Compendium October 1999

Compendium October 1999

20TH ANNIVERSARY

Small Animal/Exotics

PHARM PROFILE

PHENOBARBITAL* Albert Boeckh, DVM Texas A&M University

P

henobarbital is a long-acting barbiturate that is used as a hypnotic, sedative, and anticonvulsant to treat epilepsy and focal cortical seizures in dogs and cats and as a laboratory reagent in human medicine. Phenobarbital and its injectable sodium salt are subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drugs.1

PHARMACOLOGY Phenobarbital decreases seizure activity 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 hyperpolarization 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 bromide 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 complementary therapies.

plasma concentrations occur only 4 to 6 hours after administration. The half-life varies within species as well as within individual animals,2 making therapeutic drug monitoring an important part of successful phenobarbital 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 toxicosis consists of artificial respiration with oxygen to prevent hypoxia from respiratory arrest. Although less effective than oxygen, doxapram or another respiratory analeptic may be used to stimulate the respiratory center. In addition, alkalinizing the urine accelerates phenobarbital excretion by increasing drug ionization and reducing tubular reabsorption.2 DRUG INTERACTIONS Treatment with phenobarbital in-

creases the activity of hepatic microsomal 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 adrenocortical steroids. Serum thyroid hormone concentrations are also decreased as a result of increased hepatic metabolism.2 Phenobarbital also shortens the β-blocking effect of propranolol,4 reduces the anesthetic time of xylazine,5 and decreases the plasma concentrations of clorazepate2 and griseofulvin. Many drug interactions with phenobarbital that are described in humans are also likely to occur in small animals. 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 corticosteroids, cimetidine, chloramphenicol, cyclosporine, dicumarol, digitoxin, diltiazem, doxycycline, felbamate, itraconazole, metronidazole, phenylbutazone, quinidine, selegiline, theophylline, and warfarin.6,7 Once induced by phenobarbital, it may take up to 7 months for microsomal en-

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 [email protected].

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 variability in phenobarbital metabolism, dose adjustments are likely to be necessary. For cats, the suggested starting 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 intravenous bolus dose of diazepam (0.5 to 1.0 mg/kg)8 is indicated as the firstchoice therapy. If seizures are not controlled, an intravenous bolus of phenobarbital (4 mg/kg) should be administered.9 If necessary, this bolus 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 uncontrolled, a constant-rate infusion of pentobarbital (5 mg/kg/hour) is indicated.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. Recommended serum concentrations of phenobarbital range from 15 to 45 µl/ml.2 In poorly controlled animals,

20TH ANNIVERSARY

drug concentrations should be measured 3 weeks to 1 month after each dose increase until the patient is well controlled. After appropriate control is achieved, biannual drug monitoring is recommended. Patients should not be considered refractory to phenobarbital until concentrations are above 35 µl/ml. If the drug half-life is less than 36 hours, an 8-hour dosing interval is more appropriate than is a 12-hour (twice daily) dosing interval to prevent marked fluctuations in plasma drug concentration and consequent breakthrough seizures. Serum alkaline phosphatase and transaminases (alanine aminotransferase, aspartate aminotransferase) are likely to increase after prolonged phenobarbital therapy, but this increase is not necessarily correlated with liver disease. Changes in bile acids (increase) 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 include sedation, listlessness, polyphagia, 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

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.

Small Animal/Exotics

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

PREPARATIONS Oral phenobarbital is available generically 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 containing 30, 60, 65, or 130 mg/ml. Oral phenobarbital therapy is relatively inexpensive, with prices ranging from $.03 to $.06 per tablet, depending on tablet size. Injectable treatment, although slightly more expensive, is used only during emergency treatment. STORAGE AND HANDLING Phenobarbital should be stored at room temperature and protected from heat and moisture. The injectable formulation of phenobarbital is lightsensitive and should not be used if it is discolored or contains a precipitate. Veterinarians should be aware of the abuse potential of phenobarbital 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 cytochrome 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 propranolol 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 xylazine-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

7. Stanovich J, Battino D: Phenobarbital: Dosing and Therapeutic Tools Database. Drugdex® System, Micromedex, Inc, Englewood, CO, 1999. 8. Boothe D: Boothe’s 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 Veterinary College, University of Guelph, 1995, p 4. 10. Drug Enforcement Administration: Federal Controlled Substances Act 21, paragraph 1301.75.

Small Animal/Exotics

ABOUT THE AUTHOR Dr. Boeckh is a veterinary clinical pharmacologist at the Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas.