LETTERS TO THE EDITOR: Letters & Announcements
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.
Christoph H. Kindler
C. Spencer Yost
1. 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.
2. Vizi ES, Lendvai B. Side effects of nondepolarizing muscle relaxants: relationship to their antinicotinic and antimuscarinic actions. Pharmacol Ther 1997; 73: 75–89.