Theoretical characterization of ion channel blockade. Competitive binding to periodically accessible receptors.

Competitive ligand binding to periodically activated or accessible receptors is influenced by the interaction between ligand binding kinetics and the interval of time the binding site is accessible. This interaction produces a paradoxical reduction in bound receptors under certain conditions. A mathematical description of multi-ligand binding to a single binding site is presented for both the continuously and transiently accessible cases. The theoretical results predict paradoxical "agonism" and are consistent with the results of studies of lidocaine and bupivacaine binding to cardiac sodium channels.