Contributors: Rodney Bagley, Laurent Garosi, Mark Lowrie

 Species: Feline   |   Classification: Miscellaneous

Introduction

  • Guidelines have been established to aid the clinician as to when antiepileptic medication should be initiated.
  • In general antiepileptic drugs may either raise the seizure threshold or prevent the spread of the electrical activity.
  • The aim of any antiepileptic treatment is to “control” the seizures by reducing their frequency, intensity and severity with minimum side effects while maximizing the owner’s and cat’s quality of life.
  • Owners should be appropriately advised to ensure that their expectations are realistic from the outset.
  • Unless idiopathic epilepsy is considered to be the primary differential diagnosis for the seizure activity, specific treatment of the underlying cause is essential and the success of this will determine the need for symptomatic seizure therapy.
  • The decision of when to start antiepileptic treatment is still a subject of controversy:
    • Cats with a single seizure or isolated seizures separated by long periods of time (more than one month) do not require treatment.
    • Treatment is indicated when:
      • The animal has a very severe seizure or clusters of seizures, irrespective of the frequency of the seizures or seizure clusters
      • Seizures occur more than once a month and/or the owner objects to their frequency.
      • Seizures are becoming more frequent or more severe.
      • An underlying progressive intracranial disorder has been identified as the cause of the seizures.
      • Post-ictal signs are objectionable (eg aggression).
Print off the owner factsheet Treatment of epilepsy Treatment of epilepsy to give to your client.

Standard treatment

Phenobarbital 

  • The standard first line antiepileptic therapy is phenobarbital at 3 mg/kg PO BID Phenobarbital.
  • It is a barbiturate-derivative.
  • Most commonly used antiepileptic drug.
  • Cats should be dosed orally, starting with a dose of 2-3 mg/kg PO BID.
  • Steady state serum concentrations are not achieved until 1-2 weeks after treatment is initiated.
  • The full effect of the medication therefore does not appear for two weeks and doses should not be increased during this time.
  • If seizures are not being controlled at this stage, the dosage may be increased by 20% at a time, with associated monitoring of serum phenobarbital concentration.
  • In cats, repeated phenobarbital administration does not later steady state serum concentration so functional tolerance is not a problem in this species.
  • The recommended therapeutic range in cats is 20 to 35 mg/l:
    • This therapeutic range is only an indication for the adaptation of the oral dosage.
    • Most cats will “respond” (ie achieving a reduction in the frequency, intensity and severity of the seizures with minimal side effects) with serum concentrations within this range.
    • However, some cats might need to be in the upper limit of this range while others may respond to concentrations below the lower limit.
  • Determination of serum phenobarbital levels is indicated when:
    • Steady state blood levels are achieved after starting treatment (10-15 days in cats). This provides a baseline to further guide changes in dose according to clinical circumstances.
    • When the seizure frequency increases or the patient becomes refractory to the phenobarbital therapy.
    • Every 3-6 months to verify that the blood concentration has not drifted out of the intended range.
    • When drug-related side effects are suspected.
  • It does not matter when the serum concentration is measured in relation to the timing of the pill as long as the measurement is taken at the same time consistently in each individual patient.
  • There is no magic dose of phenobarbital that is needed or that is toxic to individual cats. Therefore, assessing phenobarbital concentration before deciding that a cat is getting too much or too little is extremely important.

Pharmacokinetics

  • Half-life = 46-88 hours in most dogs and cats.
  • High bioavailability (86-97%).
  • Absorbed within two hours after oral administration.
  • Maximal plasma concentration achieved four hours after oral administration.
  • 45% is protein bound in serum.
  • Chronic administration reduces elimination half-life.

Metabolism

  • Primarily metabolised by hepatic microsomal enzymes, although up to 25% is excreted unchanged renally.
  • Metabolism increases with chronic administration (autoinduction) due to the drug being a potent inducer of hepatic microsomal cytochrome P450); thus increased clearance of phenobarbital is seen along with other endogenous compounds (eg thyroid hormones).
  • Metabolism is also affected by diet and urine pH - low protein diets can increase elimination of phenobarbital.

Mechanism of action

  • Phenobarbital increases seizure threshold and decreases the spread of electrically induced discharges.
  • Primary mechanism of action - binds GABAA receptor activating BAGA receptor-gated chloride channels and increase the affinity of GABA for its own receptor.
  • This results in greater influx of chloride ions resulting in hyperpolarization of the resting membrane potential of the post-synaptic neuron and preventing further action potentials.
  • Secondary mechanisms of action include interaction with glutamate receptors to decrease neuronal excitatory postsynaptic currents and blocking presynaptic entry of calcium ions into nerve terminals.

Interactions, side effects and toxicity

  • Side effects of phenobarbital in cats can be idiosyncratic or dose-related:
    • Idiosyncratic:
      • Severe cutaneous eruptions.
      • Bone marrow dyscrasias (eg neutropenia, anemia and thrombocytopenia).
      • Marked lymphadenopathy.
    • Dose-related (often transient and resolve 1-2 weeks after starting treatment as tolerance develops):
      • Polyuria.
      • Polyphagia.
      • Ataxia.
      • Sedation.
      • Weight gain.
  • Hepatotoxicity is not reported in cats:
  • If toxic levels of phenobarbital are obtained, and seizure control is not adequate, then an additional antiepileptic is added (see below):

Summary

  • Suppresses epileptogenic foci discharges and inhibits kindling; decreases neuronal excitability and increases the action potential threshold to electrical stimulus.

Dosage and monitoring

  • Dosage: 2-4 mg/kg PO BID initial dose.
  • Serum concentrations more closely correlated with therapeutic benefit than orally administered dose.
  • Therapeutic levels of 20-35 mg/ml have been suggested to maximize seizure control while minimizing side effects.
  • The timing of when to perform serum phenobarbital concentrations is not important provided you perform it consistently at the same time in each individual.
  • Phenobarbital requires serum concentration testing Phenobarbital assay. This is indicated:
    • Steady state blood levels are achieved after starting treatment (10-15 days in cats). This provides a baseline to further guide changes in doses according to clinical circumstances.
    • When the seizure frequency increases or the patient becomes refractory to the phenobarbital therapy.
    • Every 3-6 months to verify that the blood concentration has not drifted out of the intended range.
    • When drug-related side effects are suspected.

Emergency situation

  • Status epilepticus Status epilepticus or cluster seizures.
  • Phenobarbital naïve patients:
    • Intravenous phenobarbital in 4 mg/kg boluses every 10-20 minutes to a total dose of 24 mg/kg or until the seizures stop.
  • Patients already receiving phenobarbital:
    • Intravenous phenobarbital 4 mg/kg intravenous bolus and initiating a new antiepileptic medication (eg potassium bromide or levetiracetam).
  • Phenobarbital at 18 mg/kg IV in cat that has not been on phenobarbital.

Potassium bromide

Metabolism

  • Bromide salts are rapidly absorbed from the small intestine.
  • No protein binding.
  • Exclusively excreted by the kidneys making it ideal for patients with hepatotoxicity.

Mechanism of action

  • Mechanism of action is at the GABA receptor-gated chloride channels whereby bromide replaces negatively charged chloride ions through the chloride channels causing neuronal hyperpolarization.
  • Bromide has synergistic effect with drugs that enhance chloride conduction, eg phenobarbital.

Side effects

  • Not recommended for use as an antiepileptic drug (AED) in cats due to significant risks of allergic pneumonitis (reported in 35-40% of treated cats). Furthermore, bromide is not particularly effective as AED as seizures are only controlled in approximately 35% of treated cats.
  • Can also cause clinical and radiographic signs similar to feline asthma Allergic bronchitis such as coughing and/or difficulty breathing.

Diazepam

  • Benzodiazepine Diazepam.
  • Crosses the blood-brain barrier faster than any other antiepileptic medication.
  • Chronic oral administration of diazepam is not recommended in the dog due to its very short elimination half-life and functional tolerance.

Metabolism

  • Major metabolites are nordiazepam (desmethyldiazepam) and oxazepam.
  • Metabolites have 25-33 % of the antiepileptic activity of diazepam.
  • Due to extensive first pass effect, oral systemic availability is only 1-3%.
  • Rectal administration is preferable to avoid this first pass effect.
  • Serum half-life is 3.2h.
  • Serum protein binding is 96%.
  • Compared to dogs, elimination half-life of Diazepam is longer in cats (5.5 hours instead of 1 to 3.5 hours in dogs). Tolerance to the anti-epileptic effect does not occur in cats. These two species-related differences can justify the use of this drug in maintenance therapy of epileptic seizure.
  • Can cause acute hepatic necrosis (idiosyncratic side effect that is dose- and time-independent).

Mechanism of action

  • Diazepam binds to benzodiazepine receptors on the GABA receptors and  facilitate binding of GABA to its receptor.
  • This opens the chloride channel, allowing an influx of chloride and enhanced inhibition of the post-synaptic neuron.

Dosages and monitoring

  • 0.16-0.33 mg/kg BID or TID PO.
  • Can work well compared to the effect in dogs.
  • If response inadequate or side-effects of therapy occur initiate combination therapy.
  • 1-2 mg/kg IV for acute seizure.
  • Can be used as a continuous infusion at 5-20 mg/hour IV.

Levetiracetam

  • An S-enantiomer of alpha-ethyl-2-oxo-1-prollidine acetamide and is structurally related to piracetam Levetiracetam.

    Metabolism

    • Minimal hepatic metabolism (>80% excreted in the urine).
    • 20% hydrolyzed in the serum and other organs.
    • Elimination half-life is 3-4 h in cats.
    • Steady state concentration at 48 hours.

    Mechanism of action

    • Poorly understood but distinct to other anti-epileptic medications and therefore potentially advantageous when polytherapy is required.
    • Binds to the synaptic vesicle 2A (SV2A) protein on the presynaptic terminal modulating synaptic fusion and neurotransmitter release.
    • Other modes of action include:
      • Inhibition of the sodium dependent chloride-bicarbonate exchanger.
      • Modulation of potassium and voltage-gated calcium channels.
      • Opposition of allosteric inhibition of GABA and glycine-gated currents.
      • Antagonism of neuronal hypersynchronization.
    • Some evidence in cats suggests that this drug may be better than phenobarbital in the management of myoclonic seizures.

    Dosage and monitoring

    • The recommended oral dose is 20-30 mg/kg every 8 h.
    • There is no clear understanding of the relationship between serum drug concentration and efficacy; therefore, serum monitoring is not currently performed for this medication.

    Interactions, side effects and toxicity

    • Sedation, ataxia, decreased appetite and vomiting.

    Phenytoin

    • Phenytoin Phenytoin poorly metabolized and can be very toxic in cats.

    Gabapentin

    • Gabapentin Gabapentin can potentially be used in cats at 30-60 mg/kg/day - no study has yet assessed the value of this antiepileptic drug in cats.