Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICONVULSANT DRUGS
is open for a longer time, resulting in greater chloride
flux and enhanced neuronal inhibition
● interaction with glutamate receptors to reduce neuronal
excitotoxicity
● inhibition of voltage-gated calcium channels
● competitive binding of the picrotoxin site of the chloride
channel.
Formulations and dose rates
Phenobarbital is a controlled substance, available as oral (tablets or
elixir) or injectable preparation. The injectable form is intended for
intravenous use but may be given intramuscularly. Trade names for
phenobarbital in different markets include Epiphen®, Luminal®,
Phenomav® and Bellatal®. A generic form of phenobarbital sodium
also is available.
• For the chronic treatment of seizures in dogs dosing should
begin at 2–5 mg/kg/day PO q.12 h. In dogs with frequent,
severe or prolonged seizures, therapy may be initiated at a
higher initial dosage. In some dogs or cats, the starting dosage
may result in adverse effects. Should these adverse effects not
resolve after 2 weeks of therapy, a reduction in dose may be
indicated.
Cats: 1.5–2.5 mg/kg PO q.12 h
• Steady-state serum phenobarbital concentrations should be
determined after 3 weeks of therapy. If a patient’s seizures are
adequately controlled, then serum concentrations may be
determined again after 3–6 months, or more frequently should
seizure activity resume at an unacceptable frequency. If a
patient’s seizures are not adequately controlled after 3 weeks of
therapy, the dose of phenobarbital may be increased by 25%
and serum concentrations should be determined again after 3
weeks of therapy at this higher dose. This process should be
continued until the patient’s seizures are controlled or until a
patient fails phenobarbital therapy (i.e. becomes refractory).
Dogs are refractory to phenobarbital therapy when seizure
activity or unacceptable effects persist when plasma
concentrations reach 35 µg/mL
• Dosages of phenobarbital as high as 18–20 mg/kg/day PO
divided q.8 h or q.12 h are occasionally necessary to achieve
seizure control in some patients, due to individual variations in
drug metabolism. Adverse effects are often observed at
dosages above 20 mg/kg/d
• Reductions in dosage should be made gradually as physical
dependence may develop and withdrawal seizures may occur
as serum levels decline. Therapy should not be discontinued
abruptly, except in animals that develop fulminant liver
dysfunction. Phenobarbital should be avoided in animals with
hepatic dysfunction
• Phenobarbital may be administered IV for the treatment of toxic
seizures or status epilepticus; however, a lag time of 20–
30 min may be observed prior to maximal effect. Phenobarbital
may be given at a loading dosage of 12–24 mg/kg IV to achieve
therapeutic plasma concentrations more rapidly. A phenobarbital
bolus may be given (2–4 mg/kg IV every 30 min), until a
cumulative dosage of 20 mg/kg is achieved. The dosage should
be decreased proportionately if the patient is receiving oral
phenobarbital
Pharmacokinetics
Phenobarbital is rapidly absorbed after oral administration,
although variation exists between animals.
Bioavailability is high (86–96%) and peak plasma levels
are achieved at 4–6 h after administration. Although it
is widely distributed into tissues, lower lipid solubility
means that it does not penetrate the CNS as rapidly as
other barbiturates. After IV injection, therapeutic CNS
concentrations are reached in 15–20 min. Administration
with food reduces absorption by about 10%. Phenobarbital
is metabolized primarily in the liver; 25% is
excreted unchanged by the kidneys. Alkalinization of
the urine will enhance elimination of phenobarbital and
its metabolites. Plasma protein binding is approximately
45%.
The elimination half-life of phenobarbital ranges
from 30 h to 90 h in dogs and from 3 h to 83 h in cats.
The wide ranges are a result of several variables, including
variation in drug dosages between studies and, more
importantly, different dosing regimens between studies
(single dose, a short course of several doses, or administered
chronically). In addition, drugs capable of
stimulating drug-metabolizing enzyme systems in the
liver were included in some studies. In studies in cats,
the use of different populations of cats appeared to be
a factor contributing to the reported variability in elimination
half-life.
In dogs, phenobarbital elimination half-life significantly
decreases when administered chronically (47.3 ±
10.7 h when administered for 90 days versus 88.7 ±
19.6 h in a single-dose study). It increases its own rate
of metabolism (autoinduction). Therefore the drug concentration
of phenobarbital is expected to decrease in
animals receiving chronic therapy and a dosage increase
should be anticipated in patients after 3–6 months of
therapy. In contrast, in cats, repeated phenobarbital
administration does not alter serum steady-state concentration.
However, large differences in phenobarbital
elimination rates may exist between different populations
of cats.
In dogs, the elimination half-life of phenobarbital is
similar after oral or IV administration. Steady-state
concentrations are achieved within 18 d of initiation of
therapy. Therefore dosage adjustments should not be
made until 3 weeks after treatment has commenced
or been altered. The metabolism of phenobarbital is
quite variable in dogs. Beagles metabolize phenobarbital
more rapidly (32 h elimination half-life) than mixedbreed
dogs. Clinical observations suggest that phenobarbital
elimination half-life may be shorter in
puppies.
Since there may be marked variations between the
oral dosage of phenobarbital and the serum concentration,
serum drug levels should be considered a guide to
drug therapy alterations. Therapeutic serum phenobar-
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