Anticonvulsants: what's new and exciting? (Proceedings)

Epilepsy is a heterogeneous symptom complex characterized by chronic recurrence of finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. Seizures can be caused by a variety of factors including toxic, metabolic, neurologic, infectious, inflammatory, degenerative, iatrogenic (e.g. drugs), hereditary, neoplastic and/or traumatic. These underlying causes must then be eliminated in order to adequately control the occurrence of seizures. However, the underlying cause may neither be treatable nor identified (idiopathic). In these instances, the use of anticonvulsant drugs is useful to help control the frequency and severity of seizures. It has recently been recognized in human medicine that the different forms of epilepsy may benefit from different classes of anticonvulsant drugs or a combination of them.

Anticonvulsant drugs selectively act on several molecular targets in the brain in order to modify the excitability of neurons so that seizure-related firing can be blocked without disturbing non-epileptic activity that regulate normal signals between neurons. It is estimated that 30% of epileptic patients (human and veterinary) are refractory to conventional anticonvulsant treatment. Recently, novel anticonvulsant drugs selectively targeting new neuroreceptors are being developed in order to maximize the safety and efficacy of generalized and partial seizure pharmacological treatments.

In veterinary medicine, there is presently no FDA approved anticonvulsant drug labeled for use in cats and dogs. Hence, the availability of anticonvulsant drugs for use in veterinary patients is entirely dependent on the approval of their usage in human medicine. The treatment of generalized tonic-clonic or focalized seizures in cats and dogs with currently available anticonvulsant drugs relies on a fine balance between an adequate control of seizures and the incidence/severity of associated adverse side effects. The emergence of novel anticonvulsant drugs is encouraging for the treatment of different forms of seizure in companion animals, however, in the absence of well controlled, double blinded, randomized, prospective canine and feline studies, their use is highly empirical.

Objectives

1. Provide the practitioner with a brief overview of seizure pathophysiology in cats and dogs.

2. Provide the practitioner with an understanding of the different mechanisms of action underlying antiepileptic action of available anticonvulsant drugs.

3. Provide the practitioner with relevant pharmacokinetic (PK) data that have clinical implications in the use of anticonvulsant drugs in cats and dogs.

4. Identify the adverse side effects and potential drug interactions associated with the administration of specific anticonvulsant drugs.

5. Provide the practitioner with an insight on future antiepileptic development.

Pathophysiological features of seizures

1. In the brain, Na+ and Ca2+ channels are of importance for mediating excitation whereas the opening of K+ and Cl- channels promote inhibition.

2. Synaptic transmission in the neuronal network is mediated by excitatory and inhibitory neurotransmitters. GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter (NT) rendering the resting membrane potential of the neuronal cells more negative and less susceptible to depolarization, whereas glutamate (Glu) is an excitatory NT as it elevates the resting membrane potential rendering it more susceptible to reaching the threshold required for depolarization.

3. Disruption of any of these channels or neurotransmitters results in the manifestation of seizures (Table 1).

4. During a seizure, extracellular K+ increases and Ca2+ decreases, this increases neuronal excitability and facilitates the initiation and spread of a seizure.

5. Seizures may be classified as primary (genetic) or secondary (acquired), and as generalized (tonic-clonic) or focal.

6. Primary generalized idiopathic epilepsy is the most common type of seizures in dogs, however, acquired seizures caused by an organic lesion (neoplasia, trauma, metabolic disease) also occur in this species.

7. Secondary epilepsy, caused by inflammation (meningoencephalitis), infection (FIV, FIP, FeLV, Cryptococcus, rabies), trauma, neoplasia (meningioma, central lymphoma) or cerebral ischemic encephalopathy, is the most common type of seizures in cats, characterized by partial motor seizures with or without generalization.

Table 1. Main pathophysiologic mechanisms of seizure

First generation anticonvulsant drugs

1. Phenobarbital, KBr, diazepam, phenytoin and primidone are considered first generation anticonvulsant drugs.

2. First generation anticonvulsant drugs are characterized by long terminal half lives and associated with numerous, potentially serious side effects.

3. Despite the emergence of novel anticonvulsants, PB and KBr are considered as first line anticonvulsant drugs for the treatment of epilepsy in dogs.

4. Phenobarbital and diazepam are the most commonly used anticonvulsant drugs administered to seizuring cats.

Second generation anticonvulsant drugs

1. Since 1990, second generation anticonvulsant drugs were introduced for clinical use in human patients. These include gabapentin, pregabalin levetiracetam, felbamate, clorazepate, topiramate and zonisamide.

2. In the 90's, gabapentin, felbamate and clorazepate have joined the first generation of anticonvulsant drugs in the treatment of refractory seizures in dogs, with some variable success.

3. More recently, levetiracetam, topiramate and zonisamide have been part of antiepileptic regimens used by veterinary neurologists.

4. Second generation anticonvulsant drugs are characterized by short terminal half-lives and associated with less side effects and potential for drug interactions however, many are prone to tolerance (tachyphylaxis) with chronic use.

5. Cost and frequency of administration have been major deterrents for the use of the second generation anticonvulsant drugs in veterinary patients.

General mechanisms of action

1. Anticonvulsant drugs block seizure initiation and propagation by blocking abnormal events in a single neuron or the synchronization of related neurons.

2. Not surprisingly, targets for anticonvulsant drugs include voltage-gated ion channels (Na+, K+, CA2+), ligand-gated ion channels (mainly for GABA and glutamate), and neurotransmitters, their transporters, receptors or metabolizing enzymes (Table 2).

3. Non-specific cation channels regulating intrinsic membrane properties have also been identified as potential targets for drugs exhibiting anticonvulsant activity.

Table 2. Main mechanisms of action of traditional and novel anticonvulsant drugs

Clinical pharmacology and therapeutic use

1. Anticonvulsant drugs acting on more than one target may be more effective, this is why combination treatment is very valuable in the treatment of refractory cases.

2. Successful treatment depends on the plasma drug concentrations at steady-state within a determined therapeutic range. Hence, therapeutic drug monitoring (TDM) is an important part of seizure management.

3. Compliance is an important contributing factor to non responsive cases. Epilepsy is controlled not cured; owners must be warned of the limitations of pharmacological treatment of epilepsy. This may improve owner compliance.

4. Phenobarbital is a potent cytochrome P450 (CYP450) enzyme-inducer and has the potential to alter the PK of several drugs mainly metabolized by the liver, including itself. It also has the potential to cause hepatotoxicity.

5. KBr is mainly eliminated by the kidneys. A change in dietary salt may affect plasma concentrations of this anticonvulsant drug (limit salty treats and abrupt change of diet).

6. KBr is not recommended in cats as it may cause eosinophilic bronchospasm.

7. Elevated serum lipase concentrations and possibly pancreatitis may be associated with the administration of KBr and/or PB in dogs.

8. Gabapentin is recommended for the treatment of partial seizures and may be given in combination with PB ± KBr. It is however, contraindicated in primary generalized epilepsy in humans as it may aggravate the seizure situation.

9. Levetiracetam can be used alone but more commonly in combination with PB ± KBr. It is recommended for partial seizures with or without secondary generalized seizures. It has been associated with a 70% reduction in seizure frequency with mild side effects in a small feline study.

10. Topiramate has been associated with a hyperchloremic metabolic acidosis in humans and development of calcium phosphate renal calculi by reducing citrate elimination in the urine, thus increasing the pH.

11. Zonisamide is sulfonamide-based hence has the potential of causing sulfonamide-related side effects such as KCS and polyarthropathy, blood dyscrasias and crystalluria.

12. Tolerance may develop for levetiracetam and zonisamide after a short "honeymoon period".

13. Drug interactions are expected to occur with phenobarbital, phenytoin, benzodiazepines, topiramate, zonisamide and felbamate as they are mainly metabolized by the liver.

Additional details

"Third generation" anticonvulsant drugs

Lamotrigine is a folic acid antagonist that blocks Na+ channels (pre and postsynaptically), reduces high-voltage activated Ca2+ channels and is neuroprotective based on inhibition of extracellular accumulation of glutamate in rat neocortical slices. Tiagabine inhibits GABA transporter (autoreceptor) on presynaptic membrane increasing GABA in the synaptic cleft.

Summary

Phenobarbital and KBr are still the first choice among anticonvulsant drugs. New anticonvulsants have very short half lives and potential for tolerance which makes them less practical than PB and KBr. Therapeutic drug monitoring is only recommended for phenobarbital and KBr in cats and dogs at the moment (± zonisamide); all therapeutic ranges however, are extrapolated from human studies. Drug interactions are expected for anticonvulsants mainly metabolized by the liver.

Compliance is an important contributing factor in failure of treatment. Sustained-release formulations of new anticonvulsants could help increase owner compliance. Third generation of anticonvulsant drugs may offer both neuroprotective and antiepileptic advantages.

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