Anticonvulsant profile of flunarizine and relation to Na(+) channel blocking effects.

Abstract

The present study will summarize our findings concerning the anticonvulsant properties of the Ca2+ channel blocker flunarizine in a variety of experimental models of epilepsy. Flunarizine exhibits anticonvulsant effects against tonic seizures induced by electroshock or various chemoconvulsants in mice, however, did not protect against pentylenetetrazol-induced clonic seizures. In the MES test, the efficacy of clinically established antiepileptics was increased by co-medication. In the rotarod test, a minimal "neurotoxic" dose (TD50) of 18.0 mg/kg intraperitoneally was determined. In models of complex partial seizures like the hippocampal stimulation and the amygdala kindling in rats, flunarizine showed only a moderate activity. Thus, it can be suggested that the anticonvulsant potency of flunarizine in various screening tests is lower than that of standard antiepileptics such as carbamazepine and phenytoin. Concerning the possible mode of action, whole-cell patch-clamp experiments with cultured neonatal rat cardiomyocytes showed that flunarizine depressed the fast inward Na+ current in a concentration- and frequency-dependent manner well comparable with the action of phenytoin. It is concluded that the use-dependent inhibition of voltage-dependent Na+ channels may essentially contribute to the anticonvulsant activity of flunarizine in models for generalized tonic-clonic seizures. The clinical efficacy as add-on therapy is critically discussed in view of the present data.

• Authors: Wolfgang Fischer, Holger Kittner, Ralf Regenthal, Giovambattista De Sarro
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 94 Issue 2 Pg. 79-88 (Feb 2004) ISSN: 1742-7835 [Print] England
• PMID: 14748851 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Calcium Channel Agonists
• Calcium Channel Blockers
• Convulsants
• Sodium Channels
• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
• Flunarizine
• Pentylenetetrazole

Topics

• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester (toxicity)
• Animals
• Anticonvulsants (pharmacology)
• Brain (metabolism)
• Calcium Channel Agonists (toxicity)
• Calcium Channel Blockers (pharmacology)
• Cells, Cultured
• Convulsants (toxicity)
• Dose-Response Relationship, Drug
• Drug Interactions
• Electroshock
• Flunarizine (pharmacology)
• Male
• Mice
• Pentylenetetrazole (toxicity)
• Rats
• Rats, Wistar
• Rotarod Performance Test
• Seizures (chemically induced, drug therapy, etiology)
• Sodium Channels (drug effects)