YOUNG DOG - HEALTHY
OLD DOG STRUCTURAL PROBLEM
Levetiracetam (Keppra) or zonisamide
Levetiracetam (Keppra) or Potassium Bromide
Phenobarbital and levetiracetam
Phenobarbital and KBr (side effects)
Zonisamide and KBr
Zonisamide and levetiracetam
Phenobarbital and zonisamide (double
Carboxylic acids/ Fatty acid derivatives
1. GABA transaminase inhibitor - Valproic acid
2. GABA reuptake inhibitor - Tiagabine
1. Gabapentin, Pregabalin, Vigabatrin
• Fosphenytoin, Phenytoin
• Carbamazepine,Oxcarbazepine, Rufinamide
1. Potassium - retigabine
Phenyltriazines - Lamotrigine
Oxazolidinediones Ethadione, Paramethadione, Trimethadione
Ureas – Phenacemide, Pheneturide
Monosaccharides - Topiramate
Dicarbamate medication approved
for use in 1993
Increases seizure threshold and
prevents seizure spread by
neurotransmission in the brain
In dogs used as an add on for
refractory seizures, not generally
used as monotherapy
Undergoes hepatic metabolism by P450 system and is also excreted by the kidneys
1/2 5-6 hours with steady state reached in 1 -2 days
Dose 15-20 mg/kg q8 hours, has been used as high as 65 mg/kg
Non sedating with a high margin of safety
Idiosyncratic aplastic anemia secondary to bone marrow suppression and
Similar but rare and reversible hepatotoxicity and blood dyscrasias seen in
CBC, chemistry at 1 month after starting treatment, then q 3-6 months
Treatment of partial seizures and seizure-like activity
with felbamate in six dogs.
• J Small Anim Pract. 2001 Aug;42(8):403-8.Ruehlmann D, Podell M, March P.
• Six dogs with partial seizures or partial seizure-like activity
• Median duration of therapy was nine months (range two to 22 months).
• All dogs experienced a reduction in seizure frequency after felbamate
• Reversible haematological adverse effects were detected in two dogs,
with one dog developing concurrent keratoconjunctivitis sicca.
Designed to mimic GABA, but does not have similar pharmacological
properties of GABA nor does it bind to GABA receptors
Facilitates transport of GABA out of cells to act on the GABAA receptor to
increase inhibitory activity and block sodium channels
Undergoes partial hepatic metabolism, but mostly excreted by the kidneys
Treatment with gabapentin of 11 dogs with refractory
• Vet Rec. 2006 Dec 23-30;159(26):881 -4. TPlatt SR, Adams V, Garosi LS, Abramson
CJ, Penderis J, De Stefani A, Matiasek L.
• 11dogs with refractory idiopathic epilepsy
• All had generalised tonic-clonic seizures and had been treated with a combination of
phenobarbital and potassium bromide
• Compared for the three months before and after
• Six of the dogs showed a positive response. minimum 50 per cent reduction in the
number of seizures per week was interpreted as a positive response
• Mild side effects of ataxia and sedation were observed in five of the dogs, but they
were not severe enough to warrant the treatment being discontinued during the trial.
Improving seizure control in dogs with refractory epilepsy using
gabapentin as an adjunctive agent
Aust Vet J. 2005 Oct;83(10):602-8. Govendir M, Perkins M, Malik R. Faculty of Veterinary
Science, Building B14, The University of Sydney, New South Wales
DESIGN: 17 dogs;16 of which have idiopathic epilepsy.
PROCEDURE: Patients were stabilised using phenobarbitone and/or potassium bromide
and dosed additionally with gabapentin at 35 to 50 mg/kg/d (divided twice or three
times daily) for 4 months.
RESULTS: There was no significant decrease in the number of seizures over the
study period for the entire cohort, however three dogs stopped seizuring
• Side effects observed - sedation and hind limb ataxia.
• Long-term, a further two patients became seizure free and ten patients remained on
gabapentin indefinitely. No long-term side effects have become apparent.
CONCLUSION: Addition of gabapentin increased the interictal period and shortened the
post-seizure recovery in some canine epileptics. In some dogs, seizures were
prevented completely, while in others there was an increase in interictal period.
Sulfonamide based drug that became available for use in 2000
Is used in human for treatment of focal and generalized seizures with
minimal side effects
Works by blocking the propagation of epileptic discharges and suppressing
focal epileptogenic activity
Metabolized mainly by hepatic microsomal enzymes, but does not induce P450
system T1/2 15 hours
Dose 10 mg/kg q 12 hours, but if add on treatment with drugs inducing hepatic
enzymes, decrease dose to 5 mg/kg q 12 hours
High margin of safety
Can be used as monotherapy
Transient sedation, ataxia, inappetance, metabolic acidosis, liver intoxication,
Can reduce side effects by gradually increasing the dose
If being used with phenobarbital, recommend reducing phenobarbital dose by
Zonisamide therapy for refractory idiopathic epilepsy in dogs.
• J Am Anim Hosp Assoc. 2004 Jul-Aug;40(4):285-91
• Dewey CW, Guiliano R, Boothe DM, Berg JM, Kortz GD, Joseph RJ, Budsberg SC.
Department of Surgery, Long Island Veterinary Specialists, Plainview, New York
• Twelve dogs with poorly controlled idiopathic epilepsy were entered into a
prospective, open-label, noncomparative study. Oral zonisamide was administered as
an additional therapy at a dosage adequate to achieve serum drug concentrations of
10 to 40 microg/mL. Seizure frequency before and after initiation of zonisamide
therapy was recorded. A dosing interval of q 12 hours was sufficient to maintain
serum zonisamide concentrations within the therapeutic range.
• The mean dosage of zonisamide required was 8.9 mg/kg q 12 hours.
• Seven (58%) dogs responded favorably, experiencing a mean reduction in
seizures of 81.3%.
• Five dogs had an increase in seizure frequency.
• Mild side effects (e.g., transient sedation, ataxia, vomiting) occurred in six dogs.
Prospective study of zonisamide therapy for refractory idiopathic
epilepsy in dogs
• J Small Anim Pract. 2007 Mar;48(3):134-8. von Klopmann T, Rambeck B, Tipold A.
Department of Small Animal Medicine and Surgery, University of Veterinary Medicine
Bischofsholer Damm Hannover, Germany.
• METHODS: Thirteen dogs fulfilled the inclusion criteria of poor seizure control despite
adequate serum levels of phenobarbital, potassium bromide or both. One further dog
was treated with zonisamide as monotherapy because of severe blood dyscrasia due
to phenobarbital treatment..
• RESULTS: Data of 11 dogs could be evaluated: nine of them were responders.
The median reduction of seizure frequency of all dogs on zonisamide add-on therapy
was 70 per cent (range 14 to 100 per cent).
• Only transient central nervous system side effects were reported. No further increase
of liver enzymes occurred. In three of the responder dogs, seizure control
subsided after individual time periods (between 69 days and seven months).
Sulfamate substituted monosaccharide
Blocks seizure spread by rapidly potentiated
GABA activity in the brain
In people it is used for generalized and partial
In people it is primarily excreted by the kidneys
1/2 20-30 hours (people), 2-4 hours (dogs),
steady state reached in 1 -3 days
Dose 2-10 mg/kg q 12 hours, best to start low
GI upset, inappetence, irritability, ataxia
Synaptic Vesicle Protein 2 A, is required
for normal nervous system functioning
and is the binding site of the antiepilepsy drug levetiracetam
Mostly excreted unchanged in the
urine, the remainder is hydrolyzed in
the serum and by other organs
No hepatic metabolism in humans or
1/2 3-4 hours but may exert
anticonvulsant effects that last longer
than its presence in the bloodstream
Dose 20 mg/kg q 8 hours
The efficacy and tolerability of levetiracetam in pharmacoresistant
• Vet J. 2008 Jun;176(3):310-9. Epub 2007 Apr 30.
• Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE.
• 8/14 dogs responded significantly to the treatment and seizure frequency
was reduced by 50%.
• In dogs that remained refractory, the dosage was increased to 20 mg/kg TID
for 2 months. One further dog responded to levetiracetam treatment.
• Levetiracetam responders had a significant decrease in seizure frequency
of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure
days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month).
• However, 6/9 responders experienced an increase in seizure frequency
and seizure days after 4-8 months continuing with the levetiracetam
treatment at the last effective dosage.
Levetiracetam as an adjunct to phenobarbital treatment in cats
with suspected idiopathic epilepsy.
• J Am Vet Med Assoc. 2008 Mar 15;232(6):867-72.Bailey KS, Dewey CW, Boothe
DM, Barone G, Kortz GD.
• ANIMALS: 12 cats suspected to have idiopathic epilepsy that was poorly
controlled with phenobarbital or that had unacceptable adverse effects
• PROCEDURES: Cats were treated with levetiracetam (20 mg/kg [9.1
mg/lb], PO, q 8 h).
• Median seizure frequency prior to treatment with levetiracetam (2.1
seizures/mo) was significantly higher than median seizure frequency after
initiation of levetiracetam treatment (0.42 seizures/mo0
• 7 of 10 cats were classified as having responded
• Two cats had transient lethargy and inappetence.
Structural analogue to GABA
No effect on GABA receptors
1/2 6 ½ hours (people)
Current study in dogs dose
2-4 mg/kg q 12 hours
Pregabalin as an adjunct to phenobarbital, potassium bromide, or
a combination of phenobarbital and potassium bromide for
treatment of dogs with suspected idiopathic epilepsy.
• J Am Vet Med Assoc. 2009 Dec 15;235(12):1442-9 Dewey CW, Cerda-Gonzalez S, Levine JM,
Badgley BL, Ducoté JM, Silver GM, Cooper JJ, Packer RA, Lavely JA. Department of Clinical
Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
• OBJECTIVE: Pregabalin as an adjunct to phenobarbital, potassium bromide
• ANIMALS: 11 client-owned dogs
• RESULTS: Seizures were significantly reduced (mean, 57%; median, 50%) after
• 9 dogs that completed the study; 7 were considered responders with mean and
median seizure reductions of 64% and 58%, respectively.
• Adverse effects for pregabalin were reported in 10 dogs.
No published clinical studies in dogs
One published pharmacokinetic study
Dose 10-20mg/kg BID
Clinical experience – good
Rufinamide: a new antiepileptic medication for the treatment of
seizures associated with lennox-gastaut syndrome.
• Ann Pharmacother. 2010 Apr;44(4):658-67. Epub 2010 Mar 16. Wisniewski CS.
• STUDY SELECTION AND DATA EXTRACTION: Published controlled trials
• DATA SYNTHESIS: Rufinamide is a new antiepileptic agent that differs structurally
from other antiepileptic drugs and is approved as adjunctive therapy for LennoxGastaut syndrome (LGS). I
• prolonging sodium channel inactivity, stabilizing cell membranes
• It is absorbed and metabolized extensively, then excreted renally as an inactive
• Clinical trials show that adjunctive rufinamide is effective at reducing seizure
frequency in patients with LGS and refractory partial seizures
• rufinamide is well tolerated, causing headache, dizziness, and fatigue at rates of
• CONCLUSIONS: Data show that rufinamide is safe and effective as an adjunctive
agent for LGS and may be used to treat partial seizures.
No clinical studies in
Initial dose is 50 mg/kg per
day. This may be increased
up to 100 mg/kg per day,
with a maximum of 4g
250 mg, 500 mg capsules;
Inhibits cytochrome P450
The third-generation AEDs consist of 20 novel
brivaracetam (BRI), carabersat (CRB), carisbamate
(CBM), DP-valproic acid (DP-VPA), eslicarbazepine
acetate (ESL), fluorofelbamate (FFBM),
fosphenytoin (FPHT), ganaxolon (GNX), lacosamide
(LCM), losigamone (LSG), pregabaline (PGB),
remacemide hydrochloride (RMC), retigabine (RTG),
rufinamide (RUF), safinamide (SAF), seletracetam
(SEL), soretolide (SRT), stiripentol (STP), talampanel
(TLP) and valrocemide (VLR).
Absence seizures, appear to be staring into space These seizures are
sometimes referred to as petit mal seizures, which is an older term.
Tonic seizures cause stiffening of muscles of the body
Clonic seizures cause repeated jerking movements of muscles on both
sides of the body.
Myoclonic seizures cause jerks or twitches of the upper body, arms, or
Atonic seizures cause a loss of normal muscle tone - will fall down or may
drop head involuntarily.
Tonic-clonic seizures cause a mixture of symptoms, older term: grand mal
Simple focal motor seizure
Remain conscious - sudden focal jerking of a muscle group
Complex focal seizure
Change in or loss of consciousness. dreamlike experience.
may display strange, repetitious behaviors (automatisms) such as blinks, twitches, mouth
movements, walking in a circle.
60% of childhood epilepsy resolves and 60%
controlled with monotherapy
60 percent of people with epilepsy have focal
These seizures are frequently described by the area
of the brain in which they originate.
Bromide first used in the late 1800’s
Negative side effects made it a less than ideal medication
Discontinued in 1912 in US
Reappeared in 1980’s for veterinary use
Used in Europe for people
Despite its shortcomings, phenobarbital
became the main drug prescribed for
epilepsy for the next 26 years.
Phenytoin (Dilantin) was introduced in 1938
is still a major drug used today in human seizure control.
From 1945 to 1960 a series of anticonvulsant drugs based on
Carbamazepine (Tegretol) 1974
Valproic acid (Depakene) 1978
Drugs not routinely used in veterinary medicine
Carbamazepine (Tegretol, Carbatrol)
Valproic acid (Depakene)/Divalproex (Depakote)
Ethosuximide (Zarontin)/Methsuximide (Celontin)
Anticonvulsant Recent History
In the 1990’s another crop of new medications appeared
These drugs are reported to have fewer side effects, but
with similar efficacy (questionable) in the control of
When/Why to Start Treatment
More than 1 seizure in a 4-6 week period
Active intracranial disease (neoplasia,
Clinical findings, treatment, and outcome of dogs with status epilepticus
or cluster seizures: 156 cases (1990-1995).
• J Am Vet Med Assoc. 1999 Nov 15;215(10):1463-8. Bateman SW, Parent JM.
• Underlying causes of seizures were primary epilepsy (26.8%), secondary epilepsy
(35.1%;), reactive epileptic seizures (6.7%), primary or secondary epilepsy with low
serum antiepileptic drug concentrations (5.7%), and undetermined (25.8%).
• 186 resulted in admission to the ICU. CRI of diazepam or phenobarbital
• Of 194 admissions, 74.7% (145) resulted in discharge from the hospital
• 2.1% (4) in death, and 23.2% (45) in euthanasia.
• Poor outcome (death or euthanasia) was significantly associated with GME, loss of
seizure control after 6 hours of hospitalization, and the development of partial status
Management – New Options
Zonisamide (Zonegran) 5-10mg/kg BID
Levetiracetam (Keppra) 20-60mg/kg TID
250mg, 500mg, 750mg
Pregabalin (Lyrica) 2-4mg/kg BID
25, 50, 75, 100, 150, 200, 225, and 300 mg capsules
Rufinamide (Banzel) 10-20mg/kg BID
200mg, 400mg tablets
Topiramate (Topomax) 2-5mg/kg BID
25, 50mg tablets
Gabapentin (Neurontin) 10-30mg/kg T-QID
100, 300, 400, 600, 800mg Capsules/tablets
Lacosamide (Vimpat) 100-200mg BID (humans)
50, 100, 150, 200mg tablets
Clobazam (Onfi) 0.5mg/kg BID?
5, 10, 20mg tablets
Stiripentol (Diacomit) 50-100mg/kg/day B-TID
250, 500mg tablets, suspension
DON’T USE FORMULARY
KBr – Respiratory toxic in Cats
Lamotrigine (Lamictal) – cardiotoxic in dogs
Verapamil – no effect
12 year old Chihuahua
• Meds: Phenobarbital, Kbr, gabapentin, clorazepate
9y Lab Mix
Pheno, Kbr, Lyrica, gabapentin, Zonisamide, valproic acid,
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