Antiepileptic Drug Therapy
Michael Podell
Successful treatment of seizure disorders in small animals
requires proper patient assessment, understanding the principles
of antiepileptic drug (AED) therapy, designing a strategy for
pharmacotherapy, and plans for emergency treatment. Several
levels of assessment are needed in managing an epileptic patient
to include the diagnosis, effectiveness of therapy, and
health-related quality of life assessments. Three levels of
diagnosis are important in determining the appropriate AED
therapy: 1) confirmation that an epileptic seizure has occurred,
and if so, the seizure type(s) manifested; 2) diagnosis of the
seizure etiology; and 3) determination of an epileptic syndrome.
Monotherapy is the initial goal of treating any cat or dog with
epilepsy to reduce possible drug-drug interactions and adverse
effects. Unfortunately, many of the AEDs useful in people cannot
be prescribed to small animals either due to inappropriate
pharmacokinetics (too rapid of an elimination), and potenhal
hepatotoxicity. Thus, the most commonly used AEDs m veterinary
medicine are from the same mechanistic category, that of
enhancing inhibition of the brain. Antiepileptic drugs can be
classified into three broad mechanistic categories: 1)
enhancement of inhibitory processes via facilitated action of
gamma amino-butyric acid (GABA); 2) reduction of excitatory
transmission; and 3) modulation of membrane cation
conductance. Pharmacotherapy strategies should be designed
based on the decision when to start treatment, choice of the
appropriate AED, and proper AED monitoring and adjustment.
Information is presented for the current AEDs of choice,
phenobarbital and bromide. Additional guidelines are provided for
administration of newer AEDs, felbamate and gabapentm. All
owners should be aware that emergency therapy may be
necessary if recurrent or severe seizures occur in their pet. A
rapid, reliable protocol is presented for the emergency
management of se~zuring cats and dogs in the hospital and at
home. Home treatment with per rectal administration of diazepam
m the dog has proven to be an effective means of reducing seizure
frequency and owner anxiety. Treating each animal as an
individual, applying the philosophy that seizure prevention is
better than intervention, and consulting specialists to help
formulate or revise treatment plans will lead to improved success
in treating seizure disorders in the cat and dog.
Copyright © 1998 by W.B. Saunders Company
he treatment of seizure disorders in small animals is
T similar in many respects to the treatment of various other
ailments in veterinary medicine: an antecedent historical
From the College of Veterinary Medicine, Ohio State University, Colum-
bus, OH.
Address repnnt requests to Michael Podell MSc, DVM, Diplomate
ACVIM (Neurology), Director, Comparative Neurology Service, Associate
Professor, Department of Vetennary Clinical Sciences, College of Veteri-
nary Medicine, Member of the Comprehensive Cancer Center, The James
Hospital, College of Medicine, The Ohio State UnlversW, 601 Tharp
Street, Columbus, OH 43210.
Copyright © 1998 by W.B. Saunders Company
1071-0949/98/1303-000858 00/0
Clinical Techniques in Small Animal Practice, Vol 13, No 3 (August), 1998 pp 185-192
problem arises, a proper diagnosis is made to confirm the
condition, and therapy is imtiated to treat the underlying
disease and/or signs of the disease. Important differences arise,
however, when approaching antiepileptic drug (AED) therapy
in the cat and dog. First, a specific underlying etiology is often
not identified. The clinician commonly makes a therapeutic
decision based on second-hand historical accounts alone.
Treatment is initiated when the animal is typically in a normal
physical state, with little ability to predict frequency of future
seizure recurrence. Complicating this issue, there is a limited
range of effective AEDs from which to choose. Even after
initiation of therapy, the odds of complete cessation of seizure
activity in the patient are stacked against the clinician. Finally,
all therapeutic modalities carry some risk of altering the
behavior and/or physiology of the patient. Thus, it is not
surprising that AED therapy in small ammal medicine remains
a frustrating problem for all clinicians that treat epileptic
animals.
This article is designed to help clinicians understand the
variables for consideration prior to antiepileptic drug (AED)
commencement by presenting some of the fundamental factors
relevant to AED initiation and maintenance, followed by
specific guidelines of currently known information to treat
seizure disorders in the cat and dog. An outline of recom-
mended general strategies that will be discussed in this chapter
is provided in Table 1. The goal of this approach is to provide a
basis for future flexibility of treatment as newer drug therapies
are introduced to veterinarians.
Assessment of the Patient
Several levels of assessment are needed in managing an
epileptic patient including the diagnostic, effectiveness of
therapy, and health-related quality-of-hfe assessments. Three
levels of diagnosis are important in determining the appropri-
ate AED therapy. 1 First, ascertain that an epileptic seizure has
occurred, and if so, the seizure type(s) manifested. This
information is critical to prevent unnecessary treatment of
nonepileptic animals, and to choose the most effective AED for
that seizure type (see following). A complete descnpnon of
seizure types can be found in the article by Phihp A. March,
"Seizures: Classification, Etiologies, and Pathophysiology."
The second level of diagnosis is the seizure etiology. Primary
epileptic seizures (PES) are diagnosed if no underlying cause
for the seizure can be identified. While this term is often
reserved for inherited epilepsy in people, I prefer to include all
idiopathic epileptic seizures in this category, as the genetic
component of epilepsy is difficult to ascertain in many ani-
mals. 6 Secondary epileptic seizures (SES) are the direct result
of structural cerebral pathology. An animal is categorized as
having epilepsy if recurrent PES or SES are diagnosed, indicat-
ing the presence of a chronic brain disorder. Reactive epileptic
seizures (RES) are a reaction of the normal brain to transient
1 85
TABLE 1. General Strategies for Antiepileptic Drug Therapy
1. Be certain that an eptlepbc seizure has occurred
2. Identtfy the seizure ebology
3. Always treat the underlytng disease
4. Start anbepileptic drug therapy early in the course of disease
5. Start with the appropnate antieptlepbc drug therapy
6. Momtor serum antteplleptic drug concentrattons appropriately
7. Know when and how to adjust medication dose and type
8. Know how to identify and treat an emergency sltuabon
9. Seizure preventton is better than intervention
10. Consult a speciahst if your plan is not working
systemic insult or physiologic stresses. Thus, a patient with
recurring RES is not defined as having epilepsy, as there is not a
primary chronic brain disorder underlying the seizure activity.
In contrast, nonepileptic seizures are paroxysmal events with
severe consequences to the body but without any epileptic
electroencephalographic activity (eg, syncopal attacks). Proper
identification is important to allow initiation of proper primary
therapy to the underlying etiology. In particular, treatment of
RES may entail only correcting the underlying metabolic
disturbance, without further need for AED therapy. In certain
cases (eg, hepatic encephalopathy), starting certain types of
AED therapy may exacerbate the clinical signs of the disease.
The third level of diagnosis is determination of an epileptic
syndrome. An epileptic syndrome is a complex symptom, of
which the main feature is the occurrence of electroclinically
characteristic epileptic seizures. 4 Syndromes can also be catego-
rized as primary, secondary, or reactive. Identification of an
epileptic syndrome has distinct implications on therapeutic
prognosis in people. Epileptic syndromes are increasingly
being diagnosed in human medicine, but are still poorly
understood in veterinary medicine.
Therapeutic effectiveness assessment is important to deter-
mine if the current medication at a specific dose is helpful. The
ability to accurately determine all seizure events in our patients
is difficult, as many animals are left unobserved for many hours
of the day. However, the use of an "epilepsy monitoring"
calendar is extremely helpful to determine observed events,
and possible events, as noted by changes in the animal's
behavior, presence of urinations/defecations, or excessive sali-
vation, to correlate to last dose admmistered. Finding that an
animal is predilected to seizures only in early morning hours
prior to the first daily dose can be helpful to either increase the
frequency of the dosing, or differentially administer more
medication at the last evening dose.
Assessment of health-related quality-of-life is one of great
importance, but at times, overlooked. As veterinarians, we
should take into consideration not only the physical quality of
life of the patient, but also the mental and societal impact of the
pet's condition on the owner. Management of epilepsy in cats
and dogs often requires a lifetime commitment by owners.
These owners must be willing to medicate their pet multiple
times per day, travel to emergency clinics at unpredictable
times, follow-up with periodic reevaluations and diagnostic
testing, and watch their pet carefully for adverse effects of
therapy. The balance between quality-of-life and therapeutic
success is often a key issue for an owner to continue treating
their pet. Despite continuous financial and emotional commit-
ment, a significant portion (up to 40%) 7 of dogs, may still
continue to seizure. Thus, proper chent educatmn is critical in
preparing owners about their pet's condition and the potential
associated lifestyle changes.
186
Principles of Drug Therapy
Maintaining a seizure-free status without any unacceptable
adverse effects is the ultimate goal of AED therapy. This
balance is achieved in less than half of epileptic people, 8 and
probably, just as many dogs. 910 Prior to starting AED treat-
ment, owners and veterinarians should have a realistic expecta-
tion of what to expect over the course of therapy. First and
foremost is that seizure control does not equal elimination. A
decrease in the number of seizures, the severity of individual
seizures and postictal complicauons, while increasing the
interictal period is the realistic goal. Clients must be informed
that this may be a lifetime, daily treatment regimen, there will
be frequent reevaluations, and that there is a potential for
emergency situations to arise, along with the inherent risks of
the drug.
Monotherapy is the goal of treating any cat or dog with
epilepsy to reduce possible drug-drug interactions and adverse
effects. Several limitations exist in the selection of AEDs for use
in veterinary medicine: (1) toxicity; (2) tolerance; (3) Inappro-
priate pharmacokinetics; and (4) expense. 11 Unfortunately,
many of the AEDs useful in people cannot be prescribed to
small animals either due to inappropriate pharmacokinetics
(too rapid of an elimination), or potential hepatotoxicity. Thus,
the most commonly used AEDs in veterinary medicine are
from the same mechanistic category, that of enhancing inhibi-
non of the brain. Antiepilepuc drugs can be classified into
three broad mechanisnc categories~2: (1) reduction of excita-
tory transmission (Fig 1); (2) enhancement of inhibitory
processes via facilitated action of gamma amino-butyric acid
(GABA) (Fig 2); and (3) modulation of membrane cation
conductance (Fig 1).
Drugs that increase inhibitory neurotransmission will hyper-
polarize post-synaptic neuronal membranes, thus raising the
seizure threshold of this cell. The outcome is the ability to
Excitatory Nerve Terminal
)) l( ~ / , ~ Carbamazep,ne
presynaptlc neuron Phenytom
~ - N~+ , , _ ~ , ~ Valproate
Lamotngine
Gabapentm~
[[ depolarization ~ Felbamate?
glutamate
Felbamate?
glycme
Na+, Ca2+
Fig 1. Potential interaction sites of antiepileptic drugs at the
glutamate excitatory nerve terminal. Depolarization and sub-
sequent release of glutamate from the presynaptic terminal
requires sodium (Na+) influx. A variety of antiepileptic drugs
are listed which may inhibit sodium conductance, and thus
prevent depolarization and subsequent glutamate release.
Glutamate acts on the N-methyI-D-aspartate (NMDA) receptor
and is associated with cellular permeability of sodium (Na +)
and calcium (Ca 2+) in the post-synaptic terminal. Felbamate
may have be able to block the function of this receptor, and
thus prevent post-synaptic depolarization.
PODELL
 Inhibitory Nerve Terminal and frequency, and diagnostic evaluation. In general, AED
presynaptlc neuron glutamate
therapy should be started early in the course of disease. I
ron/~ IGAD~ recommend that monotherapy should be started in the cat or
dog in the following situations: (1) an identifiable structural
etiology is present; (2) status epilepticus has occurred; (3) two
or more isolated seizures occur within a &week period; (4) two
or more cluster seizure episodes occur within an 8-week
period; and (5) if the first seizure was within 1 week of trauma.
A log should be kept by the owner to document observed
seizures and record problems to provide an objective method
of the benefit of therapy.
Choose the appropriate antiepileptic drug. Selection of the
appropriate AED is based on the pharmacokinetic properties of
that drug, the efficacy (potency of the drug plus the spectrum
/ postsynaptlc neuron
of seizure types treated), and the adverse effects. Limited
information is available about the pharmacokinetic properties
Fig 2. Potential interaction sites of antiepileptic drugs at the
GABA inhibitory nerve terminal. GABA is synthesized from in the cat and dog of many of the available AED drugs.
glutamate in the presynaptic terminal via the enzymatic Acceptable criteria of an AED is one that can be given two to
action of glutamic acid decarboxylase (GAD) and can be three times per day, has documentable efficacy, and is well-
metabolized by GABA aminotransferase (GABA-T) to form tolerated by the animal. Pharmacokinetic data of drugs that
succinic acid semialdehyde (SSA). Attachment of GABA,
phenobarbital, or benzodiazepines on the GABAA receptor may fit this description in the cat and dog are listed in Table 2.
will facilitate chloride (CI-) passage into the cell, creating a Ant~epileptic drug monitoring and adjustment. The goal of
state of cellular hyperpolarization. therapeutic drug monitoring is to manipulate a dose of drug
using serum concentrations as a guide to optimize efficacy,
avoid potential toxicity, determine if tolerance is present, and
prevent the spread of epileptic activity in the brain. The GABAa to detect poor compliance. The clinical uses of AED monitor-
receptor is associated with a permeable chloride ion channel ing are listed in Table 3. As noted, establishing a baseline
(Fig 2). Attachment of GABA, benzodiazepines, or phenobarbi- determination that the drug has achieved a steady-state thera-
tal (PB) will result in increased chloride permeability, and peutic concentration early after initiation of treatment is
subsequent membrane hyperpolarization. Drugs that increase critical for decision making if there is seizure recurrence.
the availability of GABA to the receptor by inhibition of Steady-state serum concentration is attained after five elimina-
degradation or reuptake pathways will also enhance inhibitory tion half-lives of an oral drug (Table 2). The therapeutic serum
neurotransmission. Examples of such drugs are tiaglbine and concentration range is a statistical estimate of minimum
vigabatrm. Bromide (BR) therapy is theorized to produce effectiveness of a drug (lower limit) and the maximal safety
synergistic inhibition with drugs that open the chloride (upper limit). It should be used as a guide only. Many variables
channel via GABA-receptor activation, such as phenobarbital. come into play in patient response, including age, underlying
The close physical and tonic properties of BR to chloride allow disease, concurrent medications, and individual metabolism
BR to flood chloride channels when high concentrations are differences. In general, trough serum concentrations should be
achieved in the extracellular fluid of the brain. The net result is measured when there is poor seizure control to determine if an
a lower resting membrane potential, thus producing a higher inadequate dose is being given, and peak concentrations
seizure threshold. measured when there is a concern of drug toxicity.
Reduction of excitatory neurotransmission can be accom- If an animal continues to seizure with a previously docu-
plished by altering glutamate-mediated neurotransmission mented serum therapeutic concentration, several possibilities
(Fig 1). The classic mechanism of action of past AEDs was
sodium-channel blockade to prevent depolarization of the
presynaptic neuronal membrane, and thus, reduced release of TABLE 2. Antiepileptic Drug Pharmacokinetic Data
the excitatory neurotransmitter, glutamate. Glutamate attaches
to the N-methyl-D-aspartate (NMDA) receptor, which opens Time to Achteve
Volume of Mean Steady-State
sodium and calcium membranes channels, leading to postsyn- Distnbutton Ehmination Concentratton
aptlc depolarization. Many AEDs that work directly at the Route (L/kg) Half-hfe (days)
sodium membrane ionic level to prevent neuronal depolariza- Cat
tion cannot be used in veterinary medicine due to either a high Phenobarbtta129,32 IV 07 43 hrs NA
risk of toxicity or too rapid of an elimination half-life. PO 09 58 hrs 9
Diazepam 33 IV 1.7 to 2.0 21 hrs* NA
Phenytoin (DILANTIN) is the classic example, m that less than
PO 20 hrs* 4
2% of dogs studied were well-controlled, compared with 48% Bromide2834 PO 0.3 11to21days 56to105
and 52% of dogs on PB and primidone, respectively, ~3 Newer Dog
drugs that may be effective to reduce post-synaptic excitation Phenobarbital 16 IV 0.7 92 hrs NA
PO 07 24t0 47 hrs 10
are felbamate and gabapentin. Dtazepam35 IV 1.8 4 6 hrs* NA
Clorazepate36 PO 1.6 5 9 hrs 1
Bromide 37 PO 0.3 25 to 46 days 83 to 120
Strategies of AED Pharmacotherapy Felbamate25 PO 1.0 5.9 hrs 1
Gabapentin38 PO 9 2.2 hrs <1
Deciding when to start treatment. The decision to initiate
AED therapy is based on the underlying etiology, seizure type *Total benzodiazepmeehmmation; NA = not apphcable.

ANTIEPILEPTIC DRUG THERAPY 1 87


TABLE 3. Clinical Uses of Antiepileptic Drug Monitoring
1. Estabhsh basehne measurements m newly treated pattents
2. Titrate dose to achteve better effectiveness m seizuring patients
3. Determine presence of hepattc enzyme auto-induction that will reduce
serum concentration
4. Opttmtze treatment with multiple anttepflepttc drug therapy
5. Determine presence of drug-drug interactions
6 Determine if toxtc effects are drug related
7 Detectton of poor owner or patient compliance
8. Evaluate tf changes Jn hepatic or renal functton are altenng serum
antiepilept~c drug concentrattons
may exist. First, and probably the most common situation, is
that tolerance, or the loss of effectiveness, may be present (Fig
3). A positive, acquired drug tolerance can either be metabolic
or functional in nature. With metabolic tolerance, more drug is
progressively needed to maintain the same therapeutic serum
concentration. This condition occurs with induction of hepatic
microsomal enzymes by the drug itself (autoinduction), or by
concurrent drug therapy. A second consideration is the occur-
rence of poor owner or patient compliance. A reduction in the
trough serum concentranon of 20% or more is suggestive of a
compliance problem. Either the owner is not administering the
drug, or the animal is not swallowing the full dose. A third
potential problem is the existence of drug-drug interactions.
Drugs that induce the hepatic microsomal enzymes will
increase the elimination half-life of the AED, thus lowering the
serum concentration at that set dose. This situation typically
occurs when multiple AED therapy is instituted. Examples of
enzyme-inducing AEDs include PB, primidone, phenytoin,
felbamate, and valproic acid. Cellular adaptations have oc-
curred to prevent full efficacy of the drug in functional
tolerance.
After determining the serum concentration (trough or
peak), the clinician should then make the proper correction.
Adjustments of the serum concentration can be calculated with
I ACQUIRED [
- - DOSE
- - [SERUM]
IoTABOLI I tase (ALP)37 These changes can occur as quickly as 2 weeks
REGULATION
OF
RECEPTORS
_._.J.
I
ENZYME REGULATION.DEUSED P R O G ~ S S ~ON
] one is that with time, physical dependence of the drug does
INDUCTION TOLERANCE~ OF DELIVERY OF DISEASE ]
It
Fig 3. Algorithm of acquired drug tolerance, or loss of
effectiveness. Negative acquired tolerance is usually the
result of denervation supersensitivity, a rare o c c u r r e n c e with
antiepileptic drug therapy. Positive tolerance can either be
metabolic or functional in nature. With metabolic tolerance,
there is not a parallel increase in serum concentration as the
drug dose increases. This scenario is typically due to auto-
induction of the p450 hepatic enzymes. In contrast, with
functional tolerance, there is a parallel increase in serum
concentration as the drug dose is increased. The lack of
response can now be due to down regulation of receptors in
the brain, decreased drug delivery through the blood brain-
barrier (BBB), actual disease progression, or a combination
of these factors.
188
the following formula:
Desired concentrauon
× Current # mg AED per day
Actual concentration
= New total # m g AED per day
The total dose can then be divided as needed. This formula can
be used for multiple-dosing oral drugs with hnear pharmacoki-
netic parameters (eg, PB), but not with drugs such as BR that
do not possess such properties.
Specific Antiepileptic Drug Therapy in the Dog
Phenobarbital. A phenyl barbiturate, PB has the longest
history of chronic use of all AEDs in veterinary medicine. The
major reasons for this fact are that PB is a relatively inexpen-
sive, well-tolerated drug that can be administered two to three
times per day with well-documented success to prevent
seizures in cats and dogs. I3-15 Phenobarbital has a high
bioavailability, being rapidly absorbed within 2 hours with a
maximal plasma concentration obtained within 4 to 8 hours
after oral administration. 16 Almost one-half of the drug is
protein bound. The majority of PB is metabolized by the liver
with approximately one-third excreted unchanged in the urine.
PB is an auto-inducer of hepatic microsomal enzymes (p450
system) which can progressively reduce the elimination half-
life with chronic dosing. PB should be given initially at least
every 12 hours at a dose of 2.5 mg/kg per dose with subsequent
increases in dosing most likely within 30 days to maintain a
trough therapeutic serum concentration between 20 to
40 lag/mE
Overall, PB is well tolerated at therapeutic serum concentra-
tions in the dog. Idiosyncratm drug reactions to PB are usually
associated with unusual behavioral changes after starting the
drug. Hyperexcitability, restlessness or excessive sedation are
infrequent problems that appear not to be dose-related which
will resolve typically within 1 week of starting the treatment.
Historical chronic adverse effects usually revolve around
polydipsic and polyphagic behavior. As a result, dogs may
develop psychogenic polydipsia with associated polyuria. The
most common clinical laboratory change associated with
chronic PB therapy is an elevation of serum alkaline phospha-
after therapy. Neither endogenous adrenocortlcotrophlc hor-
mone (ACTH) nor exogenous response to ACTH is altered by
PB dosing, m Three serious and potentially life-threatening
complications can occur with long-term PB therapy. The first
develop. Withdrawal seizures can develop as serum PB concen-
trations decline between 15 to 20 pg/mL. The second serious
problem associated with chronic PB therapy is the develop-
ment of functional tolerance to the drug (Fig 3). The last, and
potentially, most life-threatening adverse effect of chronic AED
therapy is drug-induced hepatotoxicity. Hepatotoxicity to
primldone (which is metabolized predominantly to PB) either
alone or in combination with other AEDs, has been shown to
occur in experimental and clinical conditions in dogs. 17'19
Documentation of a serum PB concentration above 35 lag/mL
carries the highest associauon with the development of hepato-
toxicity.2°
Drug-drug interactions are prominent with PB treatment
due to its relatively high protein binding and primary hepauc
PODELL
metabolism. In the blood, PB is distributed throughout the
body in an unbound or protein-bound state. The unbound
fraction is the component which enters through the blood-
brain barrier. Therefore, an increase m the unbound portion
will increase the total amount of PB concentration in the brain.
Concomitant administration of drugs that are highly protein
bound will competitively displace PB from its protein bound
state to an unbound state. Examples include all nonsteroidal
antiinflammatory drugs (eg, aspirin) and digoxin. The net
result can be excessive sedation, ataxia, and/or weakness from
high PB concentration in the brain. Measuring bound serum
PB concentration may actually be lower than prior time points.
Another potential mechanism to increase circulating PB concen-
tration, and thus produce excessive sedation, is concurrent
administration of drugs that inhibit the p450 system, such as
chloramphenicol and cimetidine. Conversely, drugs that in-
duce the p450 system will lead to a state of metabolic tolerance,
lowering serum PB concentration. Moreover, prolonged admin-
istration of such drugs may predispose the animal to drug-
induced hepatotoxicity in addition to poor seizure control
from lower AED concentrations.
I recommend that trough serum PB concentrations be
measured at 14, 45, 90, 180, and 360 days after the initiation of
treatment, at 6-month intervals thereafter, and if a dog has
more than two seizure events between these times. Dosage
adjustments can be made with the formula provided above.
Overall, PB is an AED that can provide excellent seizure
control in primary epileptic dogs with careful serial monitoring
of trough serum drug concentrations.
Bromide. The recommended add-on AED of choice today
in the dog is BR. Concomitant BR and PB decreased seizure
numbers and severity in the majority of dogs in two studies,
with seizure-free status ranging from 21% to 26% of all dogs
treated. 2~,22 In general, all canine refractory idiopathm epilep-
tics may benefit from BR despite prior seizure history onset or
duration. By allowing a reduction of the use of drugs metabo-
lized by the liver, BR therapy may also reduce the incidence of
hepatotoxicity.
Bromide is administered as the inorganic salt, potassium
bromide, as a 200 mg/mL solution dissolved in doubled
distilled water (Table 4). Sodium bromide should be used if a
state of adrenal insufficiency (Addison's disease) or renal
disease exists that may prevent normal potassium homeostasis.
Otherwise, there is no advantage to the use of oral sodium
bromide. Through retrospective studies, the therapeutic range
of BR has been established in dogs on concurrent PB to be
approximately 100 to 200 mg/dL (1.0 to 2.0 mg/mL). Using
only trough level measurements is recommended to maintain
uniformity of comparison and to avoid peak serum concentra-
tions just after oral administration. My ultimate goal is to
achieve a steady-state trough serum concentrations of 25
lag/mL and 150 to 200 mg/dL for PB and BR, respectively.
Further reductions in PB can be attempted if a seizure-free
period is maintained for 6 months. Dogs treated with subse-
quent monotherapy BR should have BR concentrations above
250 mg/dL (2.5 mg/mL), and preferably closer to 300 mg/dL
(3.0 mg/mL), for optimal seizure control. Gradual increases in
dose of 100 to 200 mg per week allow for better adaptation to
the drug. In general, the upper therapeutic limit of BR is
dictated more by the individual animal's ability to tolerate
ANTIEPILEPTIC DRUG THERAPY
adverse effects. The most common adverse effects seen with
combination BR and PB therapy are polydipsia, polyphagia,
increased lethargy, ataxia, and caudal limb paresis with increas-
ing serum concentration. The mechanism of the weakness and
ataxia has not been elucidated, but is thought to be centrally
mediated. Bromide intoxication to the point of stupor is rare,
especially with close monitoring of serum concentrations.
Therapy of BR intoxication consists of IV normal saline
administration to enhance BR renal excretion. Careful monitor-
ing is advised as dogs may become more susceptible to seizure
actiwty with lowering of the BR serum concentration.
Benzodiazepines. Dlazepam in the dog is best used for the
treatment of emergency seizures by intravenous and per rectal
administration (see below). Chronic oral administration of
diazepam is not recommended due to the lack of effectiveness
to stop seizures, the very short half-life, potential for increased
hepatic enzyme induction, physical dependence, and cross-
tolerance to prevent effective use of intravenous diazepam to
stop emergency seizures. A long-acting benzodiazepine, cloraz-
epate, is a diazepam pro-drug with more suitable pharmacoki-
netic properties for chronic use in the dog, especially as an
initial drug to treat complex partial seizures (Table 2). How-
ever, similar problems may arise as with chronic oral diazepam,
especially the potential for severe seizure activity upon rapid
drug withdrawal. 23
Felbamate. Felbamate (FELBATOL) is a dicarbamate with
proven ability to block seizures induced by a variety of
methods in laboratory animal models. 24 Felbamate is believed
to increase seizure threshold and prevent seizure spreading by
reducing excitatory neurotransmission in the brain Neuropro-
tective effects have also been shown through this ability to alter
excitatory neurotransmission. In clinical trials in people,
felbamate has been shown to be most useful as monotherapy in
the treatment of uncontrolled partial epilepsy. The drug is
metabolized by the hepatic microsomal p450 enzymes and is
increased in younger dogs. 25 In dogs, the drug has a high
bioavailability and protein binding capability. The elimination
half-life of 6 hours is relatively short (Table 2), with steady
state concentrations reached after 1 day. I have seen the most
success in using felbamate to control dogs with initial complex
partial seizures, but have seen improved seizure control in dogs
with generalized seizures refractory to prior PB and BR therapy.
For these dogs, my goal is to replace the PB with felbamate
therapy while maintaining BR serum concentrations above 300
Dg/mL to reduce potential drug-drug interaction and hepatotox-
icity. My recommended starting dose is 20 mg/kg orally three
times per day. Liver function should be momtored periodically,
especially when the total dose is above 3,000 mg per day.
Measurement of active drug metabolites is expensive, and is
often poorly correlated with seizure control. Felbamate is a
nonsedating drug, but has been reported with a higher
incidence of aplastic anemia and liver toxicity in people.
Higher doses can cause anxiousness, inappetence, and other
personality changes. Expense and limited availability may
reduce the usefulness of this AED in veterinary medicine.
Gabapentin. Gabapentln (NEURONTIN) is an interesting
new AED whose mechanism of action is still not fully
understood. Initially designed to mimic GABA in the brain,
gabapentin can readily pass through the blood-brain barrier.
Once in the brain, however, gabapentin does not mimic the
189
 TABLE 4. Summary of Antiepileptic Drug Therapy in the Dog
Drug Indications
Phenobarbital oldentification of a structural
lesion
oStatus epileptlcus
oTwo or more isolated seizures
within an 6-week period
oTwo or more cluster seizures
episodes within a 8-week
period
oThe first observed seizure is
within a week of head trauma
oProlonged, severe, or unusual
postictal penods
Potassium oPersistent seizure activity with
bromide steady state trough serum
phenobarbital concentration
>30 IJg/mL for at least one
month
oHepatotoxlcity from phenobar-
bital or primary hepatic dis-
ease
oSevere cluster seizures
Felbamate oComplex partial seizures
oRefractory to phenobarbital
and bromide therapy
Clorazepate oComplex partial seizures
oRefractory to phenobarbital
and bromide therapy
Gabapentm oComplex partial seizures
oRefractory to phenobarbital
and bromide therapy
Diazepam per oGeneralizedclustereplleptlc
rectum seizures
oStatus eplleptlcus
Administration
Initial oral dose: 2.5 mg/kg PO
BID
IV loading dose: Total mg IV :
(Body weight [kg] × (0.8
L/kg) x (25 IJg/mL)
Potassium bromide dissolved in
double dlstdled water as 200
mg/mL solution
Dose: 30 mg/kg/day orally in
food as initial dose
20 mg/kg PO TID as initial
dose
2 mg/kg PO BID
Initial dose: 100-300 mg PO
TID.
Increase: Up to 1,200 mg PO
TID over 4 weeks
On phenobarbital" 2 mg/kg per
rectum of diazepam parental
solution (5 mg/mL)
Off phenobarbital: 1 mg/kg
Administer at the onset of a sei-
zure up to three times in 24
hours
Monitoring Potential Adverse Effects
oMeasure trough serum pheno- oTranslent: lethargy, behavior
barbital change
oTherapeutlc range is between oPersistent Polyuna, poly-
20-40 IJg/mL dlpsla, polyphagia, weight
oEvaluate serum chemistry gain, excessive sedation
panel at 45 days and every 6 oSevere: hepatotoxicity
months
oMeasure trough serum con- Lethargy
centrat~ons 30 days, 120 days Polydipsla
and every 6 months after initia- Polyuria
t~on. Pancreatitis
oOptJmal therapeutic range is Atax~a
100-200 mg/dL (1.0-2.0 Stupor
mg/mL) with concurrent phe-
nobarbital (25-30 pg/mL).
oUpper therapeutic limits dic-
tated by adverse effects
oMonotherapy: >-300 mg/dL
(3.0 mg/mL)
oNo actwe drug metabohtes are Hep~otoxlclty (people)
commercially measurable Aplastlc anemia (people)
oMonitor complete blood counts Inappetence
every 6-12 weeks to check for Anxiousness
bone marrow suppression
oMonitor liver enzymes every
6-12 weeks to check for hepa-
totoxiclty
oMonitor nordlazepam concen- As for phenobarbital;
trations at 10, 30 days and Withdrawal seizures may occur
every 6 months. with abrupt stoppage of
oEvaluate serum chemistry dosing
panel at 45 days and every 6
months
No actwe drug metabolites are Sedation
commercially measurable No organ toxicity reported
Instruct owners to stay with pet Sedation
for 1 hour post-administration

pharmacologic properties of GABA, nor does it bind to GABA
receptors. In laboratory animals, gabapentin does effectively
block seizures induced by a variety of proconvulsant methods.
New evidence suggests that gabapentin may facilitate the
extracellular transport of GABA out of cells to act on the
GABAA receptor. 26 The dog is the only known species to
partially biotransform the drug to N-methyl-gababpentin. A
major benefit of the drug is that the parent and metabolite
drugs are excreted renally, thus it will not induce drug-drug
interacuons with other AEDs with hepatic metabolism (eg,
PB). At this time, clinical trials in people have shown gabapen-
tin to be most useful as an add-on therapy in the treatment of
medically refractory partial and generalized seizures. Dosing
every 6 hours in the dog may be necessary due to the rapid
elimination half-life (Table 2). Lower starting doses are recom-
mended to avoid excessive sedation. Reduced doses are needed
in patients with renal insufficiency. Serum monitoring is not
recommended, as the drug has a very high therapeutic index,
little drug-drug interactions, and is expensive.
Specific Antiepileptic Drug Therapy in the Cat
Phenobarbital. As in the dog, PB is the recommended first
line AED in the epileptic cat (Table 5). I5 The pharmacokinetlc
properties are similar to that in the dog; however, the cat is
more sensitive to the sedative effects and eliminates the drug
slower (Table 2). Thus, the therapeutic range is lower, typically
between 10 to 30 pg/mL and dosing is highly individualized.
Most cats can be treated with 7.5 mg orally twice daily, with
subsequent increases in the evening close to avoid excessive
daytime sedation. Idiosyncratic reactions include blood dyscra-
sia, dermatitis, and persistent, unusual behavior disturbances.
Predictable, dose-dependent adverse effects include polydip-
sia, polyuria, polyphagia. More severe problems may include
hepatotoxicity and coagulopathy. Overall, PB can be used
successfully in the cat with proper monitoring, as described for
the dog.
Benzodiazepines. Diazepam is recommended for cats refrac-
tory to PB as an alternative, but not concomitant, AED. The

190 PODELL
 TABLE 5. Summary of Antiepileptic Drug Therapy in the Cat
Drug Indications Administration Monltonng Potential Adverse Effects

Phenobarbital Identification of a structural
lesion
Status epdept~cus
Two or more isolated seizures
within a 6-week period
Two or more cluster seizures
episodes within an 8-week
penod
The first observed seizure Is
within a week of head trauma
Prolonged, severe, or unusual
postqctal penods
Potassium Persistent seizure activity with
bromide steady state trough serum
phenobarbital concentrahon
>20 pg/mL for at least one
month
Hepatotox~c~tyfrom phenobar-
Nta] or primary hepahc dis-
ease
Severe cluster seizures
Poor toleration of adverse
effects of phenobarbital
Diazepam IV: Generahzed cluster epileptic
seizures
Status epdeptlcus
PO. Maintenance treatment as
for phenobarbital therapy
Clorazepate Maintenance treatment as for
phenobarbital therapy
Inihal oral dose: 2.5-5 mg/kg PO
dally (once to BID)
IV loading dose: Total mg IV =
(Body weight [kg] × (0.9
L/kg) × (15 p/mL)
Potassmm bromide in capsule
formulation at 100 mg per
capsule
Dose: 20-30 mg/kg/day orally
with food as initial dose
IV: 0.5 mg/kg
PO: 0.5 to 2.0 mg/kg PO BID to
TID
3.75 to 7 5 mg PO QD-BID
Measure trough serum pheno- Transient: lethargy, behavior
barbital change
Therapeutic range is between Persistent: Polyuna, polydlpsia,
10-30 pg/mL polyphagia, weight gain
Evaluate serum chemistry panel excessive sedation
at 45 days and every 6 Severe: hepatotox~c~ty
months
Measure trough serum concen- Lethargy
trations 21 days, 90 days and Polydlpsla
every 6 months after initiation Polyuria
Therapeutic range: 100-200 Pancreat~hs
mg/dL (1.0-2.0 mg/mL) with Atax~a
concurrent phenobarbital; Stupor
>200 mg/dL (2.0 mg/mL) as
sole therapy
Plasma nordiazepam concen- Lethargy and sedation
tration can be measured but Polydipsia
rapid elimination half-hfe Polyuria
makes ~nterpretafion dafficult Polyphag~a
Liver enzymes changes should Weight gain
be monitored at 7, 14, 45 Idiosyncratic hepatotoxiclty
days after start and every 6
months to evaluate for hepa-
totoxicity
As for diazepam As for dJazepam

dose range is 0.5 to 2.0 mg/kg two to three times per day.
Gradual adaptation is necessary to prevent excess sedation.
Potential complications include similar behavior problems as
described for PB therapy, physical dependence, possible with-
drawal seizure activity, and acute fulminant hepatic necrosis.
The latter problem is an idiosyncratic reaction that can be
fatal. 27 Therefore, all cats treated with diazepam should have
liver enzymes monitored within the first week of therapy and
again within one month. Diazepam is metabolized to the active
metabolites, nordlazepam and oxazepam. Trough serum nordi-
azepam concentration should be in the therapeutic range of
200 to 500 ng/mL.
Cats with partial seizure activity only may be treated
successfully with a long-acting benzodiazepine, clorazepate.
Although the precise pharmacokInetic properties of this drug
are not well-described in the cat, I have had success in
controlling partial seizure activity in cats at a dose range of
3.75 to 7.5 mg orally once to twice daily. Similar precautions
are necessary as with diazepam.
Bromide. Potassium BR use in the cat is now receiving
more attention after the successful reports of its use in the dog.
At an oral daily dose of 30 mg/kg, steady-state concentration is
achieved between 8 to 15 weeks in the cat 34 (Table 2). Both
sodium and potassium BR are well-tolerated with chronic
administration. Capsule formulation (50 to 100 mg per cap-
sule) is the easiest method of administration. I recommend the
use of BR as the first add-on medication to cats refractory to PB
therapy. Trough serum concentrations should be monitored at
30 and 60 days and then every 6 months, or earlier if seizure
frequency increases or signs of toxicity occur.
Emergency Therapy
Hospital Emergency Treatmentfor Seizures
A rapid, reliable protocol is necessary for the emergency
management of seizuring cats and dogs. The physiologic
sequelae of frequent or continuous seizure activity (status
epilepticus) leading to increased intracranial pressure and
neuronal necrosis include systemic arterial hypertension, loss
of cerebrovascular regulation, disruption of the blood-brain
barrier and cerebral edema. Animals should be considered to
require emergency evaluation and possible therapy if any of the
following conditions is present: (1) a single seizure persists for
greater than 5 minutes; (2) status epilepticus, defined as a state
of continuous seizure activity lasting longer than 30 minutes or
repeated seizures with impaired consciousness if the recur-
rence rate does permit a return of consciousness; (3) more than
one seizure per hour, regardless of seizure length; and (4) three
or more seizures per day, regardless of seizure length.
The main AEDs for emergency seizure treatment are benzo-
diazepines and barbiturates. Diazepam (0.5 mg/kg IV bolus)
rapidly achieves effective drug concentrations in the brain, and
should be the first line of therapy to stop seizure activity. As an
emergency AED, PB has the dual advantage of achieving high
serum concentrations and reducing cerebral metabolic rate
following intravenous (IV) dosing. Intravenous PB is rapidly
distributed in the cat and dog. -~9,3°These facts translate into PB
providing a rapid, high drug concentration to stop seizures
while serving as a cerebral protectant. Tables 4 and 5 provide
formulae for calculation of a loading IV dose of PB to achieve a

ANTIEPILEPTIC DRUG THERAPY 191

therapeutic serum concentration in the dog and cat. More
detailed protocols have been published.1
At Home Emergency Treatmentfor Seizures
Financial and emotional constraints of recurrent emergency
therapy are often the limiting factor in an owner's decision to
continue treating their pet. A safe, affordable home treatment
for cluster seizures would reduce owner cost, decrease patient
morbidity, and contribute positively to the overall AED therapy,
Per rectal (PR) diazepam administration by owners of dogs
with primary epilepsy and generalized cluster seizures was
associated with a significant decrease in the number of cluster
seizure events in a 24-hour period, and a decrease in the total
number of seizure events when compared to an identical time
period without such therapy. 31 As a consequence of this
change, there was a significant decrease in the total cost in
emergency care per dog, compared with a similar time period
prior to the onset of use of PR diazepam. Recent pharmacoki-
netic studies of PR diazepam in normal dogs in our laboratory
demonstrated that chronic PB therapy in the dog reduces total
benzodiazepine concentration after IV and PR administration
presumably due to increased hepatic clearance of diazepam
and/or its metabolites oxazepam and nordiazepam. Administra-
tion of diazepam PR at 2 mg/kg proved to achieve effective
plasma benzodiazepine concentrations above 300 lJg/L in dogs
on chronic PB with minimal adverse effects. This dose can be
given up to three times in a 24-hour period, but should not be
given within 10 minutes of a prior dose. No information is
reported for rectal AED therapy in the cat.
Summary
Understanding the fundamental principles underlying AED
therapy will allow the clinician to adapt current knowledge to
future drug implementation. Specific recommendations have
been introduced to serve as guidelines for the currently
available AEDs. Treating each animal as an individual, applying
the philosophy that seizure prevention is better than interven-
tion, and consulting specialists to help formulate or revise
treatment plans will lead to improved success in treating
seizure disorders in the cat and dog.
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PODELL