Anesth Analg 2002;95:1459
© 2002 International Anesthesia Research Society
LETTERS TO THE EDITOR
The Potency of New Muscle Relaxants on Recombinant Muscle-Type Acetylcholine Receptors
Vladimir Nigrovic, MD
Department of Anesthesiology, Medical College of Ohio, Toledo, Ohio
To the Editor: I congratulate Dr. Paul and coworkers on their exciting findings (1). Three questions related to these findings come to mind.
- In view of the frequently discussed relationship between the onset of neuromuscular block and potency of muscle relaxants, did the authors observe a dependence of the onset and offset rates of inhibition on the potency of muscle relaxants (defined as IC50 at the
 -nAChR)?
- The Hill exponent of around 1 for -nAChR (as shown in the authors’ Table 1) is smaller than the exponent in dose-response studies in humans, reported to vary from 4 to 6 (2). Can the authors offer reasons for this difference?
- Figure 5 from Dr. Paul and colleagues’ article relates the values of IC50to the ED50values in humans. The correlation might have been more meaningful if IC50 (a concentration) were related to IC50 (also a concentration) for producing neuromuscular block in vitro. Such data are, for example, available for guinea-pig phrenic nerve-diaphragm preparation (3). The correlation is similar to that presented in Figure 5. However, the IC50 values reported by Paul and coworkers (1) are between 30 and 60 times lower than the in vitro IC50 values for neuromuscular block. Is there a reason for this difference?
References
- Paul M, Kindler CH, Fokt RM, Dresser MI, Dipps NCJ, Yost CS. The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors. Anesth Analg 2002; 94: 597–603.[Abstract/Free Full Text]
- Kopman A, Klewicka M, Neuman G. An alternative method for estimating the dose-response relationships of neuromuscular blocking drugs. Anesth Analg 2000; 90: 1191–7.[Abstract/Free Full Text]
- Vizi ES, Lendvai B. Side effects of nondepolarizing muscle relaxants: Relationship to their antinicotinic and antimuscarinic actions. Pharmacol Ther 1997; 73: 75–89.[Medline]
Response
Matthias Paul,
Christoph H. Kindler, and
C. Spencer Yost
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California
In Response: Dr. Nigrovic has raised some interesting points. First, our study did not attempt to investigate differences in the clinical onset and offset times of muscle relaxants measured by the twitch depression. These effects span the range of tens of seconds to minutes in vivo and incorporate variables such as blood flow, protein binding, and membrane permeability. In our study, muscle relaxants were applied directly onto the receptor in less than 1 second (chamber size of 25 µl, perfusion rate of 4–5 ml /min), and the peak-effect (i.e. the peak current) followed almost instantly. However, these drug application speeds were still not rapid enough to determine agent-specific differences in onset or offset at the receptor level.
Second, Hill coefficients relate drug concentrations to effects and can only be compared when the effects are similar. In our study, the effect (namely the inhibition of acetylcholine-activated currents) was produced directly by ligand on the naked receptor, and the resulting Hill coefficient of about 1 was in agreement with blockade of one receptor-binding site. In vivo studies use force of muscle contraction as the effect, which is not directly produced by a ligand, but which is interposed between a current-contraction relationship. Thus, the two derived Hill coefficients are not comparable. In addition, presynaptic effects of nondepolarizing muscle relaxants may be involved that would have a significant effect on the Hill coefficient found with in vivo studies.
Finally, the ultimate aim of our study was to examine the relative potencies of muscle relaxants using a postsynaptic model, not to find a model representing absolute potencies found in vivo. Any two models (recombinant nAChRs expressed in oocytes versus guinea pig hemidiaphragm) are likely to produce different absolute IC50 values. However, as suggested by Dr. Nigrovic, we have made a comparison between the relative IC50 values for different muscle relaxants from our study (nanomolar range) (1) and the relative IC50 values determined with guinea pig hemidiaphragm (micromolar range) (2), and the same potency relationships were found (Fig. 1). This striking correlation supports our conclusion that the differences in drug dosages needed to achieve clinically appropriate muscle relaxation appear to be governed by differences in drug-receptor affinity.
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Figure 1. Correlation of half-maximal response (IC50) values at the adult muscle-type nicotinic acetylcholine receptor (1) and published IC50 values for reduction of muscle twitch in a guinea-pig hemidiaphragm model (2).
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References
- Paul M, Kindler CH, Fokt RM, Dresser MI, Dipps NCJ, Yost CS. The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors. Anesth Analg 2002; 94: 597–603.
- Vizi ES, Lendvai B. Side effects of nondepolarizing muscle relaxants: relationship to their antinicotinic and antimuscarinic actions. Pharmacol Ther 1997; 73: 75–89.
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