Local Anaesthetics: the Essentials Eur J Anaesthesiol 2014 (Invited Review, in Press)
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UvA-DARE (Digital Academic Repository) Local anesthetics: New insights into risks and benefits Lirk, P. Publication date 2014 Link to publication Citation for published version (APA): Lirk, P. (2014). Local anesthetics: New insights into risks and benefits. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:01 Oct 2021 Local anesthetics – an introduction Chapter 1.2 Local anesthetics: an introduction Based on Lirk P, Picardi S, Hollmann MW Local anaesthetics: the essentials Eur J Anaesthesiol 2014 (invited review, in press) 17 Chapter 1.2 This introductory section is based on an invited Review for the European Journal of Anaesthesiology, and seeks to address 10 essential questions regarding the clinical use of local anaesthetics. Local anaesthetics are a heterogeneous group of compounds which block voltage-gated sodium channels. Each drug is characterized by distinctive physicochemical properties. Sodium channel block is caused by conformational change and the creation of a positive charge in the channel lumen. Different local anaesthetics can reach the LA binding site from the cytoplasmic compartment (“classic hydrophilic pathway”), directly via the lipid membrane (“hydrophobic pathway”), or can enter via large-pore channels (“alternative hydrophilic pathway”). Next to sodium channel blockade, LA exert beneficial effects on pain, stabilize the inflammatory response and the haemostatic system. Inflamed tissue is harder, but not impossible, to anesthetize. Increasing dose or adding a vasoconstrictor, can lead to successful blockade. Systemic toxicity of LA is potentially fatal. When preventative measures are taken, the incidence of cardiac arrest is low. Intralipid has been proposed for resuscitation of systemic LA overdose, and enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood. Intralipid is not an antidote against LA and cannot replace meticulous conduct of regional anaesthesia. All LA are toxic, dependent on dose. The question whether local anaesthetics protect against perioperative tumour progression cannot be answered at this moment, and results from clinical (retrospective) studies are equivocal. Future areas of interest will be design of new subtype-specific sodium channel blockers. At the same time, older LA such as 2-chloroprocaine are reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques in some indications. 18 Local anesthetics – an introduction Local anaesthetics (LA) are widely used for regional anaesthesia and pain therapy. This review seeks to address 10 essential topics regarding LA use in daily practice. General physicochemical properties Local anaesthetics are a heterogeneous group of compounds which block voltage-gated sodium channels. Structurally, LA consist of a hydrophobic aromatic group, an amide group, and the connecting intermediary chain. This means that they possess both hydrophobic and –philic properties. According to the type of intermediary chain, LA can be divided into ester-type and amide-type compounds. According to duration of action, LA can be divided into short-acting (e.g., chloroprocaine), intermediate-acting (e.g., mepivacaine, lidocaine), and long-acting (e.g., bupivacaine, ropivacaine) compounds. The metabolism of esters is by plasma cholinesterases and tissue esterases, whereas amides are primarily metabolized hepatically through the mixed-function oxidase system. 1 Conversely, defects in the metabolizing steps lead to higher systemic concentrations of LA. Concerning allergic potential, currently used LA are widely considered to be among the safest perioperative drugs. 2 All currently used LA are chiral, which means they feature an asymmetric carbon atom and two potential spatial molecular configurations, called enantiomers. The only exception to this rule is lidocaine, which is achiral. 3 The clinical relevance of chirality is that in comparison to racemic mixtures containing both enantiomers, pure enantiomers may offer pharmacologic advantages such as enhanced blockade and decreased toxicity. 4 However, the differences in clinical use when comparing equipotent doses are modest, such that both conventional drugs as bupivacaine, as well as the newer isoforms continue to be in widespread use. 5 LA have distinct physicochemical properties which determine their mode of action, most notably pKa value, lipophilicity, protein binding, and intrinsic vasoactivity. The main characteristics of clinically used drugs are summarized in Table 1. Importantly, the free systemic fraction of LA, not bound by plasma proteins, is the principal determinant of systemic adverse effects. The rate of 19 Chapter 1.2 absorption into the systemic circulation depends upon the site of injection. For example, equal plasma concentrations of lidocaine are attained when 300 mg are given intercostally, or 500 mg epidurally, or 1000 mg subcutaneously. 6 A multifactorial approach to choosing safe doses on an individualized basis per patient has been advocated, for which the reader is referred to the comprehensive review by Rosenberg and colleagues. 6 In plasma, LA are bound to albumine, an abundant protein with weak affinity for LA, and, more importantly, alpha-1-acidic glycoprotein (AAG), less abundant but potent in binding LA. 7 Since AAG is an acute phase protein, synthesis increases postoperatively and after trauma, decreasing free local anaesthetic, and protecting against systemic toxicity. For example, Veering et al. demonstrated that continuous postoperative infusion of epidural bupivacaine leads to increasing levels of total local anaesthetic in the systemic circulation, but at the same time, increasing AAG levels postoperatively bind bupivacaine, resulting in stable levels of systemic free drug. 8 Synthesis of AAG does not mature until one year of age, such that neonates are theoretically at higher risk of elevated free LA plasma levels. 7 Experimental evidence suggests that in pregnancy, protein binding of the more lipophilic bupivacaine is decreased, similarly increasing risk of systemic toxicity. 9 Conclusion: Local anaesthetics are a heterogeneous group of compounds which block voltage-gated sodium channels. Each drug is characterized by distinctive physicochemical properties. The free plasmatic share determines systemic toxicity. The primary target: voltage-gated sodium channels Local anaesthetics (LA) are primarily characterized by their ability to block voltage-gated sodium channels (VGSC), transmembrane proteins consisting of one main alpha-subunit, linked to one or more beta-subunits. 10 Crystallographic images of sodium channels have become available, improving insight into function and blockade. 11 The alpha subunit of the VGSC constitutes the functional ion channel, and harbours the binding site for LAs. 12 This subunit consists of four domains numbered DI-DIV, each consisting of 6 segments numbered S1-S6 (Figure 1). 10 13 In 20 Local anesthetics – an introduction contrast, the beta subunits of the VGSC modulate kinetics and voltage dependence of activation and inactivation. 12 The S4 segments are considered the “voltage sensor”, while specific amino acid sequences between segments S5 and S6 mediate the channel’s specificity for sodium. 14 The binding sites of LA are the S6 segments of domains I, III and IV. 12 Figure 2 gives a schema of the VGSC in cross-section, with (from the outside) the extracellular pore, the selectivity filter, the central cavity, and the innermost activation gate. LA preferably bind to activated and resting channels, because in these states, the activation gate is open, a property described as use-dependent block. 12 Under experimental conditions, binding of the LA to the receptor leads to reversible and concentration-dependent reduction of peak sodium current 10 by modulating the dynamic conformation of the voltage sensing segments S4 across domains of VGSC, 15 and by the creation of a positive charge within the channel’s lumen, directly impeding sodium flux. 16 Importantly, the family of VGSC consists of at least 10 different subtypes, depending on the gene for the alpha subunit. Dysfunction or mutation has been linked to several pathophysiological states, such as inherited erythromelalgia (syndrome of pain and erythema), 17 paroxysmal extreme pain disorder, 18 congenital insensitivity to pain, 18 cardiac arrhythmias, 19 and epilepsy. 20 Lastly, drugs other than local anaesthetics can effectively block the neuronal sodium channel. Interestingly, two members of the opiate family, pethidine and buprenorphine, have clinically relevant local anaesthetic properties. 21,22 Conclusion: Sodium