New anticonvulsant drugs show promise in dogs, cats

source-image
Mar 01, 2008

Q: Please review management of refractory seizure activity in dogs and cats.

A: Dr. C.W. Dewey gave an excellent lecture at the 2007 American College of Veterinary Internal Medicine Forum on "Recent and Upcoming Developments with the New Anticonvulsant Drugs." Here are some relevant points:

During the past 10 to 15 years, a number of new anticonvulsant drugs have been introduced for the treatment of human seizure disorders, some of which have been shown to be safe and effective for use in dogs. These drugs include gabapentin, felbamate, zonisamide and levitiracetam.

These anticonvulsant agents currently are used as an "add-on" drug for dogs with refractory seizure disorders. With the exception of levitiracetam, information on the use of such drugs in feline seizure disorders is anecdotal. But as these drugs get older and begin to emerge as less-expensive generic products, their clinical applicability in veterinary medicine continues to expand.

In general, these drugs have fewer side effects than the standard drugs, phenobarbital and potassium bromide, and are being considered more frequently as first-line anticonvulsant therapy for canine epilepsy. In addition to expanded use as maintenance anticonvulsant agents in dogs (and to a lesser extent in cats), two of these drugs (levitiracetam and zonisamide) have potential use in emergency settings (i.e., for status epilepticus and cluster seizures).

New anticonvulsant drugs

Gabapentin appears to exert its anticonvulsant effect primarily via interaction with neuronal voltage-gated calcium channels. Inhibition of these channels is thought to decrease excitatory neurotransmission. Gaba-pentin typically is administered orally at a dosage of 10 mg/kg every eight hours in dogs. There are anecdotal reports of gabapentin use in cats with seizures (5-10 mg/kg PO, q8-12 hours).

Clinical efficacy reports in refractory epileptic dogs treated with gabapentin as an add-on therapy indicate that fewer than half of such dogs are responders (i.e., experience a 50 percent or more reduction in seizures after adding gabapentin). However, gabapentin is the least effective of the new anticonvulsant drugs. Side effects typically are mild, and include minor sedation and pelvic limb ataxia.

Gabapentin is available in generic form at a much lower price than the trade-name formulation.

Felbamate is suspected to exert its anticonvulsant effects via potentiating GABA-mediated neuronal inhibition, mitigating NMDA-mediated neuronal excitation and inhibiting voltage-gated neuronal sodium and calcium channels.

Felbamate typically is dosed initially at 15 mg/kg orally every eight hours. There is limited published information regarding its efficacy, but it is generally believed to be an effective anticonvulsant add-on agent. Side effects are uncommon, but hepatotoxicity (usually with concurrent high phenobarbital blood levels), reversible blood dyscrasias and keratoconjunctivitis sicca have been reported with felbamate use in dogs. There is no information on its use in cats.

Considering the hepatic and blood dyscrasia issues associated with felba-mate use in humans and dogs (uncommon as they may be), it is unlikely that there will be much impetus to pursue research into feline felbamate use. There is no generic formulation available for felbamate.

Levitiracetam has been shown to have a unique intracellular binding site, a synaptic vesicle protein (SV2A), the affinity of binding to which appears to be correlated with the drug's anticonvulsant potency. Binding to SV2A affects neurotransmission via interactions between synaptotagmin and calcium ions, but the precise biochemical pathways remain undetermined.

Levitiracetam is an attractive anticonvulsant option due to its lack of side effects and favorable pharmacokinetic profile (e.g., no hepatic metabolism, 100 percent oral bioavailability, no drug-drug interactions). There is limited published information regarding its efficacy as an add-on anticonvulsant in dogs, but so far it is favorable. The dose usually used is 20 mg/kg orally every eight hours. A lower-cost, generic form of oral levitiracetam is available.

Zonisamide has proven to be an effective add-on anticonvulsant drug in dogs, with few side effects. There are multiple proposed mechanisms of action for zonisamide, including blockage of T-type calcium and voltage-gated sodium channels in the brain, facilitating dopaminergic and serotonergic neurotransmission, free-radical scavenging, enhancing GABA activity and decreasing glutamate-mediated processes.

Dogs concurrently receiving pheno-barbital therapy tend to require a higher zonisamide dose (10 mg/kg, q 12 hours) than dogs not receiving phenobarbital (5 mg/kg, q 12 hours). The BID dosing schedule for zonisamide is an advantage over the other new anti-epileptic drugs for many dog owners. It is available in the generic form.