Simulation of the reversal of neuromuscular block by sequestration of the free molecules of the muscle relaxant.

The study examined in simulations the interaction between a muscle relaxant and an antagonist that binds the free molecules of the relaxant, as experimentally demonstrated for rocuronium and sugammadex. The hypothetical muscle relaxant D and the hypothetical antagonist X were assigned pharmacokinetic properties to define the time course of their concentrations in plasma, and pharmacodynamic properties to define binding of D to either X or the receptors at the motor end plates. D, X, and their complex DX were postulated to diffuse between plasma and the effect compartment.

The relationship between twitch depression and twitch fade during neuromuscular block produced by vecuronium: correlation with the release of acetylcholine.

Background: Train-of-four stimulation pattern following the administration of non-depolarizing neuromuscular blocking drugs reveals fade on successive contractions. Fade is caused by the release of fewer acetylcholine molecules by the fourth (A4) than by the first stimulus (A1). The current study was conducted to define the relationship between the clinically observed fade and the simulated decline in acetylcholine release (A4/A1) that would be necessary to produce it.

Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation.

Volume of the effect compartment in simulations of neuromuscular block.

Background: The study examines the role of the volume of the effect compartment in simulations of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants.

Methods: The molar amount of the postsynaptic receptors at the motor end plates in muscle was assumed constant; the apparent receptor concentration in the effect compartment is the ratio of this amount and the volume arbitrarily assigned to the effect compartment. The muscle relaxants were postulated to diffuse between the central and the effect compartment and to bind to the postsynaptic receptors.

Myasthenia gravis and myasthenic syndrome: simulation of twitch strength with or without therapy.

To examine the quantitative relationship between indirectly evoked twitch and decreases in the number of either postsynaptic receptors or acetylcholine molecules released by a single stimulus, we studied these variables in a computer-simulated model of neuromuscular transmission. Twitch strength decreased if the number of receptors decreased to below 30% of normal or the number of acetylcholine molecules released by a stimulus decreased to below 80%. Inhibition of acetylcholine hydrolysis to 50% restored twitch strength in the presence of a decreased number of receptors.

Analysis of the pharmacodynamic parameters in a model for neuromuscular block.

Background: The study examines the roles of the pharmacodynamic parameters and of the assumptions underlying the pharmacokinetic-pharmacodynamic model proposed by Sheiner and coworkers to interpret the time course of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants.

Material/methods: The model of Sheiner et al. was modified by considering (a) a multiexponential equation for the time course of the relaxant's concentrations in plasma, (b) the transport of a hypothetical muscle relaxant from plasma to the site of action via diffusion, and (c) NMB as a function of the relaxant's concentration at the site of action, of gamma and IC50.

Simulation of interaction between two non-depolarizing muscle relaxants: generation of an additive or a supra-additive neuromuscular block.

Goal: To examine in a model of neuromuscular transmission the interaction between two non-depolarizing muscle relaxants. An additive or a supra-additive interaction was evaluated as a function of the affinities of acetylcholine and the muscle relaxants for the two binding sites at a single receptor.

Methods: Affinity of acetylcholine for site1 was postulated to be higher than for site2.

Competition between acetylcholine and a nondepolarizing muscle relaxant for binding to the postsynaptic receptors at the motor end plate: simulation of twitch strength and neuromuscular block.

Unlabelled: The goal of the study was to simulate twitch strength and neuromuscular block produced by nondepolarizing muscle relaxants.

Methods: In the proposed model, affinities of the two binding sites at a single postsynaptic receptor for acetylcholine (A) and the muscle relaxant (D) define the formation of three complexes with A only, three complexes with D only, and two complexes with both A and D. Twitch strength was postulated to be a function of the receptors with both binding sites occupied by A, and two constants.

Physiologic-pharmacologic interpretation of the constants in the Hill equation for neuromuscular block: a hypothesis.

Neuromuscular block (NMB) is simulated in pharmacodynamic models using the concentration of a muscle relaxant (MR) in the effect compartment and two constants, gamma and IC50. No physiologic or pharmacologic interpretation is offered for either constant. We desired to explore whether the constants are properties of the muscle or the MR and to simulate NMB when the MR binds to two sites at a single receptor.