Onset of the neuromuscular block simulated in an anatomical model

• Published in: British journal of clinical pharmacology Vol. 43; no. 1; pp. 55 - 63
• Main Authors: Nigrovic, V, Banoub, A, Diefenbach, C, Mellinghoff, H, Buzello, W
• Format: Journal Article
• Language: English
• Published: England 01-01-1997
• Subjects: Dose-Response Relationship, Drug; Humans; Models, Biological; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents - pharmacokinetics; Neuromuscular Nondepolarizing Agents - pharmacology; Receptors, Drug - metabolism; Time Factors
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.1997.tb00033.x

The aim of this study was to develop a pharmacodynamic model for nondepolarizing muscle relaxants (neuromuscular blocking agents, NMBAs) based on anatomical, physiological, and pharmacological considerations and analyse whether the time to onset of the submaximal neuromuscular block (NMB) depends on the affinities of the NMBAs for the postsynaptic receptors or on the pharmacokinetic properties of the NMBAs.
A quantitative description of the development of neuromuscular block was achieved by formulating a pharmacodynamic model based on anatomical, physiological and pharmacological considerations. The principal characteristics of the model are: (1) Diffusion of the NMBAs out of the capillaries into the interstitial space of muscle and from there into the synaptic space of the motor end plates (2) Receptor concentration in the synaptic space of 300 microM and the total amount of receptors in 100 g muscle of between 1.43 x (10(-11) to 10(-10) mol. (3) Interaction of NMBAs with the receptors defined by the association (k(assoc) = 4 x 10(8) min-1 x M-1) and dissociation (k(dissoc) one of 4, 40, or 400 min-1) rate constants.
The simulations demonstrated that different affinities of the NMBAs for the postsynaptic receptors (defined by k(assoc)/k(dissoc)) do not influence the onset of the submaximal NMB. On the other hand, the time to the peak submaximal NMB is dependent on the pharmacokinetic properties of the drugs: Those NMBAs that leave plasma rapidly produce the block faster but the fraction of the dose that contributes to the block is small. This fraction is larger for those NMBAs that produce NMB later and, hence, these NMBAs require smaller equieffective doses.
We conclude that those muscle relaxants that produce neuromuscular block rapidly require larger equieffective doses due to their more rapid initial disappearance from plasma.