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The Pharmacodynamics and Pharmacokinetics of Alcuronium

Parker, C. J. R. MA, MD, FRCA; Hunter, J. M. MB, BCh, PhD, FRCA

Letter to the Editor
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University Department of Anaesthesia, Royal Liverpool University Hospital, Liverpool, L69 3BX United Kingdom.

To the Editor:

We congratulate Dr. Diefenbach and his colleagues on their report [1]; it is a useful addition to the literature. We would like to comment on the methods used to analyze the data.

The effect model is mixed with the model for disposition; thus, it is not clear what the pharmacokinetic model is modeling. The usual purpose of peripheral compartments in such a model is to explain the multiexponential decline in plasma concentration profile, and their parameters are specified by the plasma concentration profile alone. The concentration profile in any peripheral compartment is not necessarily similar to that at the site of effect. A better approach was provided by Sheiner et al. [2], who postulated an effect compartment of negligible volume.

The Hill Equation isused to relate effect to hypothetical peripheral compartment concentrations. This implies that zero effect is associated with zero drug concentration. The data presented (Table 1) give robust evidence that this is not the case. By 390 min after administration, when drug effect had regressed completely, the plasma concentration was still 0.2 mg/L, and the peripheral compartment concentration would be somewhat higher (Figure 1). There is thus a threshold for neuromuscular block, which is to be expected because the neuromuscular junction has a considerable "margin of safety" [3]. It is possible to incorporate this threshold into the pharmacodynamic model [4]. To do so would give more correct values of the midpoint and slope of the concentration-effect curve and, in particular, a lower slope.

C. J. R. Parker, MA, MD, FRCA

J. M. Hunter, MB, BCh, PhD, FRCA

University Department of Anaesthesia, Royal Liverpool University Hospital, Liverpool, L69 3BX United Kingdom

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REFERENCES

1. Diefenbach C, Kunzer T, Buzello CW, Theisohn M. Alcuronium: a pharmacodynamic and pharmacokinetic update. Anesth Analg 1995;80:373-7.
2. Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modelling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979;25:358-71.
3. Paton WDM, Waud DR. The margin of safety of neuromuscular transmission. J Physiol 1967;191:59-90.
4. Parker CJR, Hunter JM. A new four parameter threshold model for the plasma atracurium concentration relationship. Br J Anaesth 1992;68:548-54.
© 1995 International Anesthesia Research Society