Seizure disorders represent the most frequent neurologic problem encountered in dogs. Although there are multiple causes of seizures, the most common cause is idiopathic epilepsy. About 25% to 30% of epileptic dogs have conditions that are poorly controlled despite adequate plasma concentrations of typically used anticonvulsant drugs (i.e. phenobarbital and bromide).1,2 Phenobarbital and bromide have similar adverse effects, including sedation, polyphagia, weight gain, polyuria, and polydipsia.1,2 In our experience, these side effects are often compounded when the two drugs are administered concurrently. Exacerbation of polyphagia, weight gain, polyuria, and polydipsia also occurs in dogs with seizure disorders requiring glucocorticoid therapy to control clinical signs (e.g. brain tumors, granulomatous meningoencephalomyelitis). Small-animal clinicians recognize a need for safe and effective alternatives to phenobarbital and bromide.
Numerous anticonvulsant drug options are available for people with seizure disorders. Unfortunately, most of these drugs are eliminated too rapidly when administered in dogs to be of much practical use.1,2 However, some of these alternative drugs have shown promise in dogs with seizure disorders. These drugs include clorazepate, felbamate, gabapentin, levetiracetam, and zonisamide (Table 1). For each of these drugs, published or unpublished data on the pharmacokinetics and side effects in dogs are available. Some of the information regarding their efficacy is anecdotal, based primarily on clinical experience. For most of these anticonvulsants, however, there is published information concerning efficacy in dogs with seizure disorders.
Table 1: Dosing, Costs, and Side Effects of Alternative Anticonvulsant Drugs in Dogs
The drugs discussed in this article cost considerably more than phenobarbital or bromide. Because of their increased expense, these drugs are typically used as add-on therapy to standard anticonvulsant drug regimens. In some cases, these drugs have been used as replacement therapy or as sole anticonvulsant agents. Such use of these alternative drugs is more commonly pursued with smaller dog breeds. This article provides small-animal clinicians with a reference source for alternatives to phenobarbital and bromide.
Clorazepate (clorazepate dipotassium) is a benzodiazepine prodrug that acts by enhancing gamma-aminobutyric acid (GABA) activity in the brain.1-5 Clorazepate tablets are available in both regular and sustained-release formulations, but there appears to be no advantage to using the sustained-release tablets in dogs.1,6 After oral administration, clorazepate is rapidly hydrolyzed in the stomach to nordiazepam, its active metabolite. Nordiazepam subsequently undergoes hepatic metabolism. The serum elimination half-life of nordiazepam after clorazepate administration is typically four to six hours, but it may be as short as three hours in some dogs.1-5 We recommend an initial dosage of 0.5 to 1 mg/kg given every eight hours. A dosage of 2 mg/kg given every 12 hours has also been suggested.2-5 The therapeutic range in dogs receiving clorazepate is 100 to 400 ng/ml of nordiazepam.2 Because of the short and somewhat variable elimination half-life of the drug, it is important to obtain both peak and trough serum concentrations when monitoring patients. The side effects of clorazepate are similar to those of other benzodiazepine drugs (e.g. sedation, ataxia).2,3 Severe withdrawal seizures are possible if clorazepate is abruptly discontinued.7
Several potential problems are associated with clorazepate administration. With long-term use, serum nordiazepam concentrations tend to decrease with time, usually necessitating a dose increase. Although the problem is not as profound as with diazepam, long-term use of clorazepate may also lead to tolerance of its antiseizure effects. It has been demonstrated that concurrent administration of phenobarbital and clorazepate leads to marked reductions in serum nordiazepam concentrations, necessitating increased doses of clorazepate.1,2,5 Conversely, there is some evidence that simultaneous administration of clorazepate and phenobarbital can lead to increased serum phenobarbital concentrations.2 We recommend performing serum chemistry profiles every six months to monitor hepatic function in dogs receiving clorazepate, especially in those receiving phenobarbital concurrently.