Compendium October 1999

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Phenobarbital is a long-actingbarbiturate that is used as a hyp-notic, sedative, and anticonvul-

sant to treat epilepsy and focal corticalseizures in dogs and cats and as a lab-oratory reagent in human medicine.Phenobarbital and its injectable sodi-um salt are subject to control underthe Federal Controlled Substances Actof 1970 as schedule IV (C-IV) drugs.1

PHARMACOLOGYPhenobarbital decreases seizure ac-

tivity by enhancing responsiveness tothe inhibitory postsynaptic effects of

the neurotransmitter -aminobutyricacid (GABA). Phenobarbital opens aGABA-mediated chloride channel,resulting in increased intracellularconcentration of chloride and hyper-polarization of the cell membrane.2

Phenobarbital also inhibits glutamateactivity and probably decreases calciumfluxes through the cell membrane.2

As a weak acid, phenobarbital iswell absorbed orally, although peak

plasma concentrations occur only 4to 6 hours after administration. Thehalf-life varies within species as well

as within individual animals,

2

mak-ing therapeutic drug monitoring animportant part of successful pheno-barbital therapy.

CAUTIONSPhenobarbital is known to induce

liver failure in dogs, the developmentand severity of which are related tothe duration of therapy and plasmaconcentrations of the drug. Animalsthat need to be maintained at high

phenobarbital concentrations (above30 g/ml) are more predisposed todevelopment of liver disease.

ACUTE TOXICITYTreatment of phenobarbital toxi-

cosis consists of artificial respirationwith oxygen to prevent hypoxia fromrespiratory arrest. Although less ef-fective than oxygen, doxapram or an-other respiratory analeptic may be usedto 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 INTERACTIONSTreatment with phenobarbital in-

Compendium October 1999 20TH ANNIVERSARY Small Animal/Exotics

creases the activity of hepatic micro-somal enzymes that metabolize drugsand hormones, thereby increasing

liver metabolism of drugs.3

Hepaticenzyme induction takes weeks tomonths to occur and may recur afterevery dose increase.2

In dogs, phenobarbital shortensthe effects of estrogens, androgens,and progestational and adrenocorti-cal steroids. Serum thyroid hormoneconcentrations are also decreased as aresult of increased hepatic metabo-lism.2 Phenobarbital also shortens the-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 humansare also likely to occur in small ani-mals. These interactions usually resultin a decrease in plasma concentrationor a decrease in the half-life of thedrug in question. Examples relevantin 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 Onceinduced by phenobarbital, it may takeup to 7 months for microsomal en-

Albert Boeckh, DVMTexas A&M University

P H A R M P R O F I L E

PHENOBARBITAL*

Pharm Profileintroduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like

Pharm Profileto 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 [email protected].

*Pharm Profile featured potassium bro-

mide in the July 1999 issue. Virtually allpatients treated with potassium bromidehave been or are currently being treated

with phenobarbital as well. Althoughthere are no new indications for the useof phenobarbital, it is being featured thismonth with regard to the complemen-tary therapies.


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zymes to return to their baselinestate.3

DOSAGE AND ADMINISTRATIONPhenobarbital effectively controls

seizures in 60% to 80% of caninepatients.2 A starting oral dose of 2mg/kg twice daily is adequate fordogs8; 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, whichis a medical emergency because of theresultant hyperthermia and energyexpenditure, the use of an intrave-

nous bolus dose of diazepam (0.5 to1.0 mg/kg)8 is indicated as the first-choice therapy. If seizures are notcontrolled, an intravenous bolus ofphenobarbital (4 mg/kg) should beadministered.9 If necessary, this bo-lus administration can be repeatedup to a total of 16 mg/kg, allowingat least a 20-minute interval betweenboluses. If seizures are still uncon-trolled, a constant-rate infusion ofpentobarbital (5 mg/kg/hour) is in-

dicated.9

As soon as the animal canswallow, long-term oral maintenancetherapy of phenobarbital should beinitiated at 2 mg/kg twice daily orcontinued at an increased level.

Because of marked variability indrug metabolism, therapeutic drugmonitoring plays an important rolein determining optimal therapy. Rec-ommended serum concentrations ofphenobarbital range from 15 to 45l/ml.2 In poorly controlled animals,


Client Counseling Information

I Phenobarbital is contraindicated in animals allergic to barbiturates.

I Inform your veterinarian if your pet is pregnant, may be pregnant, islactating, or has liver disease.

I 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 thenext dose; two doses should not be administered at the same time.

drug concentrations should be mea-sured 3 weeks to 1 month after eachdose increase until the patient is wellcontrolled. After appropriate controlis achieved, biannual drug monitor-

ing is recommended. Patients shouldnot be considered refractory to phe-nobarbital until concentrations areabove 35 l/ml. If the drug half-lifeis less than 36 hours, an 8-hour dos-ing interval is more appropriate thanis a 12-hour (twice daily) dosing in-terval to prevent marked fluctuationsin plasma drug concentration andconsequent breakthrough seizures.

Serum alkaline phosphatase andtransaminases (alanine aminotransfer-

ase, aspartate aminotransferase) arelikely to increase after prolonged phe-nobarbital therapy, but this increaseis not necessarily correlated with liverdisease. Changes in bile acids (in-crease) and albumin and cholesterol(decrease) are more indicative of truehepatic pathology.2 Liver functionshould be monitored every 6 monthsin well-controlled patients and moreoften in patients maintained at highconcentrations of phenobarbital. If

evidence of hepatic disease develops,clinicians should consider switchingthe therapy to another anticonvulsantthat is not hepatically metabolized,such as potassium bromide.

Side effects of phenobarbital in-clude sedation, listlessness, polypha-gia, polydipsia, and polyuria. Somedogs appear fatigued and weak intheir rear legs. Hepatotoxicity due tothe formation of toxic metabolites isa real concern, especially in animals

that need to be maintained at thehigh end of the therapeutic range.

PREPARATIONSOral phenobarbital is available ge-

nerically as 16-mg capsules; a 15mg/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. Injectabletreatment, although slightly more ex-pensive, is used only during emer-gency treatment.

STORAGE AND HANDLINGPhenobarbital should be stored at

room temperature and protected fromheat and moisture. The injectableformulation of phenobarbital is light-sensitive and should not be used if itis discolored or contains a precipi-tate. Veterinarians should be awareof 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 AbusePrevention and Control Act, 1970.Enacted as Public Law 91513.

2. Boothe DM: Drugs acting on the centralnervous 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 Biophys271:284299, 1990.4. Vu VT, Bai SA, Abramson FP:

Interactions of phenobarbital and propra-nolol in the dog. Bioavailabil ity,

metabolism and pharmacokinetics. JPharmacol Exp Ther224:5661, 1983.

5. Nossaman BC, Amouzadeth HR, SangiahS: Effects of chloramphenicol, cimetidine

and phenobarbital on tolerance to xy-lazine-ketamine anesthesia in dogs. Vet

Hum Toxicol32(3):216219, 1990.6. Physicians GenRx: The Complete Drug

Reference. St. Louis, Mosby, 1996, pp

16591671.


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

Database. Drugdex System, Micromedex, Inc, Englewood, CO, 1999.8. Boothe D: Boothes Small Animal Formulary, ed 4. Denver, CO,

American Animal Hospital Association Press, 1998, p 98.9. Parent J: Status epilepticus, in Matthews KA (ed): Emergency &

Critical Care Notes and Protocols. Guelph, ON, Ontario VeterinaryCollege, University of Guelph, 1995, p 4.

10. Drug Enforcement Administration: Federal Controlled SubstancesAct 21, paragraph 1301.75.

ABOUT THE AUTHORDr. Boeckh is a veterinary clinical pharmacologist atthe Department of Veterinary Physiology and Phar-macology, College of Veterinary Medicine, Texas

A&M University, College Station, Texas.

Compendium October 1999

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