Bouillon T, Garstka G, Stafforst D, Shafer S, Schwilden H, Hoeft A
Department of Anesthesia, Inselspital Berne, Berne, Switzerland.
Acta Anaesthesiol Scand. 2003 Nov;47(10):1231-41. doi: 10.1046/j.1399-6576.2003.00251.x.
The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action.
Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data.
The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50.
Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.
某些阿片类药物引起的呼吸抑制是否比其他药物轻这一问题尚未得到最终解答。我们应用药代动力学/药效学（PKPD）模型来估算二氧化碳清除率降低50%时的血药浓度（C50），以此衡量阿芬太尼和匹利卡明这两种药代动力学差异极大且呼吸抑制作用明显不同的阿片类药物的呼吸抑制效能。
23例患者分别接受阿芬太尼（2.3微克·千克⁻¹·分钟⁻¹，14例患者，如先前发表）或匹利卡明（17.9微克·千克⁻¹·分钟⁻¹，9例患者）治疗，直至出现明显的呼吸抑制。通过频繁采集动脉血样来测定阿片类药物的药代动力学和动脉血二氧化碳分压（PaCO2）。使用一个间接反应模型来描述PaCO2数据，该模型考虑了因PaCO2升高引起的呼吸刺激。
使用NONMEM软件估算出以下药效学参数[总体均值和个体间变异（CV）]：k(elCO2)（二氧化碳清除率常数）0.144（单位：分钟⁻¹），F（二氧化碳反应增益）4.0（根据文献值固定）（28%），C50（两种药物）61.3微克/升（41%），k(eo阿芬太尼) 0.654（单位：分钟⁻¹）以及k(eo匹利卡明) 0.023（单位：分钟⁻¹）。与具有相同C50的模型相比，为阿芬太尼和匹利卡明分别设定C50值并不能改善拟合效果。
由于C50值没有差异，两种药物的呼吸抑制效能相当。与阿芬太尼相比，匹利卡明显著较低的呼吸抑制作用是由血浆与效应部位之间较慢的平衡过程所致。推广我们的研究结果并基于模拟分析，我们得出结论，与像阿芬太尼这样平衡较快的阿片类药物相比，像匹利卡明这样平衡较慢的阿片类药物在呼吸抑制方面本质上更安全。
