micheal podell for epilepsy therapy

Antiepileptic Drug Therapy

M i c h a e l P o d e l l

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

T he treatment of seizure disorders in small animals is 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

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 recommended 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 appropriate 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 animals. 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

Clinical Techniques in Small Animal Practice, Vol 13, No 3 (August), 1998 pp 185-192 1 8 5

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 categorized 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 determine 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 commitment, 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.

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 treatment, 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 excitatory 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 +, Ca 2+

Fig 1. Potential interaction sites of antiepileptic drugs at the glutamate excitatory nerve terminal. Depolarization and subsequent 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.

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Inhibitory Nerve Terminal

presynaptlc neuron glutamate r o n / ~ IGAD ~

/ postsynaptlc neuron

Fig 2. Potential interaction sites of antiepileptic drugs at the GABA inhibitory nerve terminal. GABA is synthesized from glutamate in the presynaptic terminal via the enzymatic action of glutamic acid decarboxylase (GAD) and can be metabolized by GABA aminotransferase (GABA-T) to form succinic acid semialdehyde (SSA). Attachment of GABA, phenobarbital, or benzodiazepines on the GABAA receptor will facilitate chloride (CI-) passage into the cell, creating a state of cellular hyperpolarization.

prevent the spread of epileptic activity in the brain. The GABAa receptor is associated with a permeable chloride ion channel (Fig 2). Attachment of GABA, benzodiazepines, or phenobarbital (PB) will result in increased chloride permeability, and subsequent membrane hyperpolarization. Drugs that increase the availability of GABA to the receptor by inhibition of degradation or reuptake pathways will also enhance inhibitory neurotransmission. Examples of such drugs are tiaglbine and vigabatrm. Bromide (BR) therapy is theorized to produce synergistic inhibition with drugs that open the chloride channel via GABA-receptor activation, such as phenobarbital. The close physical and tonic properties of BR to chloride allow BR to flood chloride channels when high concentrations are achieved in the extracellular fluid of the brain. The net result is a lower resting membrane potential, thus producing a higher seizure threshold.

Reduction of excitatory neurotransmission can be accom- plished by altering glutamate-mediated neurotransmission (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 the excitatory neurotransmitter, glutamate. Glutamate attaches to the N-methyl-D-aspartate (NMDA) receptor, which opens sodium and calcium membranes channels, leading to postsynaptlc depolarization. Many AEDs that work directly at the sodium membrane ionic level to prevent neuronal depolarization cannot be used in veterinary medicine due to either a high risk of toxicity or too rapid of an elimination half-life. Phenytoin (DILANTIN) is the classic example, m that less than 2% of dogs studied were well-controlled, compared with 48% and 52% of dogs on PB and primidone, respectively, ~3 Newer drugs that may be effective to reduce post-synaptic excitation are felbamate and gabapentin.

Strategies of AED Pharmacotherapy Deciding when to start treatment. The decision to initiate

AED therapy is based on the underlying etiology, seizure type

and frequency, and diagnostic evaluation. In general, AED therapy should be started early in the course of disease. I 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 of seizure types treated), and the adverse effects. Limited information is available about the pharmacokinetic properties in the cat and dog of many of the available AED drugs. Acceptable criteria of an AED is one that can be given two to three times per day, has documentable efficacy, and is well- tolerated by the animal. Pharmacokinetic data of drugs that may fit this description in the cat and dog are listed in Table 2.

Ant~epileptic drug monitoring and adjustment. The goal of 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 to detect poor compliance. The clinical uses of AED monitoring are listed in Table 3. As noted, establishing a baseline determination that the drug has achieved a steady-state therapeutic concentration early after initiation of treatment is critical for decision making if there is seizure recurrence. Steady-state serum concentration is attained after five elimination half-lives of an oral drug (Table 2). The therapeutic serum concentration range is a statistical estimate of minimum effectiveness of a drug (lower limit) and the maximal safety (upper limit). It should be used as a guide only. Many variables come into play in patient response, including age, underlying disease, concurrent medications, and individual metabolism differences. In general, trough serum concentrations should be measured when there is poor seizure control to determine if an inadequate dose is being given, and peak concentrations measured when there is a concern of drug toxicity.

If an animal continues to seizure with a previously documented serum therapeutic concentration, several possibilities

TABLE 2. Antiepileptic Drug Pharmacokinetic Data

Time to Achteve Volume of Mean Steady-State Distnbutton Ehmination Concentratton

Route (L/kg) Half-hfe (days)

Cat Phenobarbtta129,32 IV 0 7 43 hrs NA

PO 0 9 58 hrs 9 IV 1.7 to 2.0 21 hrs* NA PO 20 hrs* 4 PO 0.3 11to21days 56to105

Diazepam 33

Bromide2834 Dog

Phenobarbital 16 IV 0.7 92 hrs NA PO 07 24t0 47 hrs 10

Dtazepam 35 IV 1.8 4 6 hrs* NA Clorazepate 36 PO 1.6 5 9 hrs 1 Bromide 37 PO 0.3 25 to 46 days 83 to 120 Felbamate 25 PO 1.0 5.9 hrs 1 Gabapentin 38 PO 9 2.2 hrs <1

*Total benzodiazepme ehmmation; NA = not apphcable.

ANTIEPILEPTIC DRUG THERAPY 1 8 7

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

the following formula:

Desired concentrauon

Actual concentration × Current # mg AED per day

= 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 pharmacokinetic parameters (eg, PB), but not with drugs such as BR that do not possess such properties.

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 occurrence 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 occurred 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

- - DOSE - - [SERUM]

I IoTABOLI I _._.J.

ENZYME INDUCTION

I ACQUIRED [

REGULATION. DEU SED TOLERANCE~ OF DELIVERY It

REGULATION OF

RECEPTORS

P R O G ~ S S ~ ] ON OF DISEASE ]

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 autoinduction 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.

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 concentrations 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- tase (ALP)37 These changes can occur as quickly as 2 weeks 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 one is that with time, physical dependence of the drug does develop. Withdrawal seizures can develop as serum PB concentrations decline between 15 to 20 pg/mL. The second serious problem associated with chronic PB therapy is the development 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 hepatotoxicity. 2°

Drug-drug interactions are prominent with PB treatment due to its relatively high protein binding and primary hepauc

1 8 8 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 concentration, and thus produce excessive sedation, is concurrent administration of drugs that inhibit the p450 system, such as chloramphenicol and cimetidine. Conversely, drugs that induce the p450 system will lead to a state of metabolic tolerance, lowering serum PB concentration. Moreover, prolonged administration 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 metabolized 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 concentrations 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 subsequent 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

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 increasing 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 monitoring 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, clorazepate, is a diazepam pro-drug with more suitable pharmacokinetic 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 hepatotoxicity. 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

ANTIEPILEPTIC DRUG THERAPY 189

TABLE 4. Summary of Antiepileptic Drug Therapy in the Dog

Drug Indications Administration Monitoring Potential Adverse Effects

Phenobarbital oldentification of a structural Initial oral dose: 2.5 mg/kg PO oMeasure trough serum pheno- oTranslent: lethargy, behavior lesion BID barbital change

oStatus epileptlcus IV loading dose: Total mg IV : oTherapeutlc range is between oPersistent Polyuna, poly- oTwo or more isolated seizures (Body weight [kg] × (0.8 20-40 IJg/mL dlpsla, polyphagia, weight

within an 6-week period L/kg) x (25 IJg/mL) oEvaluate serum chemistry gain, excessive sedation oTwo or more cluster seizures panel at 45 days and every 6 oSevere: hepatotoxicity

episodes within a 8-week months

Potassium bromide

period oThe first observed seizure is

within a week of head trauma oProlonged, severe, or unusual

postictal penods oPersistent seizure activity with

steady state trough serum phenobarbital concentration >30 IJg/mL for at least one month

oHepatotoxlcity from phenobarbital or primary hepatic disease

oSevere cluster seizures

Potassium bromide dissolved in double dlstdled water as 200 mg/mL solution

Dose: 30 mg/kg/day orally in food as initial dose

Felbamate oComplex partial seizures 20 mg/kg PO TID as initial oRefractory to phenobarbital dose

and bromide therapy

Clorazepate oComplex partial seizures 2 mg/kg PO BID oRefractory to phenobarbital

and bromide therapy

oComplex partial seizures oRefractory to phenobarbital

and bromide therapy

Gabapentm

Diazepam per oGeneralizedclustereplleptlc rectum seizures

oStatus eplleptlcus

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

oMeasure trough serum con- centrat~ons 30 days, 120 days and every 6 months after initia- t~on.

oOptJmal therapeutic range is 100-200 mg/dL (1.0-2.0 mg/mL) with concurrent phenobarbital (25-30 pg/mL).

oUpper therapeutic limits dictated by adverse effects

oMonotherapy: >-300 mg/dL (3.0 mg/mL)

oNo actwe drug metabohtes are commercially measurable

oMonitor complete blood counts every 6-12 weeks to check for bone marrow suppression

oMonitor liver enzymes every 6-12 weeks to check for hepatotoxiclty

oMonitor nordlazepam concentrations at 10, 30 days and every 6 months.

oEvaluate serum chemistry panel at 45 days and every 6 months

No actwe drug metabolites are commercially measurable

Instruct owners to stay with pet for 1 hour post-administration

Lethargy Polydipsla Polyuria Pancreatitis Atax~a Stupor

Hep~otoxlclty (people) Aplastlc anemia (people) Inappetence Anxiousness

As for phenobarbital; Withdrawal seizures may occur

with abrupt stoppage of dosing

Sedation No organ toxicity reported

Sedation

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 gabapentin 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 recommended 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 polydipsia, 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 refractory to PB as an alternative, but not concomitant, AED. The

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TABLE 5. Summary of Antiepileptic Drug Therapy in the Cat

Drug Indications Administration Monltonng Potential Adverse Effects

Phenobarbital Identification of a structural Inihal oral dose: 2.5-5 mg/kg PO Measure trough serum pheno- Transient: lethargy, behavior lesion dally (once to BID) barbital change

Status epdept~cus IV loading dose: Total mg IV = Therapeutic range is between Persistent: Polyuna, polydlpsia, Two or more isolated seizures (Body weight [kg] × (0.9 10-30 pg/mL polyphagia, weight gain

within a 6-week period L/kg) × (15 p/mL) Evaluate serum chemistry panel excessive sedation Two or more cluster seizures at 45 days and every 6 Severe: hepatotox~c~ty

episodes within an 8-week months

Potassium bromide

Diazepam

penod The first observed seizure Is

within a week of head trauma Prolonged, severe, or unusual

postqctal penods Persistent seizure activity with

steady state trough serum phenobarbital concentrahon >20 pg/mL for at least one month

Hepatotox~c~ty from phenobar- Nta] or primary hepahc disease

Severe cluster seizures Poor toleration of adverse

effects of phenobarbital IV: Generahzed cluster epileptic

seizures Status epdeptlcus PO. Maintenance treatment as

for phenobarbital therapy

Clorazepate Maintenance treatment as for phenobarbital therapy

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 concentrations 21 days, 90 days and every 6 months after initiation

Therapeutic range: 100-200 mg/dL (1.0-2.0 mg/mL) with concurrent phenobarbital; >200 mg/dL (2.0 mg/mL) as sole therapy

Plasma nordiazepam concentration can be measured but rapid elimination half-hfe makes ~nterpretafion dafficult

Liver enzymes changes should be monitored at 7, 14, 45 days after start and every 6 months to evaluate for hepatotoxicity

As for diazepam

Lethargy Polydlpsla Polyuria Pancreat~hs Atax~a Stupor

Lethargy and sedation Polydipsia Polyuria Polyphag~a Weight gain Idiosyncratic hepatotoxiclty

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 withdrawal 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 nordiazepam 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 capsule) 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.

E m e r g e n c y T h e r a p y

Hospital Emergency Treatment for 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 recurrence 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 benzodiazepines 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 Treatment for 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 pharmacokinetic 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 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.

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192 PODELL

micheal podell for epilepsy therapy

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