Simulation of the kinetics of neuromuscular block: implications for speed of onset.
Simulation of the kinetics of neuromuscular block: implications for speed of onset.
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DOI：
10.1213/ane.0b013e31827ee17f
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发表时间：
2013-10
影响因子：
5.7
通讯作者：
Dilger JP
中科院分区：
文献类型：
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作者：
Dilger JP
不同的非去极化肌松药出现瘫痪的时间相差三倍。可能的解释包括：a)药物之间的药代动力学差异和b)药物分子在扩散到神经肌肉接头时被乙酰胆碱受体缓冲。尽管一些药代动力学模型考虑了缓冲扩散，但这些模型既没有考虑受体的高密度，也没有考虑突触的几何形状。在这里，我使用计算机模拟来计算缓冲扩散的动力学。我们的目标是确定缓冲扩散在什么条件下可以解释非去极化肌松药起效时间的差异。蒙特卡罗模拟与真实的大鼠神经肌肉连接的三维模型一起使用。模拟确定了药物结合受体数量的时间依赖性。对1000倍的药物效力范围进行了检查。在一些模拟中，交界处外的药物浓度会瞬间发生变化。在其他模拟中，浓度根据药代动力学模型的预测而变化，该模型假设血浆药物浓度随时间变化。药物在血浆和肌肉之间平衡的速率常数Keo在0.15-0.6min−1之间变化。假设神经肌肉传递有很高的安全裕度，根据受体的占有率计算抽动幅度。一些模拟使用了神经-肌肉接触宽度增加的突触模型。对突触药物浓度瞬时变化的模拟表明，达到50%抽动抑制的时间(起效时间)为0.1-30s，并与药物效力成正比。这与离子导入药物应用于孤立的神经肌肉连接相对应，但太快了，无法解释人类的发病时间。当使用药代动力学模型计算突触外药物浓度时，缓冲扩散增加了强效药物(50%抽动高度的有效浓度小于600 nm的药物)的起效时间。使用KEO=0.6min−1和神经-肌肉接触宽度扩大2-3倍的模型进行的模拟表明，缓冲扩散可以解释非去极化肌松药临床起病时间的差异。蒙特卡罗模拟提供了一种将缓冲扩散纳入药代动力学模型的生物物理上合适的方法。模拟表明，缓冲扩散可以解释不同药物起效时间的差异。然而，在量化缓冲扩散效应的大小之前，需要更好地了解人类神经肌肉连接的几何结构。
The onset time for paralysis varies three-fold among nondepolarizing muscle relaxants. Possible explanations include: a) pharmacokinetic differences among drugs and b) buffering of drug molecules by acetylcholine receptors as they diffuse into the neuromuscular junction. Although some pharmacokinetic models consider buffered diffusion, these models do not account for either the high density of receptors or synapse geometry. Here, I used computer simulations to calculate the kinetics of buffered diffusion. The goal was to determine the conditions under which buffered diffusion could account for differences in onset time among nondepolarizing muscle relaxants. Monte Carlo simulation was used along with a realistic 3-dimensional model of the rat neuromuscular junction. Simulations determined the time dependence of the number of drug-bound receptors. A 1000-fold range of drug potency was examined. In some simulations, the drug concentration outside the junction was changed instantaneously. In other simulations, the concentration changed according to predictions of pharmacokinetic models assuming time-dependent changes in plasma drug concentration. The rate constant for equilibration of drug between plasma and muscle, keo, was varied between 0.15 and 0.6 min−1. Twitch amplitude was calculated from receptor occupancy assuming a high safety margin for neuromuscular transmission. Some simulations used a synaptic model with an increased nerve-muscle contact width. Simulations with instantaneous changes in drug concentration at the synapse, indicated that the time to 50% twitch depression (onset time) was 0.1–30s and was proportional to drug potency. This corresponds to iontophoretic application of drug to isolated neuromuscular junctions, but is too fast to explain onset times in humans. When pharmacokinetic models were used to calculate the drug concentration outside of the synapse, buffered diffusion increased onset times of potent drugs (drugs for which the effective concentration at 50% twitch height is less than 600 nM). Simulations using keo=0.6 min−1 and a model with a 2–3 fold wider nerve-muscle contact width indicated that buffered diffusion could account for the differences in clinical onset times among the nondepolarizing muscle relaxants. Monte-Carlo simulation provides a biophysically appropriate way to incorporate buffered diffusion into pharmacokinetic modeling. The simulations indicated that buffered diffusion could account for differences in onset time among drugs. However, a better understanding of the geometry of the human neuromuscular junction is needed before the magnitude of the effect of buffered diffusion can be quantified.