NEUROMUSCULAR BLOCKADE - OFFSET ANOMALIES - ARE THEY SIMPLY POTENCY-RELATED RECEPTOR BONDING EFFECTS

Rapid making and breaking of bonds between quaternary ammonium compoun ds and cholinergic receptors is typical of ion-pair bonding, which is weak, and ion-pair reactions, which are extremely fast. These properti es explain the observed rapid association and dissociation of turbocur arine at receptors. The time course receptor offset is determined by t wo factors, buffered diffusion due to repetitive bonding, and a potenc y-related offset-retarding effect. The strength of the latter is a fun ction of chemical structure, which determines the microscopic molecula r rate of drug-receptor association and dissociation. Together, buffer ed diffusion and the potency-related offset-retarding effect provide a complete rational physico-chemical explanation for the marked, yet va riable, differences between onset and offset times of non-depolarizing neuromuscular blocking agents. The influence of a potency-related off set-retarding effect together with differing structural requirements f or neuromuscular blocking potency and plasma carboxyesterase hydrolysi s, suggests that a high potency ultrashort duration block is unlikely to be achieved in a non-depolarizing compound metabolized by plasma es terases alone.