Mazoit Jean-Xavier, Dalens Bernard J
Département d'Anesthésie-Réanimation, Hôpital Bicêtre, and UPRES EA 392, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Clin Pharmacokinet. 2004;43(1):17-32. doi: 10.2165/00003088-200443010-00002.
Amide local anaesthetics used for regional anaesthesia in paediatric patients are potent sodium channel blockers with marked stereospecificity, which consistently influences their action, especially their toxic action on the heart. At toxic concentrations, they induce severe arrhythmias with the potential for cardiac arrest. These agents are all bound to serum proteins, mainly to alpha(1)-acid glycoprotein (AAG), but also to human serum albumin. Protein binding ranges from 65% (lidocaine) to more than 95% (bupivacaine, ropivacaine). Because AAG is a major acute phase protein, its concentration rapidly increases when inflammatory processes develop, particularly during the postoperative period. Neonates and infants have a lower AAG concentration in serum as compared with adults; therefore, their free fraction of local anaesthetics is increased accordingly. This has important clinical implications since, at least at steady state, the toxic effects of local anaesthetics are directly related to the free (unbound) drug concentration. After injection into the epidural space, absorption into the bloodstream follows a biphasic process. The buffering properties of the epidural space are important and prevent a rapid rise in concentration. In infants and children, the epidural space seems to protect patients in a similar manner. Moreover, it has been observed that the peak plasma concentration (C(max)) of ropivacaine is delayed in infants and children when compared with adults. The time to C(max) decreases from 90-120 minutes in infants aged less than 6 months to 30 minutes in children aged more than 8 years. This delay in C(max) may also be related to the lower clearance observed in younger patients. Local anaesthetics are metabolised by cytochrome P450 (CYP). The main CYP isoforms involved are CYP3A4 for lidocaine and bupivacaine and CYP1A2 for ropivacaine. CYP3A4 is not mature at birth but is partly replaced by CYP3A7. The intrinsic clearance of bupivacaine is only one-third of that in adults at 1 month of age, and two-thirds at 6 months. CYP1A2 is not fully mature before the age of 3 years. Indeed, the clearance of ropivacaine does not reach its maximum before the age of 5 years. However, at birth this clearance is not as low as expected, and ropivacaine may be used even in younger patients.
用于小儿区域麻醉的酰胺类局部麻醉药是强效钠通道阻滞剂，具有显著的立体特异性，这始终会影响其作用，尤其是对心脏的毒性作用。在中毒浓度时，它们会诱发严重心律失常，甚至有心脏骤停的风险。这些药物都与血清蛋白结合，主要是与α(1)-酸性糖蛋白（AAG）结合，但也与人血清白蛋白结合。蛋白结合率从65%（利多卡因）到超过95%（布比卡因、罗哌卡因）不等。由于AAG是一种主要的急性期蛋白，当炎症过程发生时，尤其是在术后期间，其浓度会迅速升高。与成人相比，新生儿和婴儿血清中的AAG浓度较低；因此，他们局部麻醉药的游离部分相应增加。这具有重要的临床意义，因为至少在稳态时，局部麻醉药的毒性作用与游离（未结合）药物浓度直接相关。注入硬膜外腔后，药物吸收进入血液遵循双相过程。硬膜外腔的缓冲特性很重要，可防止浓度迅速升高。在婴儿和儿童中，硬膜外腔似乎以类似方式保护患者。此外，已观察到与成人相比，婴儿和儿童罗哌卡因的血浆峰浓度（C(max)）会延迟出现。C(max)出现的时间从小于6个月婴儿的90 - 120分钟降至大于8岁儿童的30分钟。C(max)的这种延迟也可能与年轻患者中观察到的较低清除率有关。局部麻醉药由细胞色素P450（CYP）代谢。涉及的主要CYP同工酶是利多卡因和布比卡因的CYP3A4以及罗哌卡因的CYP1A2。CYP3A4在出生时不成熟，但部分被CYP3A7取代。布比卡因的内在清除率在1个月大时仅为成人的三分之一，6个月时为三分之二。CYP1A2在3岁之前未完全成熟。实际上，罗哌卡因的清除率在5岁之前未达到最大值。然而，在出生时这种清除率并不像预期的那么低，罗哌卡因甚至可用于更年幼的患者。
