716 Review Articles Medical Education Clinical use and toxicity W. Zink · M. Ulrich of local anaesthetics Citation: Zink W, Ulrich M: Clinical use and toxicity of local anaesthetics. Anästh Intensivmed 2018;59:716­727. DOI: 10.19224/ai2018.716 Summary were an early driving force in the develop­ ment of new substances [1,2]. Once Local anaesthetics are widely used in the chemical structure of cocaine had contemporary clinical practice. Regard­ been established, attempts were made to less of their specific physicochemical reduce its toxicity by changing the mo­ properties and chemical structures, all lecular structure – an undertaking which local anaesthetic agents block neuro­ succeeded in 1905 when procaine, a syn­ nal voltage­gated sodium channels, thetic amino ester local anaesthetic, was suppressing conduction in peripheral synthesised. To this day, that substance nerves. Furthermore, these agents are is used as a reference standard for local characterised by numerous (sub­)cellular anaesthetic potency. A further milestone effects. Despite the fact that local anaes­ was reached when in 1943 lidocaine, thetics with markedly decreased toxic one of the first amino amide type local potential have been developed, systemic anaesthetics, was introduced into clinical intoxication still may be life­threatening. practice. Amino amide type local anaes­ Amongst other things, this severe com­ thetics provide a longer duration of action plication is the result of an unselective and are chemically more stable than ester block of neuronal and cardiac sodium types and so gained increasing clinical channels following excessive systemic significance in the decades that followed. accumulation, impairing central nervous In 1979, however, toxicity hinted at a and cardiac function. In contrast, the renewed setback for local anaesthesia clinical impact of local anaesthetic tissue when George A. Albright was able to toxicity is controversial, as in many cases show that a series of fatal complications there is a lack of clinical symptoms. during obstetric anaesthesia had been caused by the administration of high­dose Historic aspects bupivacaine or etidocaine [3]. In the after­ math, intensive efforts were undertaken Just a short while after local anaesthesia to determine the pathogenic mechanisms was first successfully performed in 1884 of local anaesthetic toxicity in detail, and by Karl Koller, an ophthalmic surgeon so to develop less toxic substances [4]. from Wien, it became apparent that One important finding was that optical cocaine – which he had used as a local isomers of the same substance showed anaesthetic – was not an ideal substance different affinities to voltage­gated sodium Keywords + for the job. Complications – some of channels (Na channels) and as such Local Anaesthetics – Sodium them fatal – were noted more and more possess differing toxic potentials [5]. This Channel Block – Alternative often, dashing hopes that an alternative finding resulted in the introduction of the Effects – Toxicity – Neuro­ to contemporary ether anaesthesia could “pure” local anaesthetic isomers ropi­ toxicity – Myotoxicity – Chon dro­ be established. It was for this reason that vacaine and levobupivacaine into clinical toxicity toxic complications of local anaesthesia practice. Medical Education Review Articles 717 Structure and mechanism of metrical carbon (C) atom with four The local anaesthetic potency of a different ligands which can take on action substance and the toxicity of that varying spatial configurations. This substance are determined by its spe­ results in the formation of two stereo­ Structure cific physicochemical properties, in isomers (or enantiomers) per asym­ Although a number of organic chemical particular by the type of substituent metrical C atom. These are identical compounds display local anaesthetic on the aromatic moiety and by its in their chemical structure, but their properties (ketamine is one example), optical activity [2,6]. ligands are spatially distributed in only amino esters and amino amides such a fashion that they cannot be are used in clinical practice. These two • The influence of the substituents can converted into one another by rota­ classes of substance share a character­ be shown using the example of the tion. Instead, the isomers behave as istic molecular structure made up – as three pipecoloxylidide derivates me­ image and mirror image to one an­ pivacaine, ropivacaine and (levo­) described by the so called Löfgren sche­ other or as the right to the left hand, bupivacaine. If the methyl group on matic (Figure 1) – of three sections [2,6]: so that the term chirality (handed­ the aromatic moiety of mepivacaine ness) is used in describing the rela­ • The aromatic moiety primarily is replaced by a higher alkyl chain, tionship. Stereoisomers distinguish determines the lipophilicity of the ropivacaine (propyl moiety) or bupi­ themselves by their ability to rotate local anaesthetic. vacaine (butyl moiety) is synthesised. polarised light within an aqueous • The tertiary amide of the amino This modification of the substituents solution – those which are optically group (substituted amino­nitrogen) increases the specific lipophilicity active will rotate the plane of light is present either in its protonated or [2,7], which in turn increases the by the same angle, but to the right or deprotonated (base) form and when analgesic potency, duration of action the left, clockwise or anticlockwise. positively charged constitutes the but also the systemic toxicity of the Racemates – which contain an equi­ hydrophilic end of the molecule. substance. When the length of the molar mixture of stereoisomers – are, • The intermediate chain connects alkyl chain on the aromatic moiety however, optically inactive because the aromatic moiety to the amino exceeds four carbon atoms the local the deflection of light cancels itself group and determines the categori­ anaesthetic potency will increase out. Optical activity is clinically sation of the substance as an amino further – but systemic toxicity in­ relevant because the pharmacodyna­ amide or amino ester, whilst also creases so abruptly that clinical use mics of the stereoisomers can differ influencing the pharmacokinetics of the substance forbids itself. significantly when they interact with of the substance, amongst other • The optical activity of some local other chiral molecules such as mem­ things. anaesthetics results from an asym­ brane­bound proteins (ion channels, receptors etc.) [6,8,9]. For example, laevorotatory S(­)­isomers of bupi­ vacaine and ropivacaine show signi­ Figure 1 ficantly smaller effects on cardiac Na+ channels than do the racemates or dextrorotatory R(+)­isomers, and as H2N such are less cardiotoxic. It was for this reason that the use of S(­)­ropi­ Amino ester – local anaesthetic vacaine and levobupivacaine was (procaine) introduced into clinical practice – a first for pure stereoisomers – whilst the other optically active local anaes­ CH 3 thetics are currently still used in their racemic form. Mechanism of action CH3 On a molecular level, the mechanism of action of local anaesthetics essen­ Amino amide – local anaesthetic (lidocaine) tially rests on the reversible blockade of Na+ channels in neuronal mem­ branes, inhibiting the formation and Schematic of the Aromatic moiety Intermediate chain Tertiary amide propagation of action potentials (lipophilic end) (0.6 – 0.9 nm) (hydrophilic end) molecular structure of local anaesthetics. [6,10]. 718 Review Articles Medical Education Na+ channels consist of at least two sub­ sion into the cell and then interact with plasma concentrations are delayed [7,12]. units, namely the larger α­subunit and intracellular receptors on neuronal When perfusion at the injection site is the smaller β­subunits. The α­subunit Na+ channels. The binding affinity to unphysiologically increased, however, forms the transmembrane core of the closed active channels is relatively systemic absorption may be unexpectedly channel, whilst the β­subunits are low, whereas it is high to closed rapid and peak plasma concentrations mainly responsible for anchoring the inactive and to open channels. Other reached early. channel within the cell membrane. To than this classic mode of hydrophobic The perfusion at the injection site is date, ten different ­subunits have been α block other blocking mechanisms are increased by vasodilatory effects of the identified, nine of which functionally currently being postulated [13]. local anaesthetics. Co­injection of vaso­ act as sodium channels; they have been constrictors (e.g. adrenaline 1:200,000) named Nav1.1 to Nav1.9 [6,11]. The can counter the vasodilatory effect and α­subunits are made up of four domains Pharmacokinetic aspects increase the clinical duration of action of with six transmembrane segments each. the anaesthetic [14]. Every organ system is characterised Systemic absorption by a specific pattern of distribution of Following absorption into the blood­ α­subunits. As an example, peripheral The extent and kinetics of systemic stream, local anaesthetics are transpor­ nerves express every type of α­subunit absorption are dependent on the per­- ted bound to varying degrees to plasma bar Nav1.4, whereby this diversity is fusion and density of the capillary proteins – a dynamic equilibrium between seen less in motor and proprioceptive network at the injection site and on free molecules and those bound to A fibres but rather in nociceptive C the physicochemical properties of plasma proteins