Differential Selectivity of Several Barbiturates on Experimental Seizures and Neurotoxicity in the Mouse

Abstract

Six barbiturates with diverse time-action characteristics--thiopental, pentobarbital, butabarbital, phenobarbital, diphenylbarbiturate, and barbital--were evaluated for "anticonvulsant" and "neurotoxic" effects. For the former, the MES test, clonic seizures induced by pentylenetetrazol, 90 mg/kg, s.c., and maximal seizures produced by pentylenetetrazol, 200 mg/kg, s.c., were employed. For the latter, we used a rotorod technique. Time to peak activity in the MES test was employed as the time for other tests. Pentobarbital required at least neurotoxic doses to produce substantial "anticonvulsant" activity, its protective index ranging from 0.79 to 0.98 in the three tests. Among the drugs tested, phenobarbital and diphenylbarbiturate exhibited the most favorable protective indices, ranging from 2.71 to 3.41 for phenobarbital and from 3.85 to 5.0 for diphenylbarbiturate. Barbital, another drug with a prolonged duration of action, exhibited a range from 0.84 to 2.81. Although a prolonged duration of action is an important characteristic for antiepileptic activity, this property does not confer per se a favorable protective index.

Pentobarbital inhibition of human recombinant α1A P/Q‐type voltage‐gated calcium channels involves slow, open channel block

“…The range of free PB concentrations that produce anticonvulsant activity in man is 50–100 µM (Raines et al . 1979; Heyer and Macdonald, 1982), and for anaesthesia, the range is slightly higher at 50–150 µM (Richards, 1972; Heyer and Macdonald, 1982; Franks and Lieb, 1994).…”

Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro

“…Four drugs were found to reduce selectively the effect of picrotoxin whilst causing only modest potentiation of muscimol. Of these, phenobarbitone is well known to be anticonvulsant in doses that do not cause unacceptable degrees of sedation (Raines, Blake, Richardson & Gilbert, 1979). Methylphenobarbitone is also used as an anticonvulsant but is metabolized to phenobarbitone in vivo (Butler, 1952) so the interactions of the parent compound with picrotoxin in vitro may be of minor relevance.…”

How theories evolved concerning the mechanism of action of barbiturates

“…A principal divergence relates to the unique ability of phenobarbital to protect against seizures at minimally sedating doses. The anesthetic barbiturate pentobarbital is highly effective as an anticonvulsant (ED 50 in mouse maximal electroshock seizure test, 19.3 mg/kg) but it causes motor impairment at anticonvulsant doses (TD 50 , 18.9 mg/kg) (Raines et al., 1979). In contrast, phenobarbital has similar potency to pentobarbital in the seizure test (ED 50 , 22.5 mg/kg), but it is less potent in causing sedation (TD 50 , 61 mg/kg).…”