A seizure is the clinical manifestation of excessive, hypersynchronous neuronal discharges that may present as sudden, brief, transient episodes of impairment, loss of consciousness, paroxysmal motor phenomena, psychic or sensory disturbances, or autonomic signs. Seizures can be differentiated as either epileptic (a manifestation of abnormal excessive synchronous epileptic activity of neurons in the brain) or reactive (occurring as a response from the normal brain to a transient disturbance in function, usually metabolic or toxic in nature).
Status epilepticus is defined as a seizure lasting > 5 minutes, or as two or more discrete epileptic seizures between which there is incomplete recovery of consciousness.
Cluster seizures are seizures that happen < 24 hours apart.
Anticonvulsants (antiepileptics) are used to stop an ongoing seizure, to decrease the frequency of seizures, and/or to lessen the severity of future seizures. Some of these drugs should be administered in emergency situations only (status epilepticus or cluster seizures), others are used only for maintenance treatment, and some can be used for both.
If a drug needs to be administered during a seizure, IV administration is the ideal route for anticonvulsants; however, intrarectal, intranasal, and intramuscular routes are alternatives when there is no IV access. For longterm maintenance treatment, the oral route is ideal, but absorption can be limited or variable depending on the species, the drug used and its formulation, the combination of drugs, and even diet.
Maintenance Anticonvulsants
Indications for Maintenance Anticonvulsant Treatment in Animals
The decision to start maintenance anticonvulsant treatment should be based on the frequency and severity of seizures, age of onset, likely underlying cause, results of diagnostic testing, and specific challenges associated with treating particular species.
Specific indications for treatment with maintenance anticonvulsants include the following:
a seizure episode that is protracted or severe, or an episode of status epilepticus that is not related to a toxic agent (as a follow-up to emergency treatment; see the discussions of anticonvulsants for emergency treatment of seizures in dogs and cats and in large animals and exotic species)
seizures that are secondary to a structural cause in the brain (ie, associated with a forebrain lesion such as meningoencephalitis, neoplasia, or congenital malformation) or that develop within a month after traumatic brain injury
seizures that involve unwanted behaviors, such as aggression, occurring before, during, or after the seizure, or in a prolonged postictal phase
> 1 or 2 seizures in a 6-month period not due to repeated toxin exposure
cluster seizures (> 1 seizure of unknown cause on any particular day)
Clinical Use of Maintenance Anticonvulsants in Animals
Anticonvulsant treatment should begin with administration of a single anticonvulsant drug at the minimum concentration required for effect.
Owners should be instructed to keep a calendar to document the frequency and pattern of seizures. This calendar, in conjunction with serum anticonvulsant concentration measurements, can be used as a guide for drug dosage and treatment changes.
If seizure control is achieved, the serum concentrations of only those drugs known to have a toxic effect above a certain concentration (ie, phenobarbital and potassium bromide) need to be monitored.
If seizure control is unsatisfactory, regardless of the drug administered, the trough level of drug (the drug's concentration in the bloodstream just before the next does is administered) should be measured to ensure that it is within the therapeutic range (if established). If the drug concentration is below the therapeutic range, the dosage should be increased to achieve the higher end of the recommended therapeutic concentration before adding or switching to a new drug.
Although single-drug treatment is preferred, if the drug concentration is on the high end of the therapeutic range and seizure control has not been achieved, it might be necessary to consider adding another anticonvulsant.
To discontinue any anticonvulsant, the dosage of the drug should be tapered gradually over a few weeks to avoid precipitating a seizure. Tapering is crucial with phenobarbital and benzodiazepines (eg, clorazepate), because abruptly stopping these drugs can produce severe withdrawal seizures.
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In dogs, phenobarbital and bromide are considered first-line maintenance anticonvulsants; levetiracetam and zonisamide are often used as well. In cats, phenobarbital is the usual first choice; however, use of levetiracetam and zonisamide is becoming more common.
No anticonvulsant is approved for use in large animals. In ruminants, phenobarbital has been used; however, this drug is not approved for use in these species, and withdrawal times have not been established.
In horses, phenytoin, bromide, and phenobarbital have been used. Benzodiazepines have also been used for emergency seizure treatment in this species and, in particular, for management of neonatal seizures in foals.
Bromide Salts as Maintenance Anticonvulsants in Animals
Bromide is the oldest anticonvulsant. It is usually administered as the inorganic salt of potassium bromide (KBr) but can also be administered as the sodium salt (NaBr). NaBr contains more bromide than does KBr, and dosages of NaBr should be decreased by 15% accordingly.
Bromide can be administered as a single-drug treatment in dogs with epilepsy or as an adjunctive anticonvulsant in dogs with refractory seizure disorders. With the single-drug treatment, one study documented a > 50% decrease in seizures in approximately 74% of dogs (1).
Bromide has been used in horses as a maintenance anticonvulsant; however, no study on its clinical efficacy has been reported.
Bromide is no longer recommended as a maintenance anticonvulsant in cats, because of the high risk of a potentially fatal bronchial disease characterized by a cough and marked pulmonary infiltrates that are evident on radiographs.
Mechanism of Action of Bromide Salts
Bromide appears to stabilize neuronal cell membranes by interfering with membrane transport of chloride and by potentiating the effect of gamma-aminobutyric acid (GABA), thereby hyperpolarizing membranes. For this reason, dietary chloride content should remain constant in dogs receiving bromide treatment to avoid breakthrough seizures caused by displacement of bromide.
Pharmacokinetics of Bromide Salts
Absorption
Bromide is well absorbed from the small intestine.
Distribution
Bromide can take several months to reach a steady-state serum concentration. Bromide is minimally protein bound.
Metabolism
Bromide is not metabolized by the liver and is excreted unchanged in urine.
Elimination
The elimination half-life of bromide is extremely long in dogs (25–46 days); therefore, it can take up to 4 months to achieve steady-state kinetics. The drug is excreted in urine without known hepatic metabolism or toxicosis. Dietary factors can alter serum drug concentrations: high-chloride diets result in excessive renal excretion and lower serum concentrations.
Dosing Considerations for Bromide Salts
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
In dogs, the therapeutic range for serum concentration of bromide is 1–2 mg/mL (12.5–25 mmol/L) with concurrent administration of phenobarbital, or 1–3 mg/mL (12.5–37.5 mmol/L) for bromide administered as a monotherapy. However, the dosing regimen must be tailored for each patient.
Because it can take several months to reach a steady-state serum concentration, a loading dose of bromide should be administered to achieve faster seizure control. Owners must be warned that marked sedation might occur during this treatment phase but should improve within a couple of weeks. It could be necessary to elevate the dog's food and water dishes during this loading phase to prevent aspiration due to sedation.
If the dog becomes too sedated and unable to walk, the loading-dose regimen can be discontinued, or smaller divided daily doses can be tried. The regular maintenance dosage can be started immediately afterward.
Lowering the dosages will lessen adverse effects (nausea, vomiting, and sedation) that are due to rapid increase in serum bromide concentrations.
The therapeutic range of serum bromide concentrations for horses is 1–2 mg/mL; dosage regimens associated with therapeutic efficacy for the management of seizures in horses have been described (2, 3).
For bromide use as a single-drug treatment, adjusted maintenance doses can be calculated with the following formula:
Target CSS – Actual CSS) × (Clearance/Bioavailability) = (2.5 mg/mL – Actual CSS ) × 0.02 = mg/kg/day added to existing dose
where CSS = steady-state concentration
For concomitant administration with phenobarbital, the following formula should be used:
Target CSS – Actual CSS) × (Clearance/Bioavailability) = (2 mg/mL – Actual CSS) × 0.02 = mg/kg/day added to existing dose
Monitoring of Bromide Salts
A serum sample can be submitted within 2 weeks after loading to determine whether a therapeutic concentration of bromide has been reached. However, a sample is best checked after 3 months, once steady-state concentrations have been achieved. The upper end of the therapeutic range is limited only by adverse effects. If seizure control is adequate, bromide concentrations should be monitored annually.
Adverse Effects of Bromide Salts
Bromide is usually well tolerated in dogs. The most common adverse effects are sedation, ataxia, polyuria/polydipsia, and polyphagia. Bromide can also cause gastric irritation, nausea, and vomiting. Pancreatitis has been reported when bromide is administered concomitantly with phenobarbital.
Many laboratory assays cannot distinguish between serum bromide and chloride ions, so serum chloride concentration might be reported as falsely high.
Bromide toxicosis (bromism) is characterized by lethargy, disorientation, delirium, hyperexcitability, and ataxia, progressing to quadriplegia and coma. Bromide toxicosis can occur at any concentration in an unusually sensitive dog; it is rare, though, when bromide is used alone and when serum concentrations are < 1.5 mg/mL (18.75 mmol/L). When bromide is used in combination with phenobarbital, bromide toxicosis can develop at serum bromide concentrations of 2–3 mg/mL (25–37.5 mmol/L).
Animals with severe clinical signs of bromide toxicosis should be treated with IV saline solution (0.9% NaCl), which promotes renal excretion of the bromide ion. Clinical signs should improve within 48 hours after the start of treatment, depending on the severity. The patient should be monitored for rebound seizure activity because the drug level will increase rapidly.
Phenobarbital as Maintenance Anticonvulsant in Animals
Phenobarbital is relatively inexpensive, well tolerated, and it can be administered with a convenient dosing frequency of every 12 hours. It has been shown to be effective for seizure control as a single-drug treatment in dogs; in one study, 82% of dogs achieved a > 50% decrease in seizures (4).
Phenobarbital has also been used in horses and in foals to treat seizures associated with perinatal encephalopathy.
Also see the discussion of phenobarbital in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Mechanism of Action of Phenobarbital
Phenobarbital is a barbiturate and an agonist of the inhibitory neurotransmitter GABA receptor. It works as an anticonvulsant by increasing the seizure threshold and decreasing the electrical activity of the seizure focus.
Pharmacokinetics of Phenobarbital
Absorption
Phenobarbital has high bioavailability in monogastric animals and is rapidly absorbed; its peak plasma concentration is reached within 4–8 hours after oral administration.
Distribution
In dogs and cats, it takes approximately 2 weeks to reach a steady-state plasma concentration of phenobarbital because of the drug's long half-life (in dogs, 37–75 hours [mean 53 hours]; in cats, 35–56 hours [mean 43 hours]). Phenobarbital is highly protein bound.
Metabolism
Phenobarbital is metabolized mainly by the liver, with approximately one-third excreted unchanged in urine. Phenobarbital is a potent autoinducer of hepatic microsomal enzymes (cytochrome P450 system), and if administered chronically, it can progressively decrease its own elimination half-life and affect the hepatic metabolism of other drugs.
Elimination
Approximately one-quarter of a dose is excreted unchanged in urine.
The half-life of phenobarbital is shorter in horses, indicating a more rapid clearance in this species (approximately 24 hours after one dose, and approximately 11 hours after multiple doses). In foals, the half-life is approximately 13 hours.
In birds, the half-life of phenobarbital is very short (eg, 1.4–1.7 hours in parrots), making effective concentrations difficult to maintain.
Dosing Considerations for Phenobarbital
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
For dogs, cats, and horses, the serum drug concentration should be 15–35 mcg/mL (65–151 mcmol/L). An optimal starting trough concentration is 20–25 mcg/mL (86–108 mcmol/L).
Phenobarbital has been used in an extralabel fashion in ruminants, with dosages extrapolated from those used in horses.
Phenobarbital has been used as a maintenance treatment for seizure control in birds, with dosages extrapolated from those used for dogs.
If seizures are not well controlled after 30 days of phenobarbital treatment, the dosage should be adjusted according to the serum concentration and extent of seizure control (changes in serum concentration in increments of 5 mg/mL are targeted). The following formula can be used to adjust the dosage:
New oral daily dose (mg) = (Desired serum concentration/Actual serum concentration) × Current total dose (mg)
Also see the discussion of phenobarbital in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Monitoring of Phenobarbital
In dogs and cats, the serum concentration of phenobarbital should be checked 2–3 weeks after initiation of treatment, then 3 months later, and finally every 6–12 months. It should also be measured approximately 2–3 weeks after any dosage change.
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In dogs, monitoring should also include serum biochemical analysis and CBC.
Elevation of liver enzyme activity (particularly alkaline phosphatase activity), secondary to enzyme autoinduction, is common with phenobarbital.
In dogs, hepatotoxicosis and liver failure have been associated with chronic phenobarbital administration, especially with high serum drug concentrations (> 35 mcg/mL [150 mcmol/L]). Therefore, both serum drug concentration and liver function parameters (particularly albumin) should be monitored every 6–12 months in dogs.
In cats, phenobarbital administration has been found not to result in enzyme induction and hepatopathy, so monitoring serum drug concentration and hepatic function is generally not necessary. However, serum phenobarbital concentrations > 30 mcg/mL have been correlated with increased ALT activity in cats, so periodic monitoring of liver enzyme activity and phenobarbital concentration is still advised, particularly in cats with suspected liver disease.
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In horses, serum drug concentration should be checked periodically.
Adverse Effects of Phenobarbital
In dogs receiving phenobarbital, idiosyncratic liver toxicosis (within the first weeks of treatment) and bone marrow dyscrasia (within the first 3–6 months) have been reported. Discontinuation of the drug is recommended if these adverse effects develop.
Common adverse effects of phenobarbital include sedation, ataxia, polyuria/polydipsia, and polyphagia; these effects can decrease, however, within the first few weeks of treatment.
Other, less common adverse effects are idiosyncratic hyperexcitability, anemia, neutropenia, thrombocytopenia, superficial necrolytic dermatitis, and, rarely, pseudolymphoma. Phenobarbital can also lower thyroid hormone concentrations with chronic use causing animals to become clinically hypothyroid in rare cases.
Newer or Adjunctive Anticonvulsants
Clonazepam as Anticonvulsant in Animals
Anecdotal evidence suggests that clonazepam is a good anticonvulsant in dogs that are refractory to phenobarbital; however, it should be considered a last resort.
In cats, clonazepam has been used as an alternative to diazepam to avoid the risk of hepatotoxicosis.
Clonazepam can also be administered as a pulse treatment to control cluster seizures (see Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats).
To date, no data have been published on the use of clonazepam in large animals or exotic species.
Mechanism of Action of Clonazepam
Clonazepam is a benzodiazepine that, like diazepam, is a GABA receptor agonist, potentiating the release of monoamine neurotransmitters within the CNS. However, clonazepam is more potent than diazepam.
Pharmacokinetics of Clonazepam
Clonazepam undergoes saturable elimination, meaning that as the dose is increased or the drug is administered for > 1 week, the half-life increases (eg, from 1.5 to 3 hours). Tolerance to this drug develops more slowly than with diazepam.
Dosing Considerations for Clonazepam
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
Also see the discussion of clonazepam in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Adverse Effects of Clonazepam
Sedation, polyphagia, and paradoxical excitation (excessive excitement, anxiety, or aggression) have been reported as adverse effects of clonazepam in dogs. Diarrhea sometimes develops; starting administration of the drug every 24 hours and increasing the frequency to every 8 hours over several days can help prevent diarrhea.
Withdrawal syndrome is possible after chronic treatment and includes restlessness, weight loss, pyrexia, recumbency, and withdrawal seizures. A slow taper over 1 month should minimize these effects.
Clorazepate Dipotassium as Anticonvulsant in Animals
Clorazepate has been considered for treating seizures in animals. Anecdotal reports suggest that it might be effective for refractory cases in dogs. However, because published data on its efficacy are lacking, it should be considered only as a last resort.
Administration as a pulse treatment to stop cluster seizures is a preferred use for clorazepate (see Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats).
To date, no data have been published on the use of clorazepate in large animals or exotic species.
Also see the discussion of clorazepate dipotassium in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Mechanism of Action of Clorazepate Dipotassium
Clorazepate is a benzodiazepine with a mechanism of action similar to that of clonazepam (see above).
Pharmacokinetics of Clorazepate Dipotassium
Chlorazepate is hydrolyzed to desmethyldiazepam, an active metabolite of diazepam with a half-life of 3–6 hours in dogs.
Adverse Effects of Clorazepate Dipotassium
Because of the potential for severe and fatal withdrawal seizure activity, a slow taper is recommended if chlorazepate needs to be discontinued.
Felbamate as Anticonvulsant in Animals
Felbamate has been shown to be effective in the control of complex focal seizures in dogs. The principal advantage of felbamate is its lack of sedation.
Currently, no clinical information is available about the use of felbamate in cats and other species.
Mechanism of Action of Felbamate
Felbamate is a dicarbamate anticonvulsant that exerts its effects by blocking N-methyl-d-aspartate–mediated neuronal excitation.
Pharmacokinetics of Felbamate
Felbamate is metabolized in the liver by the cytochrome P450 system; 70% of it, however, is excreted unchanged by the kidneys. The half-life in dogs is 5–6 hours.
Dosing Considerations for Felbamate
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
The therapeutic range of felbamate is 25–100 mg/L.
Monitoring of Felbamate
Trough serum concentration of felbamate can be measured 1–2 weeks after the initiation of treatment. Regular monitoring for signs of myelosuppression and liver dysfunction in dogs is recommended (1 month after treatment is initiated, then every 3 months).
Adverse Effects of Felbamate
Adverse effects of felbamate are reportedly rare and include hepatotoxicosis, reversible myelosuppression (neutropenia, lymphopenia, and thrombocytopenia), restlessness, agitation, generalized tremors, and possibly keratoconjunctivitis sicca. In humans, felbamate has been associated with aplastic anemia and liver toxicosis, but these effects have yet to be reported in dogs.
Gabapentin as Anticonvulsant in Animals
Gabapentin is a synthetic analogue of the inhibitory neurotransmitter GABA that has both analgesic and anticonvulsant properties. It is most commonly used in human and veterinary medicine for neuropathic pain relief. Gabapentin has also been administered to treat behavior issues such as anxiety in dogs and cats (see Anxiolytics).
In dogs, gabapentin was shown to decrease seizure frequency in 50% of cases as an add-on treatment in one study (5). Another study, however, failed to show a notable decrease in the number of seizures over the study period for the cohort of 17 dogs evaluated (6).
Although no studies have supported the use of gabapentin as a sole therapy for seizure control in cats, it could be useful as an adjunctive anticonvulsant in this species.
No study has looked at the effect of gabapentin on seizure management in large animal species. However, some studies evaluating its effect on pain management have shown variable results.
Mechanism of Action of Gabapentin
The mechanism of the anticonvulsant and analgesic effects of gabapentin is not clear; however, these effects are thought to result from the blockade of calcium-dependent channels. By inhibiting the alpha-2-delta subunit of the N-type voltage–dependent channels, gabapentin decreases the calcium influx needed for the release of excitatory neurotransmitters from presynaptic neurons. This effect can suppress stimulated neurons involved in seizure activity and pain.
Pharmacokinetics of Gabapentin
In dogs and cats, gabapentin is well absorbed after oral administration; maximum blood concentrations are achieved within 2 hours. In horses, oral absorption is poor (16%).
Gabapentin undergoes both hepatic (one-third of the drug) and renal metabolism.
Gabapentin undergoes exclusive renal excretion. The half-life in dogs and cats is approximately 3–4 hours. The half-life of gabapentin in horses reported in different studies ranges from 3 to 15 hours.
Dosing Considerations for Gabapentin
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
The gabapentin dose should be decreased in cases of renal dysfunction.
Monitoring of Gabapentin
Therapeutic monitoring is not usually necessary with gabapentin, and to date, no drug interactions have been reported.
Adverse Effects of Gabapentin
Sedation and ataxia are the most common adverse effects of gabapentin in dogs. At higher dosages, decreased appetite, vomiting, and diarrhea have been observed.
Because gabapentin can produce excessive sedation in cats, dosage increases should be made in increments.
The commercially available liquid formulation of gabapentin, which is often preferred for administration in cats and small dogs, contains xylitol (300 mg/mL), which can be toxic and cause liver failure.
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Imepitoin as Anticonvulsant in Animals
Imepitoin is an anticonvulsant licensed in Europe and Australia for the management of idiopathic epilepsy in dogs. In the US, it is licensed for treatment of noise aversion in dogs but is not yet labeled for treatment of epilepsy.
The efficacy of imepitoin as a single-drug treatment has been compared to that of phenobarbital in dogs with idiopathic epilepsy; although the overall efficacy is lower, seizures are well controlled in some dogs, and the medication appears safe in this species. One study suggested a beneficial effect as an add-on treatment combined with phenobarbital in dogs (7).
Imepitoin has not been investigated as an anticonvulsant in other species. The drug is not approved for use in cats. Adverse GI effects (decreased appetite, vomiting) have been noted at higher dosages administered to healthy cats. Because of a paucity of information regarding use of imepitoin for seizure control in cats, caution should be exercised if prescribing this medication for this species.
A dosage has not been established for large animals, and withdrawal times are not established for food animals.
Mechanism of Action of Imepitoin
Imepitoin has a mechanism of action similar to that of benzodiazepines in that it decreases seizures by potentiating the inhibitory effects mediated by GABA A receptors. It might also have a weak calcium channel blocking effect. Imepitoin is metabolized by liver enzymes, so interactions with other drugs that affect P450 enzymes are possible.
Pharmacokinetics of Imepitoin
Imepitoin has a very short elimination half-life in dogs (1.5–2 hours), with peak blood concentrations attained approximately 2 hours after oral administration.
Dosing Considerations for Imepitoin
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
The drug is available in 100-mg and 400-mg tablets (which can be split). The recommendation is to start with the lower dose and increase the dose slowly until seizure control is achieved.
There are currently no guidelines for therapeutic plasma or serum concentrations of imepitoin. The dose can be increased in 50–100% increments up to the maximum dose recommended on the basis of clinical response.
Adverse Effects of Imepitoin
The adverse effects of imepitoin include sedation, lethargy, polyuria/polydipsia, and polyphagia. Less common adverse effects include hyperexcitability, hypersalivation, emesis, ataxia, diarrhea, sensitivity to sounds, and unprovoked aggression.
Levetiracetam as Anticonvulsant in Animals
Levetiracetam has been used as an adjunct anticonvulsant in dogs with refractory epilepsy and in cats. It is occasionally administered as a single-drug treatment for structural epilepsy or prophylactically before surgical correction of portosystemic shunts.
Anecdotally, levetiracetam has been shown to be effective for controlling seizures in dogs with epilepsy caused by a structural brain lesion such as neoplasia or encephalitis.
The development of tolerance with chronic administration of levetiracetam has been reported in dogs (8).
Anecdotal use of levetiracetam has been reported in horses; however, no reported study has looked at its efficacy to control seizures in this species.
Mechanism of Action of Levetiracetam
Levetiracetam has a unique mechanism of action that is mediated by binding to the presynaptic vesicular protein SV2A, which decreases release of the neurotransmitter glutamate.
Pharmacokinetics of Levetiracetam
Absorption
In dogs and cats, the immediate-release formulation of levetiracetam has excellent oral bioavailability. In foals, bioavailability after intragastric administration is excellent.
Distribution
Levetiracetam is rapidly distributed to all tissues. It is minimally protein bound.
Metabolism
Levetiracetam does not appear to undergo hepatic metabolism (at least, not involving cytochrome P450 enzymes).
Elimination
Levetiracetam is excreted primarily unchanged in urine. Clearance might be affected by concurrent administration of phenobarbital, requiring an increase in dosage. In dogs, the immediate-release formulation has a half-life of 3–4 hours. In cats, the half-life is short (3 hours). In foals, the half-life is approximately 8 hours after IV administration.
Dosing Considerations for Levetiracetam
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
In dogs, the short half-life of levetiracetam necessitates administration of the immediate-release formulation every 8 hours; the extended-release formulation can be administered every 12 hours.
Clients should be cautioned to make sure that the correct dosage form is dispensed for their pet and that the extended-release tablet remains whole to prevent loss of its extended-release property. Anecdotal reports suggest that once extended-release tablets are broken, they might pass through the dog’s GI tract undigested, even though the drug is still absorbed into the bloodstream.
The IV formulation of levetiracetam can be used in cases of status epilepticus in both dogs and cats (9, 10).
Also see the discussion of levetiracetam in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Monitoring of Levetiracetam
Treatment with levetiracetam does not generally require monitoring, and there does not appear to be a correlation between serum drug concentration and therapeutic efficacy.
Adverse Effects of Levetiracetam
Levetiracetam appears to be very safe, with rare adverse effects. Vomiting, ataxia, sedation, hyperexcitability, anorexia, and polyuria/polydipsia have been reported at routine dosage ranges in dogs. Hypersalivation has been reported in cats, and caution should be taken in patients with renal disease because of the drug's renal excretion.
Pregabalin as Anticonvulsant in Animals
In an open-label study, 7 of 11 dogs with refractory epilepsy were classified as having a positive response to treatment with pregabalin (11). However, a subsequent study found that the drug has low efficacy in treating epileptic dogs (12).
Mechanism of Action of Pregabalin
Pregabalin belongs to the same drug class as gabapentin, and its mechanism of action is similar to that of gabapentin. However, pregabalin has a greater affinity for the binding site at which these two drugs exert their effects, so it has greater potency than gabapentin.
Pharmacokinetics of Pregabalin
A pharmacokinetic study on oral administration of pregabalin in clinically normal dogs demonstrated that maximum concentrations are achieved at 1.5 hours (13), and the elimination half-life is approximately 7 hours.
Dosing Considerations for Pregabalin
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
Adverse Effects of Pregabalin
As with gabapentin, the adverse effects of pregabalin include sedation and ataxia.
Topiramate as Anticonvulsant in Animals
Before treatment with topiramate is initiated, owners should be informed of the limited information about this drug and the lack of proof of its efficacy as an anticonvulsant. One prospective open-label clinical trial evaluated the effect of topiramate as an add-on anticonvulsant in dogs with refractory epilepsy and reported a decrease in seizure frequency in 50% of the dogs studied (14). In one study of healthy cats, the extended-release formulation appeared safe (15); however, the drug's efficacy for seizure control was not studied.
Topiramate has not been studied as an anticonvulsant in other species.
Mechanism of Action of Topiramate
Topiramate is a sulfamate-substituted monosaccharide that works as an anticonvulsant via rapidly potentiated GABA activity in the brain.
Pharmacokinetics of Topiramate
The elimination half-life of topiramate is short in dogs (2–4 hours), suggesting that frequent dosing might be necessary, which could preclude the use of this drug as a maintenance anticonvulsant.
Dosing Considerations for Topiramate
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
Adverse Effects of Topiramate
Weight loss, sedation, and ataxia are the reported adverse effects of topiramate. Mild subclinical anemia was also reported in some cats (15).
Zonisamide as Anticonvulsant in Animals
Zonisamide has been used mainly as an adjunct anticonvulsant in dogs with refractory epilepsy; however, it can also be administered as a single-drug treatment. In one study, 9 of 11 dogs with refractory idiopathic epilepsy responded well to zonisamide as an add-on treatment (16); in another study, and 7 of 12 dogs responded favorably (17). In a study looking at zonisamide administration by itself, 6 of 10 dogs with idiopathic epilepsy showed a > 50% decrease in monthly frequency of seizures (18).
There are limited data on the use of zonisamide in cats. Zonisamide has been shown to decrease interictal epileptiform discharges on electroencephalograms of epileptic cats. In one study, 3 of 5 cats treated with zonisamide were reported to have a > 50% decrease in seizures (19). Cat owners should be counseled on the lack of clinical evidence supporting the use of zonisamide to treat epilepsy in cats before administration of this medication is initiated.
The use of zonisamide has not been reported in large animals or exotic species.
Mechanism of Action of Zonisamide
Zonisamide is a sulfonamide-based anticonvulsant with an undetermined mechanism of action. It might suppress voltage-gated sodium and T-type calcium channels that produce excessive excitation and thereby stabilize membranes and restrict the propagation of seizures from an epileptic focus, potentiate the action of GABA, and affect dopaminergic and serotonergic systems.
Pharmacokinetics of Zonisamide
Absorption
Zonisamide is well absorbed.
Distribution
Zonisamide is highly protein bound.
Metabolism
Zonisamide is metabolized by the cytochrome P450 enzyme system; therefore, dogs receiving concurrent treatment with a drug known to induce hepatic microsomal enzymes (eg, phenobarbital) require nearly twice the dosage of zonisamide to achieve and maintain serum concentrations when compared to dogs receiving zonisamide alone.
Elimination
Zonisamide has a relatively long half-life (18–28 hours in dogs). In cats, the reported half-life is longer (33–68 hours) than in dogs.
Dosing Considerations for Zonisamide
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
Monitoring of Zonisamide
The serum concentration of zonisamide can be measured if seizures are not well controlled by the recommended therapeutic range of 10–40 mg/mL. Trough concentrations can be measured approximately 7–10 days after either initiation of treatment or alteration of the dosage.
Adverse Effects of Zonisamide
Adverse effects of zonisamide are usually mild (eg, transient ataxia, loss of appetite, lethargy, and vomiting). Zonisamide can also affect thyroid hormones after longterm use.
Although the drug is usually safe, owners should be warned that because of the sulfonamide base, potential adverse effects (eg, keratoconjunctivitis sicca, bone marrow dyscrasia, hepatopathy, vasculitis, and metabolic acidosis) could occur. In light of that possibility, patients with a history of sulfa drug hypersensitivity should not be prescribed zonisamide. Furthermore, human caregivers with known sulfa allergies should handle zonisamide with caution if at all.
GI upset (vomiting, diarrhea, nausea) was reported in 3 of 6 cats receiving longterm treatment with zonisamide at a high dosage in one study (20). A lower dosage is recommended to limit these adverse effects.
Ataxia and sedation have also been reported. One case of pseudolymphoma has been reported in cats (21).
Older Anticonvulsants No Longer Recommended for Maintenance Treatment
Diazepam as Anticonvulsant in Animals (Former Use)
The use of diazepam as a maintenance anticonvulsant has been reported in dogs. However, diazepam is no longer considered suitable for oral maintenance treatment, because it is absorbed poorly, it has a short half-life (2.5–3.2 hours), its hepatic extraction rate is high, and tolerance to its anticonvulsant effects develops rapidly (within a week).
In cats, diazepam not only has a longer half-life (5.5 hours) than it has in dogs, but it also does not cause the development of tolerance to the drug's anticonvulsant effects as it does in dogs. For this reason, diazepam was previously used as a maintenance treatment in cats. However, acute hepatic failure has been reported in cats after oral administration of diazepam. This reaction can be severe and fatal, and it usually occurs after the initial 5 days of treatment. Because of the potential for this major adverse effect, diazepam is no longer recommended as a maintenance treatment in cats with seizures.
Also see the discussion of diazepam in Anticonvulsants for Emergency Treatment of Seizures in Dogs and Cats.
Mephenytoin as Anticonvulsant in Animals (Former Use)
Mephenytoin, although related to phenytoin, has been reported to be effective in dogs because of a slower rate of elimination. Adverse effects consist of sedation only; however, periodic hematologic monitoring is advised because blood dyscrasia and hepatotoxicosis have been reported in humans.
Because newer, safer anticonvulsants are available, the use of mephenytoin is no longer recommended.
Phenytoin as Anticonvulsant in Animals (Former Use)
Phenytoin (diphenylhydantoin) is no longer recommended for maintenance in dogs, cats, or foals, because of undesirable pharmacokinetic properties. Its metabolism is too rapid in dogs, thereby decreasing its effectiveness, and too slow in cats, increasing the risk of toxicosis (salivation, vomiting, weight loss). In foals, administration of phenytoin produces erratic plasma concentrations.
Primidone as Anticonvulsant in Animals (Former Use)
Primidone is a barbiturate that has two active metabolites: phenobarbital and phenylethylmalonamide(PEMA; or phenylethyl malonic acid). The phenobarbital metabolite is likely the major functional one, so there is no advantage to using primidone over phenobarbital.
Because hepatotoxicosis may be more likely to occur with primidone than with phenobarbital, and because primidone has been associated with hepatic necrosis and lipidosis, as well as with bile canaliculi obstruction, its use as an anticonvulsant is no longer recommended, and phenobarbital should be used preferentially. Assessment of dosing efficacy for primidone is based on the serum concentration of phenobarbital (15–45 mcg/mL).
Other adverse effects and clinical signs of primidone overdosage are similar to those of phenobarbital. Because of toxicity concerns, primidone is also not recommended for use in cats.
Valproic Acid as Anticonvulsant in Animals (Former Use)
Valproic acid has been reported to be effective as an anticonvulsant and well tolerated. Historically, valproic acid was used primarily in dogs with seizures refractory to other medications. Valproic acid has also been used to treat aggressive behavior (see Psychotropic Agents).
Common adverse effects of valproic acid include transient GI distress, alopecia, sedation, and vomiting. Hepatic failure is rare but has been reported. Use of valproic acid declined after other drugs with fewer adverse effects (eg, zonisamide, levetiracetam) became available. Use of valproic acid has not been reported in species other than dogs.
Although the exact mechanism of action is unknown, an increased amount of GABA and alteration in neuronal excitability are proposed mechanisms for the anticonvulsant activity of valproic acid.
Oral absorption of valproic acid in dogs is high (close to 100%) for the immediate-release formulation and 80% for the extended-release formulation. The half-life in dogs is very short, with an average of 1.4 hours (range 1.0–1.8 hours) (22), limiting therapeutic effectiveness of the drug unless either a schedule of frequent dosing is followed or the extended-release formulation is administered.
The short half-life of valproic acid in dogs requires administration several times a day to maintain efficacy, making adherence difficult for pet owners. Valproic acid's lack of efficacy in controlling seizures is probably due to its very short half-life. Combining valproic acid with other anticonvulsants might increase its efficacy.
No information is available about the half-life and pharmacokinetics of the extended-release valproic acid formulation in dogs. Some evidence suggests that the anticonvulsant effect might persist long after the drug is eliminated from plasma.
Therapeutic concentrations of valproic acid, extrapolated from studies in humans, are reported to be 350–830 mcmol/mL (50–120 mcg/mL) (23).
For specific therapeutic recommendations, including dosages, refer to the relevant disease chapter.
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