone increases the
phospholipid content of feline myocardium. Consequently,
it is suspected that chronic amiodarone
toxicity could occur in dogs and cats.
● Amiodarone can result in either hypothyroidism
or hyperthyroidism in humans. Amiodarone inhibits
T4 and T3 secretion from canine thyroid glands.
Consequently, thyroid function should be monitored
when amiodarone is chronically administered in veterinary
patients.
Known drug interactions
● Amiodarone alters the pharmacokinetics and
increases the serum concentrations or the effects of
several drugs in humans, including digoxin, quinidine,
procainamide, phenytoin and warfarin.
● Amiodarone administration increases the bioavailability
of diltiazem and decreases total body
clearance and volume of distribution of the drug in
the dog. This results in an increased serum diltiazem
concentration and could produce a toxic concentration.
This combination should be used cautiously
and the dose of diltiazem reduced.
Bretylium
Clinical applications
Bretylium was first developed as an antihypertensive
agent. In 1966, it was noted that it increased the fibrillation
threshold. Since then, it has found limited usefulness
as an antiarrhythmic and antifibrillatory agent in
human medicine.
Bretylium is used for the emergency treatment of lifethreatening
ventricular tachycardia or ventricular fibrillation
that recurs despite direct current shock and
lidocaine. It is generally ineffective against supraventricular
arrhythmias. Bretylium appears to have no use
as an agent to produce chemical defibrillation in dogs.
Mechanism of action
Bretylium’s primary effect is prolongation of the action
potential and refractory periods in myocardium. It also
decreases the disparity in action potential duration
between normal and diseased myocardium. Bretylium is
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