Pharmacokinetic Aspects of the Onset of Action of Neuromuscular Blocking Agents

Introduction

In order to understand the factors governing the onset of neuromuscular block, it is important to know the processes following administration of a neuromuscular blocking agent (NMBA), eventually resulting in neuromuscular block. With respect to the processes involved in the time course of neuromuscular block, four steps can be discerned:

Distribution and elimination of the NMBA, i. e., pharmacokinetics; Transport of the NMBA from the blood to the receptor site; Binding of the NMBA to the cholinoceptor; Processes initiated by the binding of the NMBA to the cholinoceptor, eventually resulting in neuromuscular block, i. e., pharmacodynamics.

A powerful tool in understanding the relationship between these processes and the time course of action of NMBAs is pharmacokinetic/pharmacodynamic (PK/PD) modelling [1] [2] [3]. By means of PK/PD analysis the pharmacokinetic behaviour (plasma concentration-time profile, and transport from plasma to the receptor site and vice versa), as well as the pharmacodynamic properties (relationship between the concentration at the receptor site - also called site of action, biophase, or effect compartment - and the effect) can be studied separately. PK/PD modelling and analysis have become essential tools in fundamental research on the factors governing the potency and time course of action of drugs, including the development of new NMBAs with a desired time course of action [4].

In this paper the onset time is defined as the time interval between administration and the time point of the peak effect in case of submaximal neuromuscular block (time to peak effect).

Literatur

• 1 Sheiner L B, Stanski D R, Vozeh S, Miller R D, Ham J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine.  Clin. Pharmacol. Ther.. 1979;  25 358-371
• 2 Donati F, Meistelman C. A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs.  J. Pharmacokinet. Biopharm.. 1991;  19 537-552
• 3 Proost J H, Wierda J MKH, Meijer D KF. An extended pharmacokinetic/pharmacodynamic (PK/PD) model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs.  J. Pharmacokinet. Biopharm.. 1996;  24 45-77
• 4 Wierda J MKH, Proost J H, Muir A W, Marshall R J. Design of drugs for rapid onset.  Anaesth. Pharmacol. Rev.. 1993;  1 57-68
• 5 Beaufort T M, Nigrovic V, Proost J H, Houwertjes M C, Wierda J MKH. Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block.  Anesthesiology. 1998;  89 707-714
• 6 Bowman W C, Rodger I W, Houston J, Marshall R J, McIndewar I. Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat.  Anesthesiology . 1988;  69 57-62
• 7 Kopman A F. Pancuronium, gallamine, and d-tubocurarine compared - is speed of onset inversely related to drug potency.  Anesthesiology. 1989;  70 915-920
• 8 Armstrong D L, Lester H A. The kinetics of tubocurarine action and restricted diffusion within the synaptic cleft.  J. Physiol. (Lond). 1979;  294 365-386