Neuromuscular blockade: offset anomalies. Are they simply potency-related receptor bonding effects?

Rapid making and breaking of bonds between quaternary ammonium compounds and cholinergic receptors is typical of ion-pair bonding, which is weak, and ion-pair reactions, which are extremely fast. These properties explain the observed rapid association and dissociation of turbocurarine at receptors. The time course receptor offset is determined by two factors, buffered diffusion due to repetitive bonding, and a potency-related offset-retarding effect. The strength of the latter is a function of chemical structure, which determines the microscopic molecular rate of drug-receptor association and dissociation. Together, buffered diffusion and the potency-related offset-retarding effect provide a complete rational physico-chemical explanation for the marked, yet variable, differences between onset and offset times of non-depolarizing neuromuscular blocking agents. The influence of a potency-related offset-retarding effect together with differing structural requirements for neuromuscular blocking potency and plasma carboxyesterase hydrolysis, suggests that a high potency ultrashort duration block is unlikely to be achieved in a non-depolarizing compound metabolized by plasma esterases alone.