Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICONVULSANT DRUGS
● Carbamazepine induces secretion of antidiuretic
hormone.
Known drug interactions
Because of induction of hepatic metabolism, the pharmacokinetics
of other drugs undergoing hepatic metabolism
are likely to be affected.
Valproic acid
Clinical applications
Valproic acid is an effective anticonvulsant in humans,
particularly for petit mal or absence seizures, but it has
not been extensively evaluated in dogs. Therapeutic
blood levels in humans are 50–100 µg/mL. Since it is
not possible to attain therapeutic blood levels even with
high-dose therapy or sustained-release formulations,
valproic acid is of limited usefulness in dogs. A clinical
trial in the early 1980s suggested that valproic acid
might have a role as an adjunctive anticonvulsant in
dogs with refractory epilepsy but there has been no
further work on its clinical efficacy. Reports of the clinical
use of valproic acid in cats are lacking. Additional
studies are necessary to evaluate the efficacy of this
drug.
Mechanism of action
The anticonvulsant activity of valproic acid is similar to
that of phenytoin, in that it prolongs recovery of voltageactivated
sodium channels from inactivation.
Formulations and dose rates
The trade names of the drug include Valproate® and Depakene®.
DOGS
• 180 mg/kg divided PO q.8 h
Pharmacokinetics
Valproic acid is rapidly absorbed from the gastrointestinal
tract. Bioavailability is 80% following oral administration.
The half-life of valproic acid is much shorter
in dogs than in humans (1.2–3.7 h versus 9–22 h). This
species difference is in part due to the lower plasma
protein binding of valproic acid in dogs (78–80% in
dogs versus 80–95% in humans), permitting a more
rapid elimination. Because of the lower plasma protein
binding of valproic acid, higher concentrations of the
drug are available to enter the CSF (20% versus 10%
in humans) and lower plasma concentrations may therefore
be sufficient for anticonvulsive effects. Valproic
acid is extensively metabolized in the liver, predominantly
by β-oxidation, and 3–7% is excreted unchanged
in the urine. Some metabolites of valproic acid have
anticonvulsant activity; however, they are much less
potent than the parent compound. It is hypothesized
that the concentrations of active valproic acid metabolites
reached in the dog brain may be sufficient to have
anticonvulsive properties.
Adverse effects
● In humans, valproic acid usually is well tolerated and
relatively free of adverse effects. Adverse effects
include thinning and curling of hair, nausea, vomiting,
abdominal pain, tremor and weight gain.
● Idiosyncratic hepatotoxicity may occur.
● There is an increased incidence in spina bifida in
children whose mothers ingested valproic acid during
pregnancy.
Known drug interactions
Valproic acid may increase serum levels of
phenobarbital.
Felbamate
Clinical applications
Felbamate is a dicarbamate anticonvulsant released for
use in humans in 1993 for the control of partial seizures.
Pharmacokinetic and toxicity studies in 40 beagles confirmed
that felbamate has a wide margin of safety, with
few adverse effects. Felbamate does not cause sedation
and may be added to phenobarbital and/or bromide
without potentiation of the sedative effect of these
drugs. It is an effective anticonvulsant when added to
phenobarbital and bromide; however, controlled clinical
trials have not been completed. In dogs, a hemogram
should be performed and liver enzymes measured regularly
to monitor for bone marrow suppression and
hepatotoxicity. This is especially important in animals
receiving concurrent phenobarbital. It has not been
evaluated in cats.
Mechanism of action
The mechanism of anticonvulsant action is unknown.
Felbamate appears to inhibit excitatory neurotransmitters
and to potentiate inhibitory neurotransmitters.
Formulations and dose rates
The trade name is Felbatol®.
DOGS
• 15 mg/kg PO q.8 h, with a maximum of 300 mg/kg/d
Pharmacokinetics
Felbamate is well absorbed after oral administration.
Approximately 70% of orally administered felbamate is
377