Mather L E, Chang D H
Centre for Anaesthesia and Pain Management Research, University of Sydney at Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Drugs. 2001;61(3):333-42. doi: 10.2165/00003495-200161030-00002.
The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a 'blunt instrument' in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as 'safer', but they must not be regarded as 'safe'.
人们认识到长效局麻药，尤其是布比卡因（事实上的长效局麻药标准品），其心脏毒性比短效局麻药大得多，这推动了布比卡因同系物罗哌卡因和左旋布比卡因的研发。这些药物与所有局麻药一样，可通过直接和间接机制产生心脏毒性后遗症，这些机制源于其局麻作用方式，即抑制电压门控离子通道。虽然所有局麻药都可引起直接负性肌力作用，但从实验室动物制剂在出现严重心脏毒性（尤其是电机械分离或恶性室性心律失常）之前所能耐受的较大剂量判断，罗哌卡因和左旋布比卡因的心脏毒性比布比卡因小。此外，从癫痫发作前所能耐受的较大剂量判断，它们对中枢神经系统的毒性也比布比卡因小。这在临床上可能很重要，因为中枢神经系统效应可能与严重心脏毒性的发生有关。由于人类临床前研究中可用剂量相对较小，其区分这些药物之间显著差异的能力是一种“钝器”。然而，来自人体研究的现有证据证实了临床前实验室动物研究的结果。由于这些药物之间临床上的显著差异更多是定量的而非定性 的，即毒性表现前能耐受更大剂量，我们得出结论，这些新型药物引起严重心脏毒性的风险比布比卡因低。因此，与布比卡因相比，新型药物可能被视为“更安全”，但绝不能被视为“安全”。
