[Gabaergic hypothesis of epilepsy and clinical experience: controversial actions of the new generation gabamimetic antiepileptic drugs].
Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in CNS can elevate level of neuronal excitability by the mechanisms of hyperpolarization. Gabaergic hypothesis of epileptogenesis influenced development of a group of gabamimetic antiepileptic drugs (AEDs). Powerful conventional AEDs barbiturates and benzodiazepines can directly activate GABA-A receptor but their usefulness is limited by development of dependence and tolerance to antiseizure activity. The second generation AEDs have been achieved by a rationale synthesis of compounds that could mimic or augment the activity of endogenous GABA. Vigabatrin (VGB) irreversibly inhibits GABA-T activity, tiagabine (TGB) inhibits GABA-reuptake system (GAT-1) and gabapentin (GPT) enhances GABA turnover in CNS. New drugs with selective and specific influence on GABA neurotransmission are non-toxic and well-tolerated, but some side-effects (aggravation of seizures, visual field deficit and psychotic reactions) seems to be strictly connected with their pharmacodynamic properties. Absence and probably myoclonic seizures noted in about 10% of patients under VGB seems to be the result of disturbed GABA inhibition in thalamic interneurons and non-controlled hyperactivity of excitatory neocortex-thalamus-neocotrex circuits. Perimetric examination might reveal peripheral, persistent binasal visual field deficit in about 30% of patients treated with VGB. This is probably the effect of cytotoxic influence of enormous accumulation of GABA in retinal neurons. Barbiturates and benzodiazepines can exacerbate intellectual functioning and behaviour. Some emotional and reactive disturbances are more characteristic for newer drugs. Serious depressive reactions and psychoses were observed respectively in 12.5 and 2.5% epileptics under VGB and anecdotically after TGB or GPT therapy. Newer selective and specific gabamimetic AEDs play an essential role as add-on therapy of pharmaco-resistant epilepsy, but they did not bring significant qualitive change in the possibilities of pharmacotherapy.
Chmielewska
B
B
Katedra i Klinika Neurologii Akademii Medycznej w Lublinie. basiach@asklepios.am.lublin.pl
D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism*; D018756:GABA Antagonists / Q000627:therapeutic use*; D006801:Humans; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D005680:gamma-Aminobutyric Acid
Gabaergiczna hipoteza padaczki w obserwacjach klinicznych--kontrowersje dotyczace leków przeciwpadaczkowych aktywujacych układ gabaergiczny.