Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 16 ANTICONVULSANT DRUGS
Known drug interactions
● The drug interactions described for phenobarbital
also apply to primidone.
● Severe CNS depression and inappetance has been
reported in dogs concurrently receiving primidone
and chloramphenicol.
Bromide
Clinical applications
Bromide is a halide, discovered in 1826 by Balard. It
was initially used as an anticonvulsant in humans by Sir
Charles Locock in 1857. Bromide was the only effective
anticonvulsant available until 1912, when phenobarbital
was introduced. Bromide was used in dogs in 1907,
but it was not until 1986 that interest in its use as
an anticonvulsasnt was reported. Initially, bromide
was used as an adjunct to phenobarbital in refractory
epileptics. Recently, it has been used as a sole anticonvulsant
therapy, particularly in dogs with hepatic dysfunction
or in patients with mild seizures. Bromide is
best suited for noncompliant owners because of its long
half-life. Bromide is approved for use in several markets
such as the UK (Epilease®) and Australia but is not
approved in the USA.
Mechanism of action
The exact mechanism of anticonvulsant action of
bromide is incompletely understood. The action appears
to involve chloride ion channels which are an important
part of the inhibitory neuronal network of the CNS.
Their function is modulated by GABA. Increased
chloride ion flow, as a result of activation of GABA
receptors by barbiturates or benzodiazepines, results
in increased neuronal inhibition and increases the
threshold for seizures. Bromide appears to cross neuronal
chloride channels more readily than chloride because
it has a smaller hydrated diameter. By competing with
chloride ions, bromide hyperpolarizes postsynaptic neuronal
membranes and facilitates the action of inhibitory
neurotransmitters. Barbiturates may act synergistically
with bromide to raise the seizure threshold by enhancing
chloride conductance via GABA-ergic activity.
Formulations and dose rates
Bromide is available as a potassium or sodium salt. Potassium
bromide is available in tablet form in some countries such as the UK
and Australia. Trade names include Epilease®, Bromapex® and
Epibrom®. Where a veterinary formulation is not available (such as
in the US), it may be formulated as a 200 mg/mL or 250 mg/mL
solution of reagent-grade potassium bromide in syrup or distilled
water. Alternatively, the powder may be placed in gelatin capsules.
Bromide is stable for more than 1 year at room or refrigerator
temperature, in glass, plastic, clear or brown containers, when in
solution with distilled water. The stability of bromide in syrup solution
is unknown. Current recommendations include keeping the bromide
syrup solution refrigerated and discarding it after 3 months.
Sodium bromide salt may be given to dogs that dislike the taste of
the potassium salt or cannot tolerate it (e.g. because of hypoadrenocorticism).
The dose of sodium bromide should be reduced by 15%
compared to the potassium salt to account for the higher bromide
content per gram (KBr = 67% bromide, NaBr = 78% bromide).
• Because reaching a steady state may require 2–3 months,
a loading dose is recommended to achieve therapeutic
concentrations more rapidly. The maintenance dose is designed
to maintain concentrations achieved after loading. Alternatively,
the maintenance dose may be given without a loading dose to
allow more gradual accommodation to effective serum
concentrations
• The appropriate dose of bromide depends on concurrent
anticonvulsants, diet and renal function. The maintenance
dosage of potassium bromide as a fi rst-line anticonvulsant is
35–45 mg/kg/d PO q.24 h or in divided doses in dogs. Steadystate
concentrations in dogs following 30 mg/kg q.24 h are
0.8–1.2 mg/mL. Bromide is not recommended in cats
• When used in conjunction with other anticonvulsants, the
recommended dosage is 22–30 mg/kg PO q.24 h or divided
(q.12 h)
• The authors’ protocol loading dosage of potassium bromide is
400–600 mg/kg divided q.6 h, given over 24 h; stop when
sedation occurs
• Serum bromide concentrations may be determined 1 month
after a maintenance dosage is instituted, regardless of
whether a loading dose was given. This approach will enable
modifi cation prior to steady state and prior to therapeutic failure
or signs of adverse reactions. Recommended target ranges are
controversial and depend on whether phenobarbital is given
concurrently. Most laboratories use 1–3 mg/mL regardless of
whether bromide is the sole agent or in combination with
phenobarbital
Pharmacokinetics
The pharmacokinetics of bromide are not well established.
Bromide is absorbed from the small intestine and
peak absorption achieved 1.5 h after oral administration.
It is not protein bound or metabolized and does
not undergo hepatic metabolism. Therefore, bromide
does not affect hepatic enzymes and is a useful anticonvulsant
for dogs with hepatic disease.
The half-life of bromide is longer in dogs than in
humans (24.9 d versus 12 d). About 2–3 weeks of
therapy are required before serum bromide levels enter
the therapeutic range; steady-state levels are achieved in
approximately 3–4 months. Higher serum concentrations
may be required for seizure control if dogs are
treated with bromide alone. The therapeutic range for
potassium bromide when administered with phenobarbital
is 0.8–2.4 mg/mL, or 0.8–3.0 mg/mL when used
alone.
Distribution of bromide is to the extracellular space.
Bromide is eliminated slowly from the body, perhaps
because of marked reabsorption by the kidneys. Its rate
372