Local Anesthetics and the Inflammatory Response

Abstract

LOCAL anesthetics (LA) are known for their ability to block Na channels. However, they have significant effects in several settings other than local and regional anesthesia or antiarrhythmic treatment, the areas in which they are used traditionally. These effects result from LAs interacting with other cellular systems as well. Interestingly, some of these effects occur at concentrations much lower than those required for Na channel blockade. For example, whereas the half-maximal inhib-itory concentration (IC 50) of lidocaine at the neuronal Na channel is approximately 50-100 M (depending on the specific channel subtype and study preparation), 1 the compound inhibits signaling through m1 muscarinic receptors (expressed recombinantly in Xenopus laevis oocytes) with an IC 50 of 20 nM, that is, 1,000-to 5,000-fold lower. 2 This sensitivity of other targets has two important consequences. First, we assume that LAs, at concentrations that result in significant Na channel blockade, also affect a number of other systems. Second, relatively low LA concentrations (such as attained in blood during epidural anesthesia or analgesia or during intravenous LA infusion) that block neuronal Na channels to a limited extent only still can have significant pharmacologic effects. We suggest that some of these "alternative actions" may be beneficial in the clinical setting, and others may be responsible for some adverse effects of LAs. Although Butterworth and Strichartz 3 a decade ago urged investigation of such actions and their mechanisms, much remains to be discovered. To demonstrate the variety of LA effects, table 1 provides an overview of various LA actions reported in the literature. This review focuses on an area in which alternative actions of LAs show much promise for clinical application: their effects on the inflammatory response and especially on inflammatory cells (mainly polymorphonu-clear granulocytes [PMNs] but also macrophages and monocytes). PMNs do not express Na channels, 4 and LA effects on these cells therefore are not caused by Na channel blockade. LA effects on these cells are not affected by Na channel blockers such as tetrodotoxin or veratridine. 5 Overactive inflammatory responses that destroy rather than protect are critical in the development of a number of perioperative disease states, such as postoperative pain, 6-8 adult respiratory distress syndrome (ARDS), 9-11 systemic inflammatory response syndrome , and multiorgan failure. 12-15 Perioperative modulation of such responses is therefore relevant to the practice of anesthesiology, and LAs may play significant roles in this regard.