Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

β-BLOCKERS
dilol is currently used by some clinicians for the treatment
of CVD and other cardiac diseases, dosing until
recently was empirical. The availability of pharmacokinetic
and pharmacodynamic data in normal dogs and
those with experimental MR greatly aids in the determination
of an evidence based dose and dosing interval
for carvedilol. However, based on evaluation of plasma
carvedilol concentrations in normal conscious dogs, a
reported target plasma carvedilol concentration of 50–
100 ng/mL is recommended.
Clinically significant β-blockade is reported to occur at
a plasma concentration >10 ng/mL. In this small number
of dogs, those dosed above 0.5 mg/kg twice per day
achieved a plasma concentration that should result in
clinically significant β-blockade (>10 ng/mL) while those
dosed at 0.3 mg/kg or below failed to achieve this level.
However, to achieve close to maximum β-blockade doses
>0.7–0.9 mg/kg or higher may be required.
One small prospective nonplacebo-controlled study
in cavalier King Charles spaniels (n = 5) with preclinical
compensated CVD reported that chronic oral carvedilol
at approximately 1 mg/kg PO is safe and well tolerated
when gradually uptitrated. There was no evidence of
disease progression over the duration of this study
(approximately 5 months). Some echocardiographic and
gated radionuclide ventriculography parameters suggested
a reduction in left atrial size, improvement in LV
function and reduced filling pressures. However, there
was no control group for comparison. In this study the
plasma carvedilol concentration was >10 ng/mL. The
true utility of carvedilol in dogs with CVD awaits prospective
placebo-controlled studies.
There are no data to evaluate regarding the use of β-
blockade in heart failure due to CVD (the clinical stage).
The same precautions as those outlined for heart failure
in general would be expected to apply. That is, β-blockers
should not be initiated in dogs with decompensated
heart failure due to CVD and initial dose and target
doses may need to be lower in heart failure versus preclinical
disease. In addition uptitration may need to be
more gradual.
Formulations and dose rates
GENERAL COMMENTS
• β-Blocker therapy in patients with overt heart failure should not
be attempted by anyone other than an individual who has
experience with this form of therapy.
• Pre-existing bradycardia is a contraindication.
• The initial dose should be low and gradually increased over
biweekly intervals.
• Adverse effects usually occur following a dose increase and
may include development of signs of progressive heart disease.
• Acutely, all β-blockers are dose dependent negative inotropes
and can therefore result in the occurrence of adverse signs
suggestive of progressive heart disease following initiation or
during uptitration. The dose should be reduced to the last
tolerated dose (not abruptly discontinued) and therapy for heart
failure should be initiated as required based on clinical signs.
• Any benefi cial effect of β-blockade is not immediate but rather
takes approximately 3 months. Maximum desirable effects may
be achieved with the highest tolerated dose.
• β-Blockers should never be discontinued abruptly but rather
weaned off should discontinuation be necessary.
• The authors’ preferred β-blocker in patients with acquired heart
disease is carvedilol.
• Plasma samples can be submitted to Auburn University Clinical
Pharmacology Lab for determination of a plasma carvedilol
concentration. Take the sample about 2 h after dosing. Target
concentration is 50–100 ng/mL.
• In patients with preclinical CVD or DCM who have been
receiving chronic β-blockers and then go on to develop heart
failure, the following recommendations may prove useful.
– If the heart failure is mild (outpatient treatment is possible)
then the β-blocker should be continued at the same dose
and heart failure therapy should be initiated including an
ACE inhibitor, pimobendan and furosemide as needed to
control signs of congestion.
– If the heart failure is severe (hospitalization and IV
furosemide are indicated) then the β-blocker dose should
be reduced by 50% (β-blockers should not be discontinued
abruptly) and heart failure therapy should be initiated
including pimobendan and parenteral furosemide as needed
to control signs of congestion and stabilize the patient.
Once stable an ACE inhibitor can be added and eventually
the β-blocker dose can be uptitrated to the previous dose if
tolerated.
• Do not combine with other β-blockers, calcium channel
blockers or sotalol (a class III antiarrhythmic with β-blocking
properties).
CARVEDILOL FORMULATION AND DOSE RATES
Carvedilol is available as 3.125, 6.25, 12.5 and 25 mg tablets. A stability
study has been reported and the drug can be reformulated into
a suspension with simple corn syrup. The suspension has an expiration
time of 90 d. Formulation of the suspension using the 25 mg
tablets facilitates accurate dosing and uptitration and is cost effective,
particularly for small dogs.
CARVEDILOL IN PRECLINICAL DCM
• The starting dose is 0.1 mg/kg (lower than that in dogs with
preclinical CVD)
• Start at 0.1 mg/kg and increase by 50–100% every 2–3 weeks
to a target dose of approximately 1 mg/kg (if possible)
CARVEDILOL IN CLINICAL DCM (HEART FAILURE)
• β-Blockers should not be routinely initiated in clinical DCM
unless there is a specifi c indication such as a supraventricular
arrhythmia (atrial fi brillation)
CARVEDILOL IN PRECLINICAL CVD
• The starting dose is 0.25 mg/kg
• Start at 0.25 mg/kg and increase by 50–100% every 2–3
weeks to a target dose of approximately 1 mg/kg (if possible)
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