Case 1 Therapeutic failure due to Phenobarbital induction of drug metabolizing enzymes Signalment:  3.5 year old male Labrador Retriever Chief Complaint:  Seizures Pertinent History:  Diagnosed as epileptic 6 months prior to presentation. Patient was suffering from severe cluster seizures. Response to phenobarbital was initially but 6 months into therapy, the patient has begun seizuring again. Drug of Interest:  Phenobarbital Concern:  Efficacy Other Drugs:  None Dosing Regimen:  4.1 mg/kg every 12 hours orally. Duration of Current Regimen:  6 months. Phenobarbital concentrations at 3 months (baseline) were 35 mg/ml (peak) and 31mg/ml (trough). Elimination half-life at that time was 40 hours. Patient Response:  Seizure control initially improved and no evidence of grogginess. Patient suffered a series of cluster seizures this weekend. Referring veterinarian interested in adding an alternative anticonvulsant (e.g., bromide). Drug Concentration: 18 mg/ml     Time:  5 hours 15 mg/ml     Time:  12 hours Drug Elimination Half-Life:  27 hours Volume of Distribution:  NA Predicted Peak:  NA Predicted Trough:  NA Recommendation:  Increase phenobarbital dose to 7.5 mg/kg every 12 hours (4.5 mg/kg x 30 mg/ml / 18 mg/ml), targeting a peak concentration of 30 mg/ml. Retest at new steady-state (which will only take 3 to 5.5 days in this patient.) Comments:  Phenobarbital concentrations decreased in this patient by close to 50% without a decrease in dose. The elimination half-life decreased by 50%. The decrease most likely reflects induction of drug metabolizing enzymes by phenobarbital, resulting in increased clearance and decreased drug concentrations. Induction will occur in most animals and should be anticipated by using a sufficiently high starting dose (2 mg/kg) for phenobarbital, and measuring drug concentrations at steady-state (approximately 2 weeks after therapy is begun) and then again at 3 months. Follow-Up:  The dose was increased to 6.5 mg/kg. Drug concentrations one month later were 33 mg/ml (peak) and 29 mg/ml (trough). Patient has been seizure free for six months. Although bromide therapy could have been started in this patient, the increase in phenobarbital concentration was easier and as effective, leaving bromide available should this patient's disease get worse. [back to top]