Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
become electrically unstable, resulting in ectopic
tachyarrhythmias.
● The administration of other drugs concurrently with
digitalis may affect the serum concentration of
digoxin.
– Quinidine is the classic example. It displaces
digoxin from skeletal muscle binding sites and
reduces its renal clearance, resulting in an
increased serum digoxin concentration. Quinidine
probably also displaces digoxin from myocardial
binding sites. This may lessen the direct
cardiac toxicity of digoxin and decrease its positive
inotropic effect. In general, the combination
of digoxin and quinidine should be avoided. If
both drugs must be used together, the rule of
thumb in human medicine is to reduce the digoxin
dosage by 50%. Since serum digoxin concentration
approximately doubles following quinidine
administration in dogs, this recommendation
appears to be valid in veterinary patients.
– In humans, there are reports of numerous other
drugs that increase the serum concentration
of digoxin, including oral aminoglycosides
(neomycin), amiodarone, anticholinergics,
captopril, diltiazem, esmolol, flecainide, ibuprofen,
indomethacin, nifedipine, tetracycline and
verapamil.
● Digoxin pharmacokinetics are not significantly
altered in cats with compensated heart failure receiving
furosemide and aspirin. This is despite increases
in serum urea and creatinine concentrations.
Dosing strategy
In general, patients should be evaluated carefully before
digoxin is administered. Factors that alter the dosage
should be noted and an initial dose chosen. The patient
should be monitored during the initial course of therapy
for signs of toxicity or improvement. A decrease in heart
rate or resolution of an arrhythmia are measurable benefits
in patients with tachycardia or arrhythmia.
Clinical responsiveness due to improved hemodynamics
in patients with heart failure is the desired endpoint
of digitalis administration but can be difficult to identify,
for several reasons. First, other drugs are generally
administered with digoxin, so it may be impossible to
identify the beneficial drug. Second, many dogs do not
respond to digoxin, so clinical resolution may never
occur. The dosage in the latter case should not be
increased unless the serum concentration has been measured
and documented to be subtherapeutic (i.e. less
than 0.5 ng/mL).
Each case should have a serum digoxin concentration
measured 3–7 d after initiating therapy and 6–8 h after
the last dose (trough concentration) or immediately any
time toxicity is suspected. The therapeutic range for
serum digoxin concentration is somewhat controversial,
although it is generally considered to be between 0.5
and 2.0 ng/mL. However, some dogs will demonstrate
toxicity at serum concentrations of 2 ng/mL. A serum
concentration above 2.5 ng/mL should be regarded as
toxic. If such an elevation is identified in a patient,
digoxin administration should be discontinued until the
serum concentration is below 1.5 ng/mL. The dosage
should be reduced accordingly several days later.
Pharmacokinetics
Approximately 60% of digoxin tablet formulations is
absorbed, while about 75% of the elixir is absorbed.
There is very little hepatic metabolism, so that almost
all of the absorbed drug reaches the vascular system. In
serum, an average of 27% of digoxin is bound to
albumin. The volume of distribution is 12–15 L/kg.
In normal young dogs, serum half-life of digoxin is
23–39 h although much interpatient variability exists.
Theoretically, it takes about five half-lives to reach
steady state, so it is commonly thought that five halflives
are required to achieve serum concentrations of
between 1.0 and 2.0 ng/mL (which is generally considered
to be the therapeutic range). However, this is not
the case.
The canine maintenance dose of digoxin generally
achieves a serum concentration of 1.5–2.0 ng/mL. The
serum concentration after two half-lives (75% of steady
state) should be 1.1–1.5 ng/mL and after three half-lives
(87.5% of steady state) 1.3–1.75 ng/mL. Consequently,
maintenance doses should theoretically achieve a therapeutic
serum concentration within 2–4 d. In one study
of dogs given 0.022 mg/kg digoxin every 24 h, the serum
concentration was within therapeutic range by the
second day. On the basis of these data, maintenance
doses of digoxin in dogs should be used to achieve a
therapeutic serum concentration in almost all situations.
Loading doses designed to achieve a therapeutic concentration
within a shorter period are not recommended in
dogs and cats.
Digoxin is primarily excreted via glomerular filtration
and renal secretion. About 15% is metabolized in
the liver. Bile duct ligation increases the half-life of
digoxin from an average of 26 h to 35 h in experimental
dogs.
The half-life is extremely variable from cat to cat,
ranging from 25 h to 50 h in one study and from 39 h
to 79 h in another report. In a more recent study, the
half-life in a group of six normal cats ranged from 30 h
to 173 h with a mean half-life of 82 h. The half-life of
digoxin increases dramatically with prolonged oral
administration. The elixir form results in serum concentrations
approximately 50% higher than those achieved
with the tablet. However, cats generally dislike the taste
448