Compendium October 1999
PHARM PROFILE
PHENOBARBITAL*
Albert Boeckh, DVM
Texas A&M University
P
henobarbital is a long-acting
barbiturate that is used as a hyp-
notic, sedative, and anticonvul-
sant to treat epilepsy and focal cortical
seizures in dogs and cats and as a lab-
oratory reagent in human medicine.
Phenobarbital and its injectable sodi-
um salt are subject to control under
the Federal Controlled Substances Act
of 1970 as schedule IV (C-IV) drugs.1
PHARMACOLOGY
Phenobarbital decreases seizure ac-
tivity by enhancing responsiveness to
the inhibitory postsynaptic effects of
the neurotransmitter γ-aminobutyric
acid (GABA). Phenobarbital opens a
GABA-mediated chloride channel,
resulting in increased intracellular
concentration of chloride and hyper-
polarization of the cell membrane.2
Phenobarbital also inhibits glutamate
activity and probably decreases calcium
fluxes through the cell membrane.2
As a weak acid, phenobarbital is
well absorbed orally, although peak
*Pharm Profile featured potassium bro-
mide in the July 1999 issue. Virtually all
patients treated with potassium bromide
have been or are currently being treated
with phenobarbital as well. Although
there are no new indications for the use
of phenobarbital, it is being featured this
month with regard to the complemen-
tary therapies.
Pharm Profile introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like
Pharm Profile to cover a particular agent, please contact column editor GiGi Davidson, BS, RPh, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email gigi_davidson@ncsu.edu.
20TH ANNIVERSARY
plasma concentrations occur only 4
to 6 hours after administration. The
half-life varies within species as well
as within individual animals,2 mak-
ing therapeutic drug monitoring an
important part of successful pheno-
barbital therapy.
CAUTIONS
Phenobarbital is known to induce
liver failure in dogs, the development
and severity of which are related to
the duration of therapy and plasma
concentrations of the drug. Animals
that need to be maintained at high
phenobarbital concentrations (above
30 µg/ml) are more predisposed to
development of liver disease.
ACUTE TOXICITY
Treatment of phenobarbital toxi-
cosis consists of artificial respiration
with oxygen to prevent hypoxia from
respiratory arrest. Although less ef-
fective than oxygen, doxapram or an-
other respiratory analeptic may be used
to stimulate the respiratory center. In
addition, alkalinizing the urine accel-
erates phenobarbital excretion by in-
creasing drug ionization and reduc-
ing tubular reabsorption.2
DRUG INTERACTIONS
Treatment with phenobarbital in-
Small Animal/Exotics
creases the activity of hepatic micro-
somal enzymes that metabolize drugs
and hormones, thereby increasing
liver metabolism of drugs.3 Hepatic
enzyme induction takes weeks to
months to occur and may recur after
every dose increase.2
In dogs, phenobarbital shortens
the effects of estrogens, androgens,
and progestational and adrenocorti-
cal steroids. Serum thyroid hormone
concentrations are also decreased as a
result of increased hepatic metabo-
lism.2 Phenobarbital also shortens the
β-blocking effect of propranolol,4 re-
duces the anesthetic time of xylazine,5
and decreases the plasma concentra-
tions of clorazepate2 and griseofulvin.
Many drug interactions with pheno-
barbital that are described in humans
are also likely to occur in small ani-
mals. These interactions usually result
in a decrease in plasma concentration
or a decrease in the half-life of the
drug in question. Examples relevant
in veterinary medicine include all cor-
ticosteroids, cimetidine, chloram-
phenicol, cyclosporine, dicumarol,
digitoxin, diltiazem, doxycycline, fel-
bamate, itraconazole, metronidazole,
phenylbutazone, quinidine, selegiline,
theophylline, and warfarin.6,7 Once
induced by phenobarbital, it may take
up to 7 months for microsomal en-
Compendium October 1999
zymes to return to their baseline
state.3
DOSAGE AND ADMINISTRATION
Phenobarbital effectively controls
seizures in 60% to 80% of canine
patients.2 A starting oral dose of 2
mg/kg twice daily is adequate for
dogs8; however, because of large vari-
ability in phenobarbital metabolism,
dose adjustments are likely to be nec-
essary. For cats, the suggested start-
ing oral dose is 4 mg/kg twice daily.8
In cases of status epilepticus, which
is a medical emergency because of the
resultant hyperthermia and energy
expenditure, the use of an intrave-
nous bolus dose of diazepam (0.5 to
1.0 mg/kg)8 is indicated as the first-
choice therapy. If seizures are not
controlled, an intravenous bolus of
phenobarbital (4 mg/kg) should be
administered.9 If necessary, this bo-
lus administration can be repeated
up to a total of 16 mg/kg, allowing
at least a 20-minute interval between
boluses. If seizures are still uncon-
trolled, a constant-rate infusion of
pentobarbital (5 mg/kg/hour) is in-
dicated.9 As soon as the animal can
swallow, long-term oral maintenance
therapy of phenobarbital should be
initiated at 2 mg/kg twice daily or
continued at an increased level.
Because of marked variability in
drug metabolism, therapeutic drug
monitoring plays an important role
in determining optimal therapy. Rec-
ommended serum concentrations of
phenobarbital range from 15 to 45
µl/ml.2 In poorly controlled animals,
Client Counseling Information
■ Phenobarbital is contraindicated in animals allergic to barbiturates.
■ Inform your veterinarian if your pet is pregnant, may be pregnant, is
lactating, or has liver disease.
■ If your pet misses a dose, give the missed dose as soon as possible.
However, a missed dose should be skipped if it is almost time for the
next dose; two doses should not be administered at the same time.
20TH ANNIVERSARY
drug concentrations should be mea-
sured 3 weeks to 1 month after each
dose increase until the patient is well
controlled. After appropriate control
is achieved, biannual drug monitor-
ing is recommended. Patients should
not be considered refractory to phe-
nobarbital until concentrations are
above 35 µl/ml. If the drug half-life
is less than 36 hours, an 8-hour dos-
ing interval is more appropriate than
is a 12-hour (twice daily) dosing in-
terval to prevent marked fluctuations
in plasma drug concentration and
consequent breakthrough seizures.
Serum alkaline phosphatase and
transaminases (alanine aminotransfer-
ase, aspartate aminotransferase) are
likely to increase after prolonged phe-
nobarbital therapy, but this increase
is not necessarily correlated with liver
disease. Changes in bile acids (in-
crease) and albumin and cholesterol
(decrease) are more indicative of true
hepatic pathology.2 Liver function
should be monitored every 6 months
in well-controlled patients and more
often in patients maintained at high
concentrations of phenobarbital. If
evidence of hepatic disease develops,
clinicians should consider switching
the therapy to another anticonvulsant
that is not hepatically metabolized,
such as potassium bromide.
Side effects of phenobarbital in-
clude sedation, listlessness, polypha-
gia, polydipsia, and polyuria. Some
dogs appear fatigued and weak in
their rear legs. Hepatotoxicity due to
the formation of toxic metabolites is
a real concern, especially in animals
Small Animal/Exotics
that need to be maintained at the
high end of the therapeutic range.
PREPARATIONS
Oral phenobarbital is available ge-
nerically as 16-mg capsules; a 15
mg/5 ml elixir; and 15-, 16-, 30-,
32-, 60-, 65-, and 100-mg tablets5 as
well as in injectable solutions con-
taining 30, 60, 65, or 130 mg/ml.
Oral phenobarbital therapy is rela-
tively inexpensive, with prices rang-
ing from $.03 to $.06 per tablet, de-
pending on tablet size. Injectable
treatment, although slightly more ex-
pensive, is used only during emer-
gency treatment.
STORAGE AND HANDLING
Phenobarbital should be stored at
room temperature and protected from
heat and moisture. The injectable
formulation of phenobarbital is light-
sensitive and should not be used if it
is discolored or contains a precipi-
tate. Veterinarians should be aware
of the abuse potential of phenobarbi-
tal and store it in a securely locked,
sturdy cabinet as required by law.10
References
1. Federal Comprehensive Drug Abuse
Prevention and Control Act, 1970.
Enacted as Public Law 91–513.
2. Boothe DM: Drugs acting on the central
nervous system, in Adams HR (ed):
Veterinary Pharmacology and Therapeutics,
ed 7. Ames, IA, Iowa State University
Press, 1995, p 375.
3. Caccio JP, Halpert JR: Characterization
of phenobarbital inducible liver cy-
tochrome P450 structurally related to rat
and human enzymes of the P450IIIA
(steroid-induced) gene subfamily. Arch
Biochem Biophys 271:284–299, 1990.
4. Vu VT, Bai SA, Abramson FP:
Interactions of phenobarbital and propra-
nolol in the dog. Bioavailability,
metabolism and pharmacokinetics. J
Pharmacol Exp Ther 224:56–61, 1983.
5. Nossaman BC, Amouzadeth HR, Sangiah
S: Effects of chloramphenicol, cimetidine
and phenobarbital on tolerance to xy-
lazine-ketamine anesthesia in dogs. Vet
Hum Toxicol 32(3):216–219, 1990.
6. Physicians GenR x : The Complete Drug
Reference. St. Louis, Mosby, 1996, pp
1659–1671.
Compendium October 1999 20TH ANNIVERSARY Small Animal/Exotics

7. Stanovich J, Battino D: Phenobarbital: Dosing and Therapeutic Tools

Database. Drugdex® System, Micromedex, Inc, Englewood, CO, 1999. ABOUT THE AUTHOR
8. Boothe D: Boothe’s Small Animal Formulary, ed 4. Denver, CO, Dr. Boeckh is a veterinary clinical pharmacologist at
American Animal Hospital Association Press, 1998, p 98. the Department of Veterinary Physiology and Phar-
9. Parent J: Status epilepticus, in Matthews KA (ed): Emergency &
Critical Care Notes and Protocols. Guelph, ON, Ontario Veterinary
macology, College of Veterinary Medicine, Texas
College, University of Guelph, 1995, p 4. A&M University, College Station, Texas.
10. Drug Enforcement Administration: Federal Controlled Substances
Act 21, paragraph 1301.75.