Anticonvulsants: what's new and exciting? (Proceedings)
Nov 01, 2009
CVC IN SAN DIEGO 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.