{n1}04-The toxicity of local anesthetics (part4) « 医药家园

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1. 1、 在gz局麻药毒性的同时，鞘内zaq的选择是什么？
   罗哌卡因的神经毒性在局麻药中{zd1}，局麻药的浓度和其神经毒性是正相关的，要合理的浓度，另外不要加入肾上腺素，会增加损害。
   2、 因为目前所有的局麻药均存在毒性，未来是否会有更好的选择？
   局麻药用于mz最主要是因为其对钠离子通道的抑制，使神经电传导中断，临床常用的局麻药，还对其它离子通道（如钙、钾通道）、受体和酶（如CACT)等产生效应，可导致许多副反应。不管任何物质都应控制一定的量，比如水是生命之源，但水多了可导致水中毒。所以，以后研究的发展，会开发出毒性更小的yw，如罗哌卡因毒性较布比卡因低，但不可能wq根除副反应，最重要的是控制好剂量、掌握好技术、熟悉yw的特点，掌握万一意外情况下的救治。未来肯定有更好的选择，安全性非常高，但不可能能根除，如同我说水的例子。

2. 参考答案：
   局麻药毒性：
   1、 在gz局麻药毒性的同时，鞘内zaq的选择是什么？
   Hodgen等[1]最近综述认为，临床使用的绝大多数脊麻yw尚缺乏关于脊髓和神经根毒性的研究。虽然作者注意到实验研究表明所有局麻药在高浓度情况下均存在神经毒性，但是同时也发现，利多卡因和丁卡因在临床使用剂量下即可产生可能的神经毒性，虽然这两种yw有较长的并令人骄傲的临床安全应用史。这可能更多地出现在使用未经稀释的5%利多卡因时。
   降低局麻药风险的一个可能方法是同时使用中枢给与镇痛剂如mf、芬太尼、舒芬太尼、可乐定，甚至新斯的明。实验研究和大量的临床使用[1]表明，这些yw的神经毒性很低。
   商业产品中使用的绝大多数抗氧化剂、防腐剂、辅料，虽然有一些研究[2]得出相反意见，但绝大多数研究表明这些成分的神经毒性较低[1]。
   2、 因为目前所有的局麻药均存在毒性，未来是否会有更好的选择？
   在降低局麻药相关的毒性方面，有两个可能的发展方向，包括a、生产一种新型的没有毒性的局麻药；b、使用其他替代yw或添加剂。
   Gerner等[3]最近报道了他们在tonicaine（一种四价利多卡因衍生物(N-β-苯乙基-利多卡因)）方面做的工作。作者证明该yw对于小鼠坐骨神经的有效阻滞时间比利多卡因长4-9倍；与运动阻滞相比，感觉阻滞更具有优势。通过tonicaine在GH3细胞的体内使用发现，相对于利多卡因，该yw对于结合位点的亲和力更高；对于Na+通道的阻滞效应为利多卡因的80倍。此外，0.5mM的tonicaine产生阻滞持续时间显著长于布比卡因，即使布比卡因的浓度为tonicaine的55倍（28.8mM），同时感觉阻滞时间长于运动阻滞（112.5 +/- 16.3 min vs. 45.8 +/- 7.1 min）。遗憾的是，因为在低浓度（1.0mM）下存在神经毒性的证据，作者结论认为tonicaine可能临床应用有限。
   最近，海藻毒素及其同系物（tr存在的化合物，为gx能的钠通道阻滞剂）被研究。这些yw被认为没有局麻药神经毒性，单独使用可能产生mz作用，或者与局麻药和用从而降低局麻药剂量。Kohane等[4]在小鼠坐骨神经中使用海藻毒素，与新石房哈毒素、decarbamoyl海藻毒素及河豚毒素（TTX）进行比较，观察这些物质的致死剂量、热痛觉丧失（热板实验）的起效和持续时间、以及运动阻滞情况（承重实验）。参数以25th和75th百分比的中位数表示，测定中位有效浓度。作者发现，达到感觉消失持续60分钟的中位有效浓度分别为：新石房哈毒素34+/-2 micromol/L；海藻毒素58+/-3 micromol/L；TTX 92+/-5 micromol/L；decarbamoyl海藻毒素268+/-8 micromol/L。因为阻滞起效时间、持续时间和致死剂量具有相似的趋势，因此作者结论认为这些物质的zl指数相似，未来这些yw可能会在临床中发挥重要作用。
   Given the concern for local anesthetic toxicity, what are the safest choices for intrathecal use?
   Hodgen et al. (1) in a review of current information, noted that most spinal drugs in clinical use have been poorly studied for spinal cord and nerve root toxicity. Although the authors observed that laboratory studies indicate that all local anesthetics are neurotoxic in high concentrations, lidocaine and tetracaine have been found to have neurotoxic potential in clinically used concentrations, despite their long and enviable clinical history of safety. This may be especially true with the use of undiluted 5% concentrations of lidocaine.
   One potential mechanism of reducing risk is through the concurrent use of centrally administered analgesics such as morphine, fentanyl, sufentanil, clonidine, and even neostigmine, which all appear to have a low potential for neurotoxicity based on laboratory and extensive clinical use (1).
   Most antioxidants, preservatives, and excipients used in commercial formulations seem to have a low potential for neurotoxicity (1), although some exceptions have been observed (2).
   Because current local anesthetics have associated toxicities, what are future alternatives?
   Two potential directions in the reduction of local anesthetic associated toxicity include developing new, less toxic local anesthetics or using other agents as substitutes or adjuncts.
   Gerner et al. (3) recently reported their work with tonicaine, a quaternary lidocaine derivative (N-beta-phenylethyl-lidocaine). The authors demonstrated the duration of effective block in rat sciatic nerve was from four to nine times longer than lidocaine, with a predominance of sensory versus motor blockade. Through the internal application of tonicaine in GH3 cells, the local anesthetic was found to have higher binding site affinity and approximately 80 times the potency in blocking Na+ currents than externally applied lidocaine. In addition, tonicaine at 0.5 mM produced a blockade that lasted signficantly longer than that produced by even a 55 times higher concentration (28.8 mM) of bupivacaine, with a longer duration of sensory than motor blockade (112.5 +/- 16.3 min vs. 45.8 +/- 7.1 min). Unfortunately, due to evidence of neurotoxicity at low concentrations (1.0 mM), the authors concluded that tonicaine may have limited clinical value.
   Recently, saxitoxin and its homologues, which are naturally occurring compounds that block the sodium channel with high potency, have been investigated. Currently believed to be devoid of local neurotoxicity, these agents have the potential for either independently providing anesthesia or reducing dosages of local anesthetics when used concurrently. Kohane et al. (4) compared sciatic nerve blocks in rats with saxitoxin to those with neosaxitoxin, decarbamoyl saxitoxin, and tetrodotoxin (TTX). The compounds were compared in terms of lethal dose, onset and duration of action for thermal analgesia (hot-plate testing), and motor block (weight-bearing). Data were expressed as medians with 25th and 75th percentiles, and median effective concentrations were determined. The authors noted that median concentrations at which analgesia of 60 minutes duration was achieved were neosaxitoxin, 34+/-2 micromol/L; saxitoxin, 58+/-3 micromol/L; TTX, 92+/-5 micromol/L; and decarbamoyl saxitoxin, 268+/-8 micromol/L. As similar trends were observed for block onset, duration and lethal dose, the authors concluded that therapeutic indices of these agents were similar. The authors concluded that these agents may be clincially important in the future.
   References:
   1. Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally. Anesth Analg 1999;88(4):797-809.
   2. Aldrete JA, Johnson DA. Evaluation of intracutaneous testing for investigation of allergy to local anesthetic agents. Anesth Analg 1970;49:173.
   3. Gerner P, Nakamura T, Quan CF, Anthony DC, Wang GK. Spinal tonicaine: potency and differential blockade of sensory and motor functions. Anesthesiology 2000;92(5):1350-60.
   4. Kohane DS, Lu NT, Gokgol-Kline AC, et al. The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo. Reg Anesth Pain Med 2000;25(1):52-9.