Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICONVULSANT DRUGS
oxidation followed by glucuronide conjugation. All
metabolites are excreted in urine and bile. The half-life
of the metabolites in dogs is 11 min. Midazolam has a
wide margin of safety and a broad therapeutic index.
The mean plasma elimination half-life in dogs is 53–
77 min when given intravenously. These properties
support the use of midazolam for the treatment of status
epilepticus.
Adverse effects
● Idiosyncratic, fatal fulminant hepatic failure was
reported in 11 cats treated with low-dose diazepam
for behavioral disorders. Only one cat survived. Risk
factors were not identified.
● Sedation is the most commonly reported adverse
effect of all benzodiazepines.
● Diazepam acts as a skeletal muscle relaxant; therefore
ataxia and weakness unrelated to sedation may
occur.
● An interesting effect of diazepam, but not other benzodiazepines,
is appetite stimulation in cats. This
effect has been used therapeutically to encourage
anorexic cats to eat (see Chapter 19).
● Occasionally, cats have an idiosyncratic behavioral
reaction whereby they become hyperactive. This may
be due to release of overt anxiety and hence release
of the behavioral inhibition that maintained a tractable
state in cats.
● Overtly friendly cats, particularly oriental breeds,
may become excessively affectionate when treated
with diazepam.
● Dogs may become aggressive when receiving
clonazepam.
● Physical dependence to diazepam is reported in dogs.
Clinical signs of diazepam withdrawal included
tremor, weight loss, elevated body temperature and
seizures.
Known drug interactions
● Benzodiazepines potentiate the action of other CNS
depressants.
● Diazepam binds extensively to plasma proteins and
should be used cautiously with other drugs that also
have high plasma protein-binding activity.
● Benzodiazepines should be used cautiously with
cimetidine. Cimetidine impairs hepatic microsomal
oxidation of diazepam and prolongs its half-life and
thus elimination from the body.
Phenytoin
Clinical applications
Although phenytoin is a very effective anticonvulsant
in humans, it is not useful in dogs or cats because of
marked pharmacokinetic differences between species. In
dogs, the drug has a relatively short elimination half-life
and, with repeated administration, enzyme induction
leads to faster elimination. In one clinical study, seizure
activity was adequately controlled in only one of 77
epileptic dogs treated with phenytoin.
Studies examining the clinical use of phenytoin in cats
are lacking. The elimination half-life reported in cats is
very long and even at low dosages, there is a high risk
for the development of toxic drug levels.
A slow-release formulation of phenytoin (slow-release
diphenylhydantoin, SR-DPH) has been used experimentally
as an anticonvulsant in the Netherlands. Seizures
were controlled similarly in dogs receiving SR-DPH and
phenobarbital. However, dogs with refractory seizures
already receiving phenobarbital had better control of
their seizures when changed to SR-DPH.
Mephenytoin is a hydantoin derivative similar to phenytoin.
Its anticonvulsant activity results from metabolism
to nirvonal. Bone marrow dyscrasias preclude its
common use in humans. Although isolated reports
suggest that it may prove efficacious in dogs with epilepsy,
hepatotoxicity, particularly when used in combination
with phenobarbital, necessitates cautious use.
Mechanism of action
The major mechanism of action of phenytoin is suppression
of repetitive action potentials by blocking sodium
channels and decreasing inward flow of sodium. At high
concentrations the release of serotonin and noradrenaline
(norepinephrine) is inhibited. Phenytoin interacts
with membrane lipids and may promote stabilization
of membranes. It also may have other effects on neurotransmitters
and the overall mechanism of action
probably involves a combination of actions at several
levels. Its effect on sodium channels is the basis for its
use as an antiarrhythmic drug (see Chapter 17).
Formulations and dose rates
Phenytoin is not recommended as an anticonvulsant in dogs and
cats.
Oral preparations of phenytoin are available in suspension, capsule
and tablet forms. Trade names include Dilantin® and Epanutin®. The
trade name of the slow-release formulation is Epitard 700® – this is
not available in all markets.
• Dogs: 100–200 mg/kg/d divided q.8 h
• Epitard 700®: start at 50 mg/kg/d and increase the dosage
over 4 weeks
Pharmacokinetics
Gastrointestinal absorption of certain formulations of
phenytoin is poor in dogs, although the microcrystalline
oral suspension is well absorbed. In dogs, phenytoin is
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