Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICONVULSANT DRUGS
of elimination can change with salt administration.
Increased dietary salt will increase the rate of elimination
of bromide and decreased dietary salt will result in
the opposite effect.
The elimination of bromide in cats is faster than in
dogs. The mean half-life is 1.56 weeks ± 0.38 weeks, or
about 12 days, in cats. Following administration of
30 mg/kg orally for 8 weeks, the mean bromide concentration
was 1.2 mg/mL (steady state).
Although bromide replaces chloride throughout the
body, the sum of these two halides remains constant.
Lower concentrations of bromide are found in the brain
than are expected from measuring the serum chloride
concentration as it appears that there is a barrier to the
free passage of bromide across the blood–brain barrier.
However, the concentration of bromide in the brains of
dogs is higher than in humans. In humans the CSF to
serum ratio is 31% whereas in dogs it is 87%. As a
result, seizure control in dogs may be achieved at a
lower serum bromide concentration than in humans.
The potential for systemic toxicity may be lower in dogs
than humans.
Adverse effects
● Clinical signs of bromide toxicity appear to be dose
dependent and include polyphagia, vomiting,
anorexia, constipation, pruritus, muscle pain, sedation
and pelvic limb weakness.
● Asthma (may be fatal) is associated with bromide
administration in cats.
● Ataxia and sedation are the major dose-limiting
adverse effects in dogs.
● Other infrequently reported adverse effects in dogs
include pancreatitis, increased attention seeking,
aggression, coprophagia and hyperactivity.
● High-dose bromide therapy has been associated with
thyroid dysfunction in humans and rats.
● Bromide toxicity was reported in a dog with renal
insufficiency, resulting in decreased clearance of
bromide and therefore a higher serum bromide
concentration.
● Reduced seizure control was reported in a dog fed a
high-chloride diet. Toxic concentrations of bromide
may be reached rapidly when chloride intake is
decreased.
● Bromide readily crosses the placenta in humans and
may cause neonatal bromism. Because of the lack of
information in dogs, bromide should be avoided in
breeding animals.
● Sodium bromide should not be used in dogs with
congestive heart failure, hypertension or liver
failure.
● Potassium bromide should be used cautiously in dogs
with hypoadrenocorticism.
Known drug interactions
● Bromide is not protein bound and is not metabolized,
therefore it does not interact with many drugs.
However, chloride-containing foods, food supplements,
fluids, drugs and loop diuretics may enhance
bromide elimination and lower serum bromide
concentrations.
● Bromide is a product of halothane metabolism in
dogs and therefore small increases in serum bromide
may be noted after halothane anesthesia.
● Pseudohyperchloridemia occurs with bromide
adminis tration. Bromide ions interfere with colorimetric
and automated ion-specific electrolyte analyzers
used to measure chloride concentration.
Benzodiazepines
Clinical applications
A large number of benzodiazepine derivatives are used
in human medicine. In veterinary medicine, diazepam is
the most widely used. In dogs, the use of diazepam as
an anticonvulsant is limited to treatment of status
epilepticus, because of the significant first-pass hepatic
clearance, rapid development of functional tolerance
and short half-life of the drug. However, in cats, diazepam
is effective as an acute and chronic anticonvulsant.
Diazepam is the first-line treatment of choice for status
epilepticus in both dogs and cats.
Clonazepam is more potent and longer lasting than
diazepam and is used as both an acute and a chronic
anticonvulsant in humans. In dogs, hepatic enzyme
induction occurs within days to weeks, rendering clonazepam
unsatisfactory as a chronic anticonvulsant. It
may be useful in dogs as a chronic anticonvulsant if used
as an adjunct to phenobarbital therapy, especially in
cases of intractable epilepsy. There are no clinical evaluations
of its use as an anticonvulsant in dogs. Because
of the development of tolerance to the anticonvulsant
effects of clonazepam in dogs, its clinical usefulness is
limited.
Lorazepam is used as an acute anticonvulsant in
humans. It is not as lipid soluble as diazepam. Pilot
studies have shown that therapeutic concentrations are
reached with IV but not per rectum therapy in dogs.
Midazolam is a water-soluble benzodiazepine. Since
it is water soluble, it is much less irritating with IV or
IM administration. It is most useful as an acute anticonvulsant
in the treatment of status epilepticus.
Clorazepate is hydrolyzed in the stomach to nordiazepam,
the active anticonvulsant. Nordiazepam is a
major metabolite of diazepam. The short half-life of
clorazepate in dogs and its confounding interactions
with phenobarbital have rendered it of extremely limited
usefulness as a maintenance anticonvulsant in dogs,
even when used in combination with phenobarbital.
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