Influence of some beta-adrenoceptor antagonists on the anticonvulsant potency of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.