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Toxikologie der Lokalanästhetika

Pathomechanismen—Klinik—Therapie

  • Leitthema
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Zusammenfassung

Unabhängig von ihren physikochemischen Eigenschaften und ihrer chemischen Struktur blockieren sämtliche Lokalanästhetika spannungsgesteuerte Na+-Kanäle und verhindern somit die Erregungsweiterleitung in peripheren Nerven. Da derartige Ionenkanäle aber nicht nur an der Erregungsweiterleitung im peripheren Nerv beteiligt sind, kommt es bei exzessiver Anreicherung der Lokalanästhetika im menschlichen Organismus zu einer generalisierten Funktionseinschränkung erregbarer Membranen. Klinisch äußert sich die systemische Toxizität der Lokalanästhetika v. a. in einer Beeinträchtigung des zentralen Nervensystems (ZNS) sowie des kardiovaskulären Systems.

Hinsichtlich des ZNS zeigen sich die in charakteristischer Reihenfolge auftretenden Symptome als weit gehend unabhängig vom verwendeten Lokalanästhetikum; die jeweiligen toxischen Plasmaspiegel sind jedoch in hohem Maße substanzspezifisch. Neurophysiologisch beruhen diese Vorgänge zunächst auf einer selektiven Funktionseinschränkung kortikaler inhibitorischer Neuronengruppen; dies begünstigt die subkortikale Entstehung von Krampfpotentialen. Bei weiter steigenden zerebralen Lokalanästhetikakonzentrationen werden im Stadium der zentralnervösen Depression schließlich auch exzitatorische Neuronenverbände blockiert; was sich klinisch als Koma, Apnoe und Kreislaufkollaps manifestiert.

Direkte kardiotoxische Effekte der Lokalanästhetika beruhen hauptsächlich auf einer stereoselektiven Reizleitungsblockade und auf einer unspezifischen Blockade des myokardialen Energiestoffwechsels. Das Spektrum der in dieser Situation auftretenden Symptome ist uneinheitlich und reicht von extremen Bradykardien über (maligne) ventrikuläre Arrhythmien bis hin zum therapierefraktären Herz-Kreislauf-Stillstand.

Von der systemischen Toxizität bzw. von allergischen Reaktionen—letztere werden nach Sensibilisierung überwiegend durch Lokalanästhetika vom Estertyp ausgelöst—müssen lokale zytotoxische Effekte abgegrenzt werden. Substanzspezifisch kann es durch Lokalanästhetika direkt an der Applikationsstelle zu neuronalen und/oder skelettmuskulären Schädigungen kommen, die sich meist innerhalb weniger Tage bis Wochen zurückbilden. Während sich die zentralen neurotoxischen Erscheinungen oftmals klar definierbaren Krankheitsbildern zuordnen lassen („transiente neurologische Symptome“, Cauda-equina-Syndrom), ist die klinische Bedeutung skelettmuskulärer Schäden bislang noch weit gehend unklar.

Die „Therapie“ der zentralnervösen bzw. kardiovaskulären Intoxikation besteht in erster Linie darin, durch entsprechende Vorsichtsmaßnahmen eine systemische Akkumulation der Lokalanästhetika zu vermeiden. Die eigentliche Behandlung einer systemischen Intoxikation erfolgt streng symptomorientiert; hypoxische und azidotische Zustände sind auf jeden Fall zu vermeiden bzw. aggressiv zu korrigieren. Inwieweit experimentelle Therapieansätze auf den menschlichen Organismus zu übertragen sind, bleibt abzuwarten.

Abstract

Regardless of their specific physico-chemical properties and chemical structures, all local anaesthetic agents block neuronal voltage-gated sodium channels, and thus suppress conduction in peripheral nerves. Since these ion channels ubiquitously appear in excitable membranes, systemic accumulation of local anaesthetic agents may affect the functional integrity of these structures.

Clinically, local anaesthetic-induced systemic toxicity results in central nervous and cardiovascular malfunction.

With regard to CNS toxicity, symptoms which are largely drug-independent appear in a characteristic biphasic sequence. Nevertheless, the plasma levels necessary to provoke these symptoms are to a large extent agent-specific. Initially, these toxic mechanisms are due to a selective blockade of cortical inhibitory neurons, which enables the formation of seizure potentials within subcortical structures. With high cerebral drug levels, however, excitatory neurons are also increasingly blocked, resulting in coma, apnoeic episodes and circulatory failure.

Direct cardiac effects of local anaesthetics can be divided into (i) stereospecific inhibition of intracardial conduction and (ii) unspecific inhibition of myocardial energy supply and ion channels. The corresponding spectrum of symptoms is not uniform and may range from extreme bradycardia, (malignant) ventricular arrhythmia to refractory cardiac arrest.

Local tissue toxicity has to be strictly delimited from systemic toxicity and allergies, respectively, which are mainly caused by aminoester agents.

Local anaesthetics may cause neuronal and striated muscle injury at the site of injection. With regard to (central) neurotoxicity, “transient neurologic symptoms” and “cauda equina syndrome” have been increasingly recognised. However, the clinical relevance of local anaesthetic-induced myotoxicity is still controversly discussed.

In order to avoid systemic accumulation of local anaesthetic agents, several safety procedures have to be considered during the application of these drugs. The treatment of systemic toxicity is strictly dependent on the expression of symptoms. However, hypoxia and acidotic episodes must be avoided and must be treated aggressively.

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  1. Klinik für Anaesthesiologie, Universitätsklinikum Heidelberg

    W. Zink & B. M. Graf

  2. Klinik für Anaesthesiologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg

    W. Zink

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  1. W. Zink
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  2. B. M. Graf
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Correspondence to W. Zink.

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Zink, W., Graf, B.M. Toxikologie der Lokalanästhetika. Anaesthesist 52, 1102–1123 (2003). https://doi.org/10.1007/s00101-003-0617-5

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