Vigabatrin effect

Mattson, R.H., Petroff, O., Rothman, D., Behar, K. Vigabatrin effects on human brain GABA levels by nuclear magnetic resonance spectroscopy. Epilepsia 35 (SuppL 5), S29-S32, 1994. 

Coupland SG, Zackon DH, Leonard BC, Ross TM. Vigabatrin effect on inner retinal function. Ophthalmology 2001 108(8) 1493-6. 

Johnson MA, Krauss GL, Miller NR, Medura M, Paul SR. Visual function loss from vigabatrin effect of stopping the drug. Neurology 2000 55(l) 40-5. 

Vigabatrin has an unacceptable adverse effect profile, but consistent findings in animal studies suggest that GABA agonists deserve further study. a-AMPA antagonism, or antikindling action, may also be important for some anticonvulsants. 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

Vigabatrin is a new antiepileptic for use in epilepsy unresponsive to other therapy. It is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for inactivation of the neurotransmitter GABA and it has shown efficacy against partial and secondarily generalized seizures. The principal unwanted effects are psychiatric disorders, including depression and psychosis, in a small number of patients. 

In accordance with these general points, all adverse effects must be reported to the nearest Pharmacovigilance Center. This Center makes the causality assessment and may inidate any necessary national surveys (e.g. concentric narrowing of the visual field with vigabatrin in 30% of cases)... 

Tolerance may occur which means that the effect of some AEDs may wear off with time (benzodiazepines, barbiturates, vigabatrin). There are exceptional cases where refractory epilepsy escapes... 

At present, the primary indication for vigabatrin is in the treatment of patients with partial seizures, but it appears to be an effective and generally well tolerated antiepileptic medication for other seizure types as well. It should not be used in patients with absence epilepsy or with myoclonic seizures. Vigabatrin is not approved as an AED in the United States, although it is approved in many other countries. 

Kayemba Kay, S.S., Beust, M., Aboulghit, H., Voisin, M., and Mout-tada, A. (1997) Catbamazepine and vigabatrin in epileptic pteg-nant woman and side effects in the newborn infant, [in French]. Arch Pediatr 4 975-978. 

The answer is c. (Hardman, p 481. Katzung, pp 404-405.) Vigabatrin is useful in partial seizures. It is an irreversible inhibitor of GABA aminotransferase, an enzyme responsible for the termination of GABA action. This results in accumulation of GABA at synaptic sites, thereby enhancing its effect. 

Changes in body weight associated with anticonvulsants have been reviewed (116), including the effects of the antiepileptic drugs that have been most commonly associated with this adverse effect (valproic acid, carbamazepine, vigabatrin, and gabapentin) (117). Unlike most anticonvulsants, topiramate, felbamate, and zonisamide can cause weight loss. 

Vigabatrin is rapidly and completely absorbed after oral administration and about 80% of the dose is recovered in the urine [4]. In healthy volunteers, its absorption was rapid and beak plasma concentrations occurred within 2 h [65]. The effect of food on the bioavailability of vigabatrin tablets has been studied [4, 66]. The AUC for fasted and fed volunteers was not significantly different. This indicates that food does not alter the extent of absorption. The pharmacokinetics profiles of vigabatrin in tablet form and in solution were strikingly similar [66]. 

The pharmacologic activity and the toxic effects of vigabatrin is associated only with S(+) enantiomer. The R(—) enantiomer appears to be entirely inactive [78]. Because the target enzyme, GABA transaminase (GABA-T), has a longer half-life than the drug itself [79, 80]. The... 

Another major concern for toxicity of vigabatrin is sever persistent visual field constriction associated with retinal cone system dysfunction [63, 82], The effect did not appear to be reversible upon discontinuation of the drug. Vigabatrin also causes GABA to accumulate in retinal glial cells in rats, suggesting a mechanism for the toxic effect [83]. 

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