Phenobarbital

Phenobarbital is an effective antiepileptic drug used in dogs and cats.^1-3

Overview

• Many adverse events associated with phenobarbital (PB) use in dogs and cats are transient; others are acceptably managed with appropriate client education.^1,3

• Hepatotoxicity can develop in dogs treated chronically with PB,^3-6 but

  • Is avoidable with diligent therapeutic monitoring

  • May be reversible with prompt drug withdrawal and supportive therapy

• Early recognition and treatment are key in resolving any complication that may arise.

Adverse Events

• Adverse events are more commonly observed in dogs than in cats.^2,3

• Common acute and transient adverse behavioral effects include sedation, hyperexcitability, and restlessness.  

  • Signs resolve in most patients within 2 weeks of starting therapy.^1,3

    • Improvement may result from induction of PB biotransformation over time.

• Frequently reported chronic and persistent side effects are polydipsia, polyuria, and polyphagia.

  • Can be intolerable to some owners, requiring changing the antiepileptic drug (AED)^1,3

• In dogs, subacute-to-chronic treatment is often associated with subclinical laboratory abnormalities, including^3,7

  • Decreased total and free thyroxine concentrations

  • Mild-to-moderate elevations in ALP and, to a lesser extent, ALT

Toxicities & Severe Reactions

• Hepatotoxicity

  • Most common clinically significant, severe complication associated with PB^3,4,8

  • Risk factors include

    • Chronic PB use

    • Serum PB concentrations >35 μg/mL (151 µmol/L)

    • Concurrent therapy with other hepatotoxic drugs (see Warnings)

  • May result in irreversible and fatal hepatic failure

  • Clinical signs

    • Abdominal effusion

    • Anorexia

    • Icterus and pigmenturia

    • Marked sedation and ataxia

    • Vomiting/diarrhea

  • Laboratory abnormalities

    • Elevated bile acid concentrations

    • Low serum albumin (hypoalbuminemia)

    • Increased serum PB concentration without dose escalation

    • Moderate-to-marked elevations in ALP and ALT

• Blood dyscrasia^3,5

  • Rare idiosyncratic reaction that usually develops within several months of therapy

  • Clinical signs

    • Anorexia

    • Fever

    • Lethargy

    • Splenomegaly

    • Spontaneous hemorrhage

  • Laboratory abnormalities

    •  Neutropenia

    • Thrombocytopenia

    • Anemia

• Superficial necrolytic dermatitis⁸

  • Multifocal dermatopathy characterized by erythema and papules that progress to erosions

    • Predilection for footpads, mucocutaneous junctions, and axillary and inguinal regions

  • Can develop with chronic PB administration

  • Often associated with laboratory, ultrasonographic, and histopathologic evidence of hepatic disease

    • Overt clinical hepatic failure is rare.

• Dyskinesia⁶

  • Rare reaction defined by abnormal, involuntary, repetitive muscle movements that distort or impair voluntary motions

Treatment Monitoring & Precautionary Measures^3-6

• CBC, serum chemistry panel, and urinalysis should be performed before PB therapy is initiated.

• After steady-state PB concentrations are confirmed (at approximately 2 weeks), monitor serum PB concentrations, serum chemistry panel findings, and serum bile acids q6mo in patients on chronic PB therapy.

• Serious hepatotoxicity requires

  • Prompt PB discontinuation

  • Appropriate symptomatic and supportive care

    • Fluids

    • Gastric protectants

    • Dietary and nutraceutical hepatic support

    • Management of hepatic encephalopathy or coagulopathy (if present)

    • Other measures as indicated

  • Acute PB withdrawal may precipitate seizures.

  • Consider loading with additional AED (eg, potassium bromide).

  • Hepatotoxicity, myelosuppression, and dyskinesia may be reversible with prompt recognition and treatment.

Warnings^3,4

• Avoid PB use in patients with preexisting hepatic disease.

• Risk for clinically significant liver dysfunction may increase when PB is administered with other hepatotoxic drugs.

• May potentiate sedative effects of CNS depressants (eg, anti-histamines, benzodiazepines, narcotics)

• Hepatic or intestinal P450 activities induced by PB may result in drug interactions by increasing drug metabolism, resulting in

  • Reduced blood concentrations and therapeutic efficacy (eg, cyclosporine, doxycycline, zonisamide, mitotane)

  • Increased active metabolites of parent compound, thus potentiating therapeutic effects or causing toxic effects (eg, acetaminophen)