Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICONVULSANT DRUGS
as digoxin, glucocorticoids, phenylbutazone and
some anesthetic drugs. As a result, the therapeutic
efficacy of these drugs may be reduced in patients
concurrently receiving phenobarbital.
● In contrast, drugs that inhibit hepatic microsomal
enzymes (e.g. cimetidine) may inhibit phenobarbital
metabolism and cause toxicity. Several cases of
chloramphenicol-induced phenobarbital toxicity in
dogs have been documented.
● Phenobarbital impairs the absorption of griseofulvin
and therefore reduces the blood level and efficacy of
this antifungal agent.
● Chronic phenobarbital treatment may influence the
results of ACTH response tests, suggesting that this
test should not be used to screen for hyperadrenocorticism
in dogs receiving phenobarbital. Although
plasma ACTH levels may be unchanged, not all
studies have confirmed this observation. Similarly,
dexamethasone suppression tests may be influenced
in some, but not all, dogs chronically treated with
phenobarbital.
● Total and free serum levothyroxine (thyroxine) concentrations
may be reduced in dogs receiving
phenobarbital.
Primidone
Clinical applications
Primidone is a deoxybarbiturate that is a structural
analog of phenobarbital. Unlike phenobarbital, it is not
a controlled substance; however, this is not sufficient
justification to use primidone in preference to phenobarbital
in dogs.
Fifty-two to 87% of epileptic dogs may be effectively
controlled with primidone. In most dogs, primidone
therapy has no advantage over phenobarbital for the
treatment of seizures. In addition, adverse behavioral
effects occur more frequently. There is a greater
potential for hepatotoxicity with chronic primidone
than with phenobarbital. There is anecdotal evidence
that some dogs refractory to phenobarbital can be
satisfactorily controlled with primidone. However, the
efficacy of primidone in this situation remains
unproven.
It was initially believed that primidone was toxic to
cats; however, recent studies suggest that this is not the
case. Although not widely used, primidone has been
recommended by some authors for cats refractory to
phenobarbital or diazepam therapy.
Phenobarbital blood levels are measured as a guide
to primidone therapy. Target therapeutic ranges are the
same as those for phenobarbital.
Formulations and dose rates
Primidone is not recommended in dogs and cats (except by some
authors – see above). Trade names for primidone include Mylepsin®
and Mysoline®.
DOGS
• Dosages vary from 29 mg/kg/d to 55 mg/kg/d divided q.8 h
• To change a dog from primidone to phenobarbital therapy, the
conversion factor is 3.8 : 1, i.e. 250 mg of primidone to 65 mg
of phenobarbital for an equivalent effect. Baseline phenobarbital
concentrations should be determined prior to conversion and
conversion should be progressive (e.g. 25% alteration each
month) in patients whose seizure history includes prolonged or
cluster seizures
CATS
• 40 mg/kg divided q.8 h
Pharmacokinetics
Primidone is rapidly absorbed after oral administration,
achieving peak serum concentrations after 2 h. It undergoes
hepatic oxidation and is excreted in the urine as
unchanged primidone, phenylethylmalonamide (PEMA)
and phenobarbital. All three compounds have anticonvulsant
activity, although primidone contributes
only 11% to the overall anticonvulsant effect and PEMA
contributes 2%. Eighty to 85% of primidone’s anticonvulsant
activity is due to phenobarbital.
The half-life of primidone is 5 h in beagles and 10 h
in mixed-breed dogs. Steady-state concentrations are
achieved after 6–8 days of treatment. However, the halflife
of primidone and PEMA decreases after 14–18 days
of treatment. Plasma protein binding is 29%. Primidone
reaches the CSF relatively slowly, with a mean penetration
half-life of 43 min.
Cats metabolize primidone differently from dogs and
plasma concentrations of primidone and PEMA may
exceed the plasma concentration of phenobarbital. The
safety of primidone at effective concentrations has not
been established adequately for cats.
Adverse effects
Adverse effects are the same as those for
phenobarbital.
● Hepatotoxicity and behavioral disturbances are more
frequent with primidone than phenobarbital.
● ALT and ALP serum levels are abnormal more frequently
in dogs receiving chronic primidone therapy
than with any other commonly used anticonvulsants.
In addition, hepatic cirrhosis secondary to chronic
use of primidone has been documented.
● Idiosyncratic primidone hepatotoxicity also may
occur.
● Sedative effects of primidone are more profound in
cats than in dogs.
371