NOVEL
ANTICONVULSANTS

Novel anticonvulsant agents for use in refractory epilepsy

 

Most epileptic dogs are managed effectively with “standard” anticonvulsant drugs i.e. phenobarbital and bromide. However, approximately one-third are refractory to appropriate doses of these drugs. Increasing the dosage of phenobarbital and bromide in an effort to improve seizure control can lead to unacceptable side-effects. There are few alternative anticonvulsants to use as additional therapies in refractory canine seizure cases, as most of the available drugs used in people have very short elimination half-lives or are toxic to dogs. The 3 human drugs which have been used as adjunctive anticonvulsant medications are felbamate, gabapentin, zonisamide and pregabalin. Clinicians at the AHT studied the efficacy of Gabapentin as an adjunctive therapy for the management of refractory epilepsy in dogs. The study included 11 dogs with refractory idiopathic epilepsy. Five dogs showed a significant reduction in seizure frequency (ie seizures reduced to less than 50% per week). However, many dogs still exhibited multiple days on which there was cluster seizure activity. Gabapentin was well tolerated - five dogs exhibited mild side effects (ataxia and sedation).

 

Felbamate has an elimination half-life in dogs of approximately 5-6 hours and requires dosing three times daily. Its use has been documented in 6 dogs which all showed an improved seizure frequency after a median duration of therapy of 9 months; potential side-effects in dogs include haematological abnormalities, keratoconjunctivitis sicca and hepatotoxity.

 

Zonisamide has an estimated elimination half-life of 15 hours in dogs, and has been administered twice daily in 12 dogs with refractory idiopathic epilepsy. In this study 58% of dogs responded favourably, experiencing a mean reduction in seizures of 81.3%. Five of the twelve (42%) dogs actually had an increased seizure frequency and 50% of the dogs exhibited side-effects which included sedation, ataxia and vomiting.

 

Pregabalin has been used in a small number of dogs as an adjunctive therapy to pentobarbital and bromide. It appears to be effective with twice daily dosage. The recommended oral dose is 2-4 mg/kg q8-12h (twice daily dosing is thought to be sufficient for most dogs). Sedation is the most commonly reported side-effect. Like zonisamide, levetiracetam and gabapentin, pregabalin has limited use in veterinary medicine.

References

Adusumalli VE, Gilchrist JR, Wichman JK, et al (1992) Pharmacokinetics of felbamate in pediatric and adult beagle dogs. Epilepsia 33, 955-960. - PubMed -

 

Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducoté JM, Silver GM, Cooper JJ, Packer RA, Lavely JA (2009) Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. JAVMA 235(12):1442-9. - PubMed -

 

Dewey CW, Guiliano R, Boothe DM, et al (2004) Zonisamide therapy for refractory idiopathic epilepsy in dogs. JAAHA 40, 285-291. - PubMed -

 

Muñana KR, Zhang D, Patterson EE (2010) Placebo effect in canine epilepsy trials. JVIM 24(1):166-70. - PubMed -

 

Platt SR, Adams V, Garosi LS, et al (2003) Gabapentin as adjunctive therapy for refractory idiopathic epilepsy in dogs. Proc ECVN Annual Symposium [abstract]

 

Patterson EE, Goel V, Cloyd JC, O'Brien TD, Fisher JE, Dunn AW, Leppik IE (2008) Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics. n J Vet Pharmacol Ther. 31(3), 253-258. - PubMed -

 

Radulovic LL, Turck D, von Hodenberg A, et al (1995) Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab Disposition 23, 441-448. - PubMed -

 

Ruehlmann D, Podell M, March P (2001) Treatment of partial seizures and seizure-like activity with felbamate in six dogs. JSAP 42, 403-408. - PubMed -

 

Wright HM, Chen AV, Martinez SE, Davies NM (2011) Pharmacokinetics of oral rufinamide in dogs. J Vet Pharmacol Ther. doi: 10.1111/j.1365-2885.2011.01353.x. [Epub ahead of print]. - PubMed -

 

Walker SD, Kälviäinen R (2011) Non-vision adverse events with vigabatrin therapy. Acta Neurol Scand Suppl. 2011;192:72-82. doi: 10.1111/j.1600-0404.2011.01602.x. - PubMed -

 

Vollmer KO, von Hodenberg A, Kolle EU (1986) Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Drug Res 36, 830-839. - PubMed -

 

Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE (2007) The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J. 2008 176(3), 310-319. - PubMed -

 

 

Drug DoseTherapeutic rangeFormulationSide effectsIndicationContraindicationCost
Phenobarbital3mg/kg BID20-35 ug/mlPO tablets or solution; IV solutionPUPD, sedation, ataxia, polyphagia, hepatotoxicity, bone marrow dyscrasiaDrug of first choiceimpaired hepatic functionreasonable for everyday use
Potassium Bromide30 mg/kg SID880-3000mg/mlPO liquid, capsule or tabletsPUPD, sedation, ataxia, hyperactivity, pruritus, vomitingWith phenobarbitone in refractory cases or in animals with liver diseaserenal impairmentreasonable for everyday use
Diazepam0.5-1 mg/kg IV (to max 20mg); 0.5-2 mg/kg PRto effectIV solution; PR suspension; PO tablets (not suitable for CHRONIC seizure control)respiratory depression, hypotension, reduced consciousness, hepatotoxicitystatus epilepticus -reasonable for everyday use
Imepitoin10-30 mg/kg BIDTo effectPO tabletsrare polyphagia, hyperactivity, polyuria, polydipsia, somnulenceIdiopathic epilepsy after evaluation of alternative treatmentSeverely impaired hepatic or renal function; severe cardiovascular disordersreasonable for everyday use
Levetiracetam5-25 mg/kg BID-TID -PO capsulessedation, ataxia, appetite lossAdd-on therapy in refractory casesrenal impairment, pregnancyexpensive
Gabapentin10-20 mg/kg TID-QID -PO capsulesataxia, sedation, potential risk hepatotoxicityAdd-on therapy in refractory cases -expensive
Zonisamide10mg/kg body weight BID as add-on to phenobarbital 5 mg/kg TID if single AED or add-on to AED not affecting hepatic microsomal enzymes 10-40 ug/mlPO capsulesataxia, sedationAdd-on therapy in refractory cases -expensive - may be beyond reach of many people with large dogs
Felbamate15-20 mg/kg TID initially20-100 mg/lPO tablets; suspensionhaematological abnormalities, KCS, hepatotoxicityAdd-on therapy in refractory casesimpaired hepatic function -
Pregabalin 2-4mg/kg
BID PO
2.8 ug/ml? May be less in some dogs PO tablesSedation, ataxia, mild increases in ALP and ALT Add-on therapy in refractory cases impaired hepatic function - -

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