Epilepsy is a commonly encountered disorder in veterinary medicine that manifests as recurring epileptic seizures. Epilepsy can be the result of genetic changes that result in abnormal neuronal function, or the result of a physical abnormality in the brain such as a tumor or inflammation. Treatment revolves around controlling epileptic seizures, most often with antiseizure medications. Several antiseizure medications, such as bromide, levetiracetam, phenobarbital, and zonisamide, are used in veterinary medicine. The decision about which antiseizure medication to initiate in a patient will depend on clinician and client preferences.
Take-Home Points
- Treatment of epilepsy largely revolves around symptomatic therapy, with the goal of controlling epileptic seizures.
- Pharmacokinetics describes the body’s interaction with a medication, while pharmacodynamics describes the physiological effects of the medication.
- Understanding a medication’s clinical pharmacology can assist with choosing an appropriate medication based on the presentation of a patient with epilepsy.
- Therapeutic drug monitoring can serve as a powerful tool to help guide clinicians in treatment decision making.
Seizures are a common neurologic manifestation in veterinary medicine. Seizures are a clinical sign that results from abnormal electrical activity in the brain and should not be considered specific for any disease of the brain. As such, medications used to treat seizures are symptomatic in nature. Two general types of seizures are recognized:
- Epileptic seizures, where there is abnormal neuronal function that transiently manifests with seizures
- Reactive seizures, where neuronal function is considered normal but there is transient disturbance due to an exogenous cause (e.g., hypoglycemia).1 For reactive seizures, treating the underlying cause should lead to seizure cessation.
Epilepsy is commonly encountered in veterinary medicine, with an approximate prevalence of 0.7% in dogs.2,3 Epilepsy is not a single disease but a general term for a group of syndromes that manifest with recurrent epileptic seizures. Strictly speaking, in veterinary medicine, epilepsy has been defined as a predisposition of the brain to generate epileptic seizures and is typically applied to patients that have at least 2 unprovoked epileptic seizures separated by 24 hours (i.e., not in a cluster).1 Epilepsy can be broadly categorized as 1 of 2 forms:
- Idiopathic epilepsy, where no structural brain abnormality is appreciated. This form of epilepsy can be subcategorized as genetic epilepsy (where a gene known to cause epilepsy has been identified) or probable genetic epilepsy.
- Structural epilepsy, where a physical abnormality in the brain is detected (usually via advanced imaging) that is causing seizures
The 2 general forms of epilepsy can be subcategorized further based on the specific etiology (if it can be determined).
Therapeutic Goals
Ideally, the therapeutic goal of epilepsy is elimination of all seizures. However, this may not be possible. Guidelines outlining therapeutic outcomes in veterinary medicine have been published, in which a definition of therapeutic success is established.4 In veterinary medicine, the primary treatment goal is seizure freedom, defined as a tripling of the interictal period (the time period between singular seizures), and having this time period be at least 3 months. If seizure freedom cannot be achieved, the secondary goal is partial therapeutic success, which is defined as the prevention of cluster seizures (2 or more seizures in a 24-hour period), prevention of status epilepticus (a seizure lasting > 5 minutes), and a relevant reduction in seizure severity and frequency. Patients that do not meet these categories fall into the therapeutic failure category or may be classified into an unknown category. The latter category may be applied to patients for which insufficient time on a medication has elapsed to appreciate a change.
Clinical Pharmacology
Clinical pharmacology involves the study of the movement of drugs in the body (pharmacokinetics) as well as the effects of these drugs in the body (pharmacodynamics). Important drug-related factors that should be considered before use include clinician comfort, client comfort/goals, pharmacokinetic properties, evidence for therapeutic success, the availability of therapeutic drug monitoring, drug availability, cost, and adverse effects.
A drug’s reference interval is a range of concentrations in which a majority of a population treated for a specific disease with a specific drug should respond to. A therapeutic interval is the range of concentrations of a drug that an individual patient responds to. As such, it is the author’s opinion that if a patient responds to an antiseizure medication with a plasma drug concentration (PDC) that falls below the reported reference interval when measured at steady state, a dose increase is not yet necessary. Alternatively, patients with a PDC at steady state that fall within the reference interval—and that exhibit toxicity or unacceptable side effects due to the medication—require a dose decrease or drug discontinuation. Steady state is defined as the time point in which the rate of addition of drug into the system (the animal) equals the rate of elimination. In drugs with longer half-lives relative to the dosing interval, this should translate to a consistent concentration during the dosing interval (e.g., minimal fluctuation). However, in drugs with short half-lives relative to the dosing interval, there can be large fluctuations in PDC.
Commonly used antiseizure medications in dogs and cats in the United States include bromide, levetiracetam, phenobarbital, and zonisamide. Other medications used for treatment of seizures in dogs and cats include cannabidiol, gabapentin, and topiramate. Therapeutic drug monitoring can serve as an important tool to assist clinicians in therapeutic decision making. Measurement of PDC for antiseizure medications may help clinicians in dose adjustments, which may include either increases, if the clinical sign (seizure) is not appropriately controlled, or decreases, if adverse effects are unacceptable.
Therapeutic Drug Monitoring
Therapeutic drug monitoring allows quantification of a medication’s PDC. In general, drugs with longer half-lives relative to the dosing interval of administration (e.g., bromide, phenobarbital, zonisamide) will have less PDC fluctuation during the dosing interval. As such, a single sample at any time point of the dosing interval should suffice. In general, peak samples should be taken for drugs that have potential for toxicity. A peak sample is a sample collected at the time when drug concentration is anticipated to be highest. However, if the drug has a wide therapeutic window, then a trough sample may be sufficient. A trough sample is considered to be the sample taken immediately before the next dose.
Collection of a peak and a trough sample plays a more important role for drugs with shorter half-lives relative to the dosing interval. For example, levetiracetam immediate release (IR) has an approximate half-life of 3 hours and is administered every 8 hours. Therefore, there will be large fluctuations in PDC within the dosing interval, and the peak concentration will differ from the trough concentration in many patients. However, for medications with longer half-lives, such as bromide or phenobarbital, the half-life is much longer than the dosing interval. Thus, in many patients, a single time point is sufficient because the peak and trough concentrations are more likely to be similar. For drugs with short half-lives, both a peak and a trough sample should be collected so that a half-life can be calculated. This may help augment the treatment regimen if the patient is not controlled.
Antiseizure Medications
Bromide
Background and Pharmacokinetics
Bromide was introduced in 1857 and was the first medication specifically used to treat epileptic seizures in humans.5 Bromide is administered as a potassium salt (KBr). In January 2021, the U.S. Food and Drug Administration conditionally approved a bromide chewable product (KBroVet-CA1; PRN Pharmacal, kbrovet.com) for seizures in dogs with idiopathic epilepsy.6 The mechanism by which bromide exerts its antiseizure properties is not fully understood but is believed to be related to γ-aminobutyric acid (GABA) receptor activation.7 KBr is administered orally and has an absolute bioavailability of approximately 50%.8
Bromide is not metabolized in the body and is excreted unchanged in urine. This property may benefit patients with hepatic impairment. However, because of this, changes to diet or water intake can lead to changes in PDC due to similar mechanisms of renal elimination. If the salt (sodium chloride, but chloride specifically) content of the diet is increased while the bromide dose is kept fixed, an increase in bromide excretion may occur, leading to decreased bromide PDC. Alternatively, if the salt content of the diet is decreased while maintaining the same bromide dose, the bromide PDC may increase. The former may lead to loss of epileptic seizure control, while the latter may lead to adverse effects. This in turn can lead to increased adverse effects (if concentrations increase) or loss of seizure control (if concentrations decrease). Bromide has a long half-life that has been demonstrated to range from 12 to 45 days in dogs (but a rough estimate can be approximately 20 days).8,9 This long half-life means that steady state will be achieved after approximately 3 months in many dogs.
Dosing Regimen and Monitoring
Bromide can be used as monotherapy or as an adjuvant therapy. As a sole agent, serum bromide concentrations associated with epileptic seizure control range from 0.8 to 3.4 mg/mL. When bromide is used in combination with phenobarbital, the range of concentrations deemed to be effective is 0.8 to 2.5 mg/mL.10 Given its long half-life, a loading dose of 400 to 500 mg/kg divided over 5 days can be administered to increase PDC more rapidly. A starting dose of 30 to 40 mg/kg is recommended. Dose adjustments should be made based on seizure control status and PDC. Given the half-life of approximately 20 days, collecting a blood sample for bromide quantifications can be done as soon as 3 weeks. At this time point, PDC should be approximately 50% of steady-state concentrations. Alternatively, if the patient is controlled, collection of a blood sample for bromide quantification should be performed when the drug reaches steady state at approximately 3 months.
The long elimination half-life of bromide is beneficial in that it allows for a once-daily dosing schedule. This may be beneficial for clients who may not be able to administer medication more frequently. However, this long half-life also means that the time to steady state is long and can take up to 3 months. In patients that require a higher PDC sooner, a loading dose can be administered. However, unless the maintenance dose exactly matches the loading dose administered (which is dependent on individual patient pharmacokinetic parameters), steady-state concentration will still require approximately 3 months to be achieved, but the starting point may occur at a higher PDC.
Adverse Effects
Treatment with bromide can lead to sedation, ataxia, and polyphagia. Pancreatitis has been reported in patients receiving both bromide and phenobarbital, but a clear relationship has not been established.11 Bromide intoxication is referred to as bromism. In 1 study assessing adverse effects associated with bromide administration, various neurologic deficits were observed and related to either intracranial signs, spinal cord clinical signs, or diffuse lower motor neuron (LMN) disease.12 In this latter group, 2 dogs that displayed LMN disease also developed megaesophagus. The pharmacokinetics of bromide in cats have been studied, but the use of this drug in cats should be avoided due to their potential to develop severe respiratory signs secondary to lower airway disease that can be fatal.13,14
Phenobarbital
Background and Pharmacokinetics
The antiseizure properties of phenobarbital were discovered serendipitously when used for its sedative properties and published in the early 1900s.15 Since then, multiple studies assessing the pharmacokinetics in dogs have been performed.16-22 Both parenteral and oral formulations exist. Phenobarbital displays near-complete absorption following oral administration and readily distributes to the brain. Phenobarbital undergoes hepatic metabolism, such that decreases in liver function may lead to increased PDC. The half-life of phenobarbital is approximately 2 to 3 days in dogs and cats.23,24 These relatively long half-lives allow for a twice-daily dosing schedule to be implemented. Steady-state concentrations are achieved within 10 to 15 days.
It is important to note that phenobarbital can induce its own metabolism, sometimes referred to autoinduction.25 If this occurs, the half-life shortens, leading to larger fluctuations in PDC during the dosing interval, which can lead to poorer seizure control. This can be mitigated by increasing the dosing interval to every 8 hours.26 There is strong evidence supporting the efficacy of phenobarbital in veterinary medicine.27,28
Dosing Regimen and Monitoring
Phenobarbital is usually initiated at a dose of 2 to 3 mg/kg PO q12h in dogs and cats. A loading dose of 12 mg/kg (range, 10 to 16 mg/kg) can be given in emergency situations.7 However, administering this dose in fractions of 4 mg/kg q4-6h may prevent oversedation in patients. Dose adjustments are made based on therapeutic outcome or intolerable side effects or if PDC is above 35 µg/mL. Although the latter may warrant a conversation with the client about possible complications, if this concentration is effective at lower concentrations, or if other medications were not effective, then the dose can be maintained as is. The established reference interval for phenobarbital use in dogs is 15 to 45 µg/mL.29 However, there is concern that concentrations > 35 µg/mL may lead to an increased risk of hepatotoxicity30; therefore, the author attempts to maintain concentrations below this value.
Therapeutic drug monitoring should first be performed at steady state (10 to 15 days). Depending on patient status, measuring PDC at 6 weeks may be warranted due to the potential for autoinduction. Given the relatively long half-life, a single blood sample should suffice at any time point during the dosing interval in most patients. If a patient is failing therapy, it may be worth submitting both a peak (1 to 2 hours after administration of the pill) and a trough (immediately prior to drug administration) sample so that a half-life can be calculated. This might lead to an increased dosing frequency to minimize fluctuations in PDC during the dosing interval.
Adverse Effects
Expected side effects that may or may not be transient include sedation, proprioceptive ataxia, polydipsia, and polyphagia. These can improve with time but may be permanent. Other life-threatening adverse effects of phenobarbital in dogs and cats include blood dyscrasia affecting either 1 cell line (neutropenia), 2 cell lines (anemia and thrombocytopenia/neutropenia), or pancytopenia.31-33 Hepatotoxicity is also reported with phenobarbital and may occur at concentrations above 35 µg/mL.31 Superficial necrolytic dermatitis has been reported in dogs administered phenobarbital,34 and rare reports of pseudolymphoma associated with phenobarbital treatment also exist in the dog and cat.35,36
Levetiracetam
Background and Pharmacokinetics
Levetiracetam is unique in that its mechanism of action involves binding to synaptic vesicle glycoprotein 2A, a protein associated with neurotransmitter vesicle exocytosis. The pharmacokinetics of levetiracetam have been studied in both dogs37-40 and cats.41,42 In dogs, the intravenous, oral, intramuscular, and rectal routes have been studied, while in cats, only the intravenous and oral routes have been investigated. Oral levetiracetam formulations include IR and extended release (ER). The ER formulation is designed to provide a slower release of the drug into the gastrointestinal tract. As such, it is important that the integrity of the tablet is not disturbed in the process of swallowing (e.g., chewing, breaking to administer).
Levetiracetam shows near complete absorption via the oral route. The elimination half-life is approximately 3 to 4 hours in dogs and 3 hours in cats for IR formulations. The elimination half-life of ER levetiracetam has been demonstrated to be approximately 4 hours in dogs and cats. In humans, approximately two-thirds of the drug is excreted unchanged in urine, while the rest is metabolized via hydrolysis to inactive metabolites.43 Levetiracetam appears to be well tolerated in both dogs and cats.32,44 There is limited evidence regarding the efficacy of this medication in both dogs and cats. However, the use of 60 mg/kg of levetiracetam IV in dogs as an emergency dose may lead to shorter hospital stays in emergency settings.45 Furthermore, levetiracetam appears to be superior to phenobarbital for the control of a unique epileptic syndrome described in cats known as feline audiogenic reflex seizures46,47 and may be beneficial for dogs with myoclonic seizures.48 Given the limited information available on this medication, it may be better suited as an adjuvant therapy in many patients.
Dosing Regimen and Monitoring
Traditionally, levetiracetam is initiated at a dosage of 60 mg/kg/d administered as either q8h for the IR formulation or q12h for the ER formulation. However, given that the elimination half-life is shorter than the dosing interval, clinicians should expect large fluctuations in PDC over the dosing period. Indeed, the peak concentration produced by a dose may decrease by 50% to 90% by the time the next dose is administered. These fluctuations can lead to poor seizure control depending on the patient’s therapeutic interval. However, as long as the trough concentration is sufficient and adverse effects are not produced at the higher concentrations, the fluctuation may not be clinically relevant. Fluctuations can be mitigated by administration of this medication more frequently, but this may not be feasible from a client perspective.
A reference interval for levetiracetam in dogs and cats has not been established. However, the human interval of 5 to 45 µg/mL is often used to guide therapeutic decisions. When submitting samples for therapeutic drug monitoring, submitting both a peak sample (1 to 2 hours post administration) and a trough sample (immediately prior to drug administration) is recommended to allow for calculation of half-life, which helps with adjustments to dosing regimen. If a single sample is submitted, then a trough sample may be most useful given that levetiracetam has a wide safety margin.
Side Effects
Levetiracetam is well tolerated in dogs and cats even at high doses. However, some clients have reported sedation, ataxia, gastrointestinal-related signs, and behavioral-related changes following administration.32
Zonisamide
Background and Pharmacokinetics
Zonisamide is a newer-generation antiseizure medication popular in Japan.49 The mechanism of action is believed to be related to modulation of calcium ion channels50,51 and slow sodium channel inactivation.52 Zonisamide also has effects on dopamine receptors53 and releases GABA from the hippocampus.53,54 Only an oral formulation exists for zonisamide.
The pharmacokinetics of zonisamide have been described for oral,55,56 rectal,57,58 and intravenous56 routes in dogs. The bioavailability of zonisamide following oral administration is approximately 70%, and reported elimination half-life is approximately 16 hours. However, based on calculations of this parameter using peak and trough concentrations from clinical patients submitted through the therapeutic drug monitoring database at Auburn University, the half-life may be longer (unpublished data). Several pharmacokinetic parameters such as maximal concentration, area under the time concentration curve, elimination half-life, and bioavailability decrease when zonisamide is administered with phenobarbital.55 In cats, zonisamide appears to have a longer half-life of 33 hours. In rats, zonisamide is metabolized in the liver via cytochrome P450 and N-acetyltransferase, which is an enzyme that is deficient in dogs.56,59 Once this metabolic pathway is overwhelmed, pharmacokinetics may not be linear, and a small dose increase can lead to a disproportionate increase in PDC.
Dosing Regimen and Monitoring
The initial starting dose of zonisamide should be approximately 5 to 10 mg/kg q12h. A reference interval for zonisamide has not yet been established, and the human interval of 10 to 40 µg/mL is often referred to.60 In dogs, both peak and trough samples may be necessary. However, based on unpublished data from the Auburn University therapeutic drug monitoring database, the half-life of zonisamide is longer for many patients (approximately 40 hours) to justify a single sample submission at any point during the dosing interval. However, if a patient is not controlled, both a peak and a trough sample should be considered as this may allow calculation of half-life, which may help in changing treatment regimens.
Side Effects
Zonisamide appears to be well tolerated in dogs and cats. Side effects appear to be less common with this medication but include sedation, ataxia, and inappetence. More rare and serious side effects reported include renal tubular acidosis,61 blood dyscrasias,62 and hepatotoxicity.63
Summary
Although these are several different medications available to the clinician treating a patient with epilepsy, medication efficacy, pharmacokinetics, and client perspective should be considered when choosing a medication. The pros and cons of each medication should be thoroughly discussed with the client prior to initiating an antiseizure medication.
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