Chapter 6. Clinical Pharmacology of Local Anesthetics

Local and regional anesthesia, defined as the selective numbing of a specific nerve distribution or region of the body to facilitate surgery, appear to be undergoing a renaissance, as judged by attendance at specialty meetings and numbers of published manuscripts. In contrast to general anesthesia, in which the molecular mechanism remains the subject of speculation, the site at which local anesthetic drugs bind to produce nerve blocks has been cloned and mutated. This chapter will focus on mechanisms of anesthesia and toxicity, especially as knowledge of these mechanisms will assist the clinician in conducting safer and more effective regional anesthetics.

The Incas regarded coca as a gift from the son of the sun god and limited its use to the "upper crust" of society.1 The Incas recognized and used the medicinal properties of cocaine long before the compound was brought back to Europe for its properties to be "discovered." The Incas sometimes treated persistent headaches with trepanation (Figure 6–1), and coca was sometimes a part of this procedure. Local anesthesia was accomplished by having the operator chew coca leaves and apply the mascerated pulp to the skin and wound edges while using a tumi knife (Figure 6–2) to bore through the bone.

By the sixteenth century, the conquistadors had disrupted Incan society and began paying laborers with cocaine paste. The laborers generally rolled the cocaine leaves into balls (called cocadas), bound together by guano or cornstarch.1,2 These cocadas released the free-base cocaine as a consequence of the alkalinity of the guano and of the practice of chewing the cocadas with ash or lime (such alkaline compounds increase pH, favoring the free-base cocaine form over the positively charged hydrochloride salt). This practice probably marks the birth of “free-basing” cocaine and is the historic antecedent of the “rock” or “crack” cocaine so often abused in Western societies.

Cocaine was brought back to Vienna by an explorer/physician named Scherzer.1 In Vienna, the chemist Albert Niemann isolated and crystallized the pure cocaine hydrochloride in 1860. The Merck Company distributed batches of this agent to physicians for investigational purposes. Sigmund Freud was the most prominent of these cocaine experimenters. Freud reviewed his experimental work in a monograph devoted to cocaine titled Über Coca. Freud and Carl Koller (an ophthalmology trainee) took cocaine orally and noticed that the drug rendered their tongues insensible. Koller and Joseph Gartner began a series of experiments using cocaine to produce topical anesthesia of the conjunctiva. The birth of local and regional anesthesia dates from 1884 when Koller and Gartner reported their success at producing topical cocaine anesthesia of the eye in the frog, rabbit, dog, and human.2–4

The use of local anesthesia quickly spread around the world. The American surgeon William Halsted at Roosevelt Hospital in New York reported using cocaine to produce mandibular nerve block in 1884 and to produce brachial plexus block less than a year later.5 These blocks were accomplished by surgically exposing the nerves, then injecting them under direct vision. Leonard Corning injected cocaine near the spine of dogs, producing what was likely the first epidural in 1885. Spinal anesthesia was first accomplished in 1898 by August Bier. Caudal epidural anesthesia was introduced in 1902 by Sicard and Cathelin.5 Cocaine spinal anesthesia was used to treat cancer pain in 1898. Bier described intravenous regional anesthesia in 1909. In 1911, Hirschel reported the first three percutaneous brachial plexus anesthesias. Fidel Pages reported using epidural anesthesia for abdominal surgery in 1921.

Cocaine was incorporated into many other products, including the original formulation of Coca-Cola devised by Pemberton in 1886. Wine tonics and other “patent” medicines of the day commonly contained cocaine (Figure 6–3), until the early 1900s when governments began regulating the use of cocaine.

All local anesthetics (LAs) contain an aromatic ring and an amine at either end of the molecule, separated by a hydrocarbon chain, and either an ester or an amide bond (Figure 6–4).3,4,6,7 Cocaine is the archetypical ester LA and is the only naturally occurring one. Procaine, the first synthetic ester LA, was introduced by Einhorn in 1904 (Table 6–1).2 The introduction of the amide LA lidocaine in 1948 was transformative. Lidocaine quickly became used for all forms of regional anesthesia. Other amide LAs based on the lidocaine structure (prilocaine, etidocaine) subsequently appeared. A related series of amide LAs based on 2′, 6′-pipecoloxylidide was introduced (mepivacaine, bupivacaine, ropivacaine, and levobupivacaine). Ropivacaine and levobupivacaine are the only single-enantiomer (single optical isomer) LAs. Both are S(–)-enantiomers, which avoid the increased cardiac toxicity associated with racemic mixtures and the R(+)-isomers (this will be discussed in a subsequent section). All other LAs either exist as racemates or have no asymmetric carbons.

Studies of the mechanisms of LA action on nerves are studies of interactions between LAs and voltage-gated Na channels, since Na channels contain the LA binding site. Na channels are integral membrane proteins that initiate and propagate action potentials in axons, dendrites, and muscle tissue; initiate and maintain membrane potential oscillations in specialized heart and brain cells; and shape and filter synaptic inputs. Na channels share structural features with other voltage-gated ion channels in their genetic “superfamily,” wich includes voltage-gated Ca and K channels. Na channels contain one larger α-subunit and one or two smaller β-subunits, depending on the species and the tissue of origin. The α-subunit, the site of ion conduction and LA binding, has four homologous domains each with six α-helical membrane-spanning segments (Figure 6–5).8,9 The external surface of the α-subunit is heavily glycosylated, which serves to orient the channel properly within the plasma membrane (Figure 6–6).

Invertebrates have only one or two Na channel α-subunit genes. Humans, in contrast, have nine active Na channel α-subunit genes on four chromosomes, with cell-specific expression and localization of gene products. The Nav 1.4 gene (by convention, geneticists refer to voltage-gated Na-channel isoforms as Nav 1.x) supplies channels to skeletal muscle, and the Nav 1.5 gene supplies channels to cardiac muscle, leaving seven Nav isoforms in neural tissue (Table 6–2). Defined genes contribute specific Na channel forms to each of unmyelinated axons, nodes of Ranvier in motor axons, and small dorsal root ganglion nociceptors.10 Whereas all Na channel α-subunits will bind local anesthetics similarly, not all of them will bind neurotoxins with the same affinity.

Na channel α- and β-subunit mutations lead to muscle, cardiac, and neural diseases.11 For example, inherited mutations in Nav 1.5 have been associated with congenital long QT syndrome, Bruguda syndrome, and other conduction system diseases.11 It has been shown that certain Nav isoforms proliferate in animal models of chronic pain. The existence of specific Nav gene α-subunit products offers the enticing possibility that inhibitors may some day be developed for each specific Nav α-subunit form. Such developments could revolutionize the treatment of chronic painful conditions.

Blocking of impulses in a nerve fiber requires that a defined length of nerve become nonexcitable (to prevent the impulse from “jumping over” the blocked segment). Thus, as the LA concentration increases, it must need inhibit a shorter length of nerve to prevent impulse conduction, as is shown in Figure 6–7. Both normal conduction and LA inhibition of conduction differs between myelinated and unmyelinated nerve fibers. Conduction in myelinated fibers proceeds in jumps from one Ranvier node to the next, a process termed saltatory conduction. To block impulses in myelinated nerve fibers, it is generally necessary for LAs to inhibit channels in three successive Ranvier nodes (Figure 6–8). Unmyelinated fibers, lacking the saltatory mechanism, conduct much more slowly than myelinated fibers. Unmyelinated fibers are relatively resistant to local anesthesia, despite their smaller diameter, due to dispersal of Na channels throughout their plasma membranes. These differences among nerve fibers arise during development when Na channels begin to cluster at Ranvier nodes in myelinated axons. Nodal clustering of channels, essential for high-speed signal transmission, is initiated by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system.12 It is the loss of clustering of Na channels in axons that underlies the electrophysiologic consequences of multiple sclerosis.

Na channels exists in at least three native conformations: “resting,” “open,” and “inactivated,” first described by Hodgkin and Huxley.13 During an action potential, neuronal Na channels open briefly, allowing extracellular Na ions to flow into the cell, depolarizing the plasma membrane. After only a few milliseconds, Na channels inactivate (whereupon the Na current ceases). Na channels return to the resting conformation with membrane repolarization. The process by which channels change from conducting to nonconducting forms is termed gating. Gating is assumed to result from movements of dipoles in response to changes in potential. The process by which voltage-gated channels operate likely involves movements of paddle-shaped voltage sensors within the channel's outer perimeter (Figure 6–9).14,15 The speed of gating processes differs among Nav α-subunit forms: skeletal muscle and nerve forms gate quicker than cardiac forms.

Local anesthesia results when LAs bind Na channels and inhibit the Na permeability that underlies action potentials.6,13 Our understanding of LA mechanisms has been refined by several key observations. Taylor confirmed that LAs selectively inhibit Na channels in nerves under voltage clamp.16 Strichartz first observed use-dependent block with LAs, showing the importance of channel opening for LA binding. Use-dependence describes how LA inhibition of Na currents increases with repetitive depolarizations. Repetitive trains of depolarizations increase the likelihood that an LA will encounter an Na channel that is open or inactivated, both of which forms have greater LA affinity than do resting channels (Figure 6–10).6,13,17 Thus, membrane potential influences both Na channel conformation and Na channel affinity for LAs. Use-dependent block appears important for LAs functioning as antiarrhythmics and may also underlie the effectiveness of reduced LA concentrations in managing pain. Finally, using site-directed mutagenesis, Ragsdale and Wang have localized LA binding to specific amino acids in D4S6 of Nav 1.2 and Nav 1.4.18,19

Some LA optical isomers confer greater apparent safety than their opposite enantiomer. For example, under voltage clamp, the R(+)-bupivacaine isomer more potently inhibits cardiac Na currents than the S(–)-bupivacaine (levobupivacaine) isomer (Figure 6–11).

Many other types of chemicals will also bind and inhibit Na channels, including general anesthetics, substance P inhibitors, α2-adrenergic agonists, tricyclic antidepressants, and nerve toxins.6,20–22 The latter two chemical classes have undergone animal and early human testing as possible replacements for LAs. Unfortunately, several of the tricyclic antidepressants have demonstrated toxic side effects.

In clinical practice LAs are typically described by their potency, duration of action, speed of onset and tendency for differential sensory nerve block. These properties do not sort independently.

Potency & Duration

Nerve-blocking potency of LAs increases with increasing molecular weight and increasing lipid solubility.23,24 Larger, more lipophilic LAs permeate nerve membranes more readily and bind Na channels with greater affinity. For example, etidocaine and bupivacaine have greater lipid solubility and potency than lidocaine and mepivacaine, to which they are closely related chemically.

More lipid-soluble LAs are relatively water-insoluble, highly protein-bound in blood, less readily removed by the bloodstream from nerve membranes, and more slowly “washed out” from isolated nerves in vitro. Thus, increased lipid solubility associates with increased protein binding in blood, increased potency, and longer duration of action. Extent and duration of anesthesia can be correlated with LA content of nerves in animal experiments.25,26 In animals, blocks of greater depth and longer duration arise from smaller volumes of more concentrated LA, compared wth larger volumes of less concentrated LA.27

Speed of Onset

Many textbooks and review articles assert that the onset of anesthesia in isolated nerves decreases with increasing LA lipid solubility and increasing pKa (Table 6–3). At any pH, the percentage of LA molecules present in the uncharged form, largely responsible for membrane permeability, decreases with increasing pKa.23,24 However, of the two LAs of fastest onset, etidocaine is highly lipid-soluble and chloroprocaine has a pKa greater than that of other LAs. Finally, LA rate of onset associates with aqueous diffusion rate, which declines with increasing molecular weight.28

Differential Sensory Nerve Block

Regional anesthesia and pain management would be transformed by an LA that would selectively inhibit pain transmission while leaving other functions intact. However, sensory anesthesia sufficient for skin incision usually cannot be obtained without motor impairment.3,4,6 As was first demonstrated by Gasser and Erlanger in 1929, all LAs will block smaller (diameter) fibers at lower concentrations than are required to block larger fibers of the same type.29,30 As a group, unmyelinated fibers are resistant to LAs compared with larger myelinated A-δ fibers.29,30 Bupivacaine and ropivacaine are relatively selective for sensory fibers. Bupivacaine produces more rapid onset of sensory than motor block, whereas the closely related chemical mepivacaine demonstrates no differential onset during median nerve blocks (Figure 6–12).31 True differential anesthesia may be possible when Nav isoform-selective antagonists become available. Certain Nav isoforms have been found to be prevalent in dorsal root ganglia, and (as previously noted) the relative populations of various Nav isoforms can change in response to various pain states.32

Other Factors Influencing LA Activity

Many factors influence the ability of a given LA to produce adequate regional anesthesia, including the dose, site of administration, additives, temperature, and pregnancy. As the LA dose increases, the likelihood of success and the duration of anesthesia increase, while the delay of onset and tendency for differential block decrease. In general, the fastest onset and shortest duration of anesthesia occur with spinal or subcutaneous injections; a slow onset and long duration are obtained with plexus blocks.33

Epinephrine is frequently added to LA solutions to cause vasoconstriction and to serve as a marker for intravascular injection.4,7 Epinephrine and other α1-agonists increase LA duration largely by prolonging and increasing intraneural concentrations of LAs.26 Blood flow is decreased only briefly, and the block will persist long after the α1-adrenergic effect on blood flow has disipated.34 Other popular LA additives include clonidine, NaHCO3, opioids, neostigmine, and hyaluronidase.

LAs have greater apparent potency at basic pH, where an increased fraction of LA molecules are uncharged, than at more acidic pH (Figure 6–13).35 Uncharged LA bases diffuse across nerve sheaths and membranes more readily than charged LAs, hastening onset of anesthesia. Not surprisingly, some clinical studies show that the addition of sodium bicarbonate to LAs speeds the onset of nerve blocks.4,7 Bicarbonate has an inconsistent action during clinical nerve block, however, in that not all studies demonstrate a faster onset of anesthesia. One might anticipate that bicarbonate would have its greatest effect when added to LA solutions to which epinephrine was added by the manufacturer. Such solutions are more acidic than “plain” (epinephrine-free) LA solutions so as to increase shelf life. Bicarbonate shortens duration of lidocaine in animals.27 Curiously, once LAs gain access to the cytoplasmic side of the Na channel, H+ ions potentiate use-dependent block.6,13

Pregnant women and pregnant animals demonstrate increased neural susceptibility to LAs.36–38 In addition, spread of neuraxial anesthesia likely increases during pregnancy due to decreases in thoracolumbar cereborspinal fluid volume.

Peak LA concentrations vary by the site of injection (Figure 6–14). With the same LA dose, intercostal blocks consistently produce greater peak LA concentrations than epidural or plexus blocks.4,7,33,39 As has been recently discussed by others, it makes little sense to speak of “maximal” doses of local anesthetics except in reference to a specific nerve block procedure.40

In blood, all LAs are partially protein-bound, primarily to α1-acid glycoprotein and secondarily to albumin.3,4,7 Affinity for α1-acid glycoprotein correlates with LA hydrophobicity and decreases with protonation.41 Extent of protein binding is influenced by the concentration of α1-acid glycoprotein. Both protein binding and protein concentration decline during pregnancy.42 During longer term infusion of LA and LA–opioid combinations, concentrations of serum binding proteins progressively increase.43 There is considerable first-pass uptake of LAs by the lungs,44 and animal studies suggest that patients with right-to-left cardiac shunting may be expected to demonstrate LA toxicity after smaller intravenous bolus doses.45

Esters undergo rapid hydrolysis in blood, catalyzed by pseudocholinesterase.3,4,7 Procaine and benzocaine are metabolized to para-aminobenzoic acid (PABA), the species underlying anaphylaxis to these agents.4 The amides undergo metabolism in the liver. Lidocaine undergoes oxidative N-dealkylation (by the cytochromes CYP 1A2 and CYP 3A4 to monoethyl glycine xylidide and glycine xylidide).3,4,7 Bupivacaine, ropivacaine, mepivacaine, and etidocaine also undergo N-dealkylation and hydroxylation.3,4,7 Prilocaine is hydroxylized to o-toluidine, which causes methemoglobinemia.4,24 Prilocaine doses >8 mg/kg may be expected to produce sufficient methemoglobin concentrations to cause clinical cyanosis. Amide LA clearance is highly dependent on hepatic blood flow, hepatic extraction, and enzyme function, and is reduced by factors that decrease hepatic blood flow, such as β-adrenergic receptor or H2-receptor blockers, and by heart or liver failure.3,4,7

Disposition of amide LAs is altered in pregnancy due to increased cardiac output, hepatic blood flow, and clearance, as well as the previously mentioned decline in protein binding. Renal failure tends to increase volume of distribution of amide LAs and to increase the accumulation of metabolic byproducts of ester and amide local anesthetics.

Theoretically, cholinesterase deficiency and cholinesterase inhibitors should increase the risk of systemic toxicity from ester local anesthetics; however, there are no confirmatory data from patients.

Some drugs inhibit various cytochromes responsible for LA metabolism; however, the importance of cytochrome inhibitors varies depending on the specific LA species. β-Blockers and H2-receptor blockers inhibit CYP 2D6, which may contribute to reduced amide LA metabolism. Itraconazole has no effect on hepatic blood flow, but inhibits CYP 3A4 and bupivacaine elimination by 20–25%.46 Ropivacaine is hydroxylated by CYP 1A2 and metabolized to 2′, 6′-pipecoloxylidide by CYP 3A4.47,48 Fluvoxamine inhibits CYP 1A2 and reduces ropivacaine clearance by 70%. On the other hand, coadministration with strong inhibitors of CYP 3A4 (ketoconazole, itraconazole) has only a small effect on ropivacaine clearance.

It is a common, but misguided, assumption that all LA actions including toxic side effects arise from interaction with voltage-gated Na channels. There is abundant evidence that LAs will bind many other targets aside from Na channels, including voltage-gated K and Ca channels, HERG channels, KATP channels, enzymes, N-methyl-d-aspartate receptors, β-adrenergic receptors, G-protein-mediated modulation of K and Ca channels, and nicotinic acetylcholine receptors.6,49,50 LA binding to any one or all of these other sites could underlie LA production of spinal or epidural analgesia and could contribute to toxic side effects.6,13,51

Central Nervous System Side Effects

LA central nervous system (CNS) toxicity arises from inhibition of excitatory pathways in the CNS, producing a stereotypical sequence of signs and symptoms as the LA concentration in blood gradually increases (Table 6–4).3,4,7,33 With increased LA doses, seizures may arise in the amygdala.3,4 With further LA dosing, CNS excitation progresses to CNS depression, and eventual respiratory arrest. More potent (at nerve block) LAs produce seizures at lower blood concentrations and at lower doses than less potent LAs. In a study of cats, both metabolic and respiratory acidosis decreased the convulsive dose of lidocaine.52

Cardiovascular Toxicity

In laboratory experiments most LAs will not produce cardiovascular (CV) toxicity until the blood concentration exceeds three times that ncessary to produce seizures; however, there are clinical reports of simultaneous CNS and CV toxicity with bupivacaine (Table 6–5).3,4,7 In dogs, supraconvulsant doses of bupivacaine more commonly produce arrhythmias than supraconvulsant doses of ropivacaine and lidocaine.53 LAs produce CV signs of CNS excitation (increased heart rate, arterial blood pressure, and cardiac output) at lower concentrations than those associated with cardiac depression. Hypocapnia reduces ropivacaine-induced changes in ST segments and left-ventricular contractility.54

LAs bind and inhibit cardiac Na channels (Nav 1.5 isoform).3,13 Bupivacaine binds more avidly and longer than lidocaine to cardiac Na channels.55 As previously noted, certain R(+) optical isomers bind cardiac Na channels more avidly than S (–) optical isomers. These laboratory observations led to the clinical development of levobupivacaine and ropivacaine. LAs inhibit conduction in the heart with the same rank order of potency as for nerve block.56,57

LAs produce dose-dependent myocardial depression, possibly from interference with Ca signaling mechanisms within cardiac muscle.56 LAs bind and inhibit cardiac voltage-gated Ca and K channels at concentrations greater than those at which binding to Na channels is maximal.6,13,58 LAs bind β-adrenergic receptors and inhibit epinephrine-stimulated cyclic-AMP formation, either of which could underlie the refractoriness of bupivacaine CV toxicity to standard resuscitation measures.59,60 In rats, the rank order for cardiac toxicity appears to be bupivacaine > levobupivacaine > ropivacaine.61–63 In dogs, lidocaine was the least potent, and bupivacaine and levobupivacaine were more potent than ropivacaine at inhibiting left-ventricular function as assessed by echocardiography (Table 6–6). In dogs, both programmed electrical stimulation and epinephrine resuscitation elicited more arrhythmias after bupivacaine and levobupivacaine than after lidocaine or ropivacaine administration.64–66

The mechanism by which CV toxicity is produced may depend on which LA has been administered. When LAs were given to the point of extreme hypotension, dogs receiving lidocaine could be resuscitated, but required continuing infusion of epinephrine to counteract LA-induced myocardial depression. Conversely, many dogs receiving bupivacaine or levobupivacaine to the point of extreme hypotension could not be resuscitated. After bupivacaine, levobupivacaine, or ropivacaine, dogs that could be defibrillated often required no additional therapy.64–66 Similarly in pigs, comparing lidocaine with bupivacaine, the ratio of potency for myocardial depression was 1:4; whereas that for arrhythmogenesis was 1:16.67 LAs produce dilation of vascular smooth muscle at clinical concentrations.68 Cocaine is the only LA that consistently produces local vasoconstriction.

Allergic Reactions

True immunologic reactions to LAs are rare.69 Accidental intravenous injections of LAs are sometimes misdiagnosed as allergic reactions. True anaphylaxis appears more common with ester LAs that are metabolized directly to PABA than to other LAs. Some patients may react to preservatives, such as methylparaben, included with LAs. In the allergy and immunology literature, several recent studies have shown that patients referred for evaluation of apparent LA allergy, even after exhibiting signs or symptoms of anaphylaxis, almost never demonstrate true allergy to the LA that was administered.69,70

Neurotoxic Effects

During the 1980s, 2-chloroprocaine (at that time formulated with sodium metabisulfite at a relatively acidic pH) occasionally produced cauda equina syndrome when large doses were accidentally injected into spinal fluid during attempted epidural administration.4,6,71–73 Reports of neurotoxicity virtually disappeared when the compound was reformulated, but have now returned following the introduction of generic products containing the original metabisulfite and pH.73 Whether the toxin is 2-chloroprocaine or metabisulfite remains unsettled: 2-chloroprocaine is now being tested as a substitute for lidocaine in human spinal anesthesia,74 and a series of publications suggest that it may be safe and effective. At the same time, other investigators have linked neurotoxic reactions in animals to large doses of 2-chloroprocaine rather than to metabisulfite.75 Presently, there is controversy about transient neurologic symptoms and persistent sacral deficits after lidocaine spinal anesthesia. These reports have persuaded many physicians to abandon lidocaine spinal anesthesia. Unlike other spinal LA solutions, lidocaine 5% permanently interrupts conduction when applied to isolated nerves or to isolated neurons.76 This may be the result of lidocaine-induced increases in intracellular calcium and does not appear to involve Na channel blockade.77 We await those studies that will determine whether chloroprocaine, or perhaps mepivacaine, will prove to be appropriate lidocaine substitutes for brief spinal anesthesias.

Treatment of Local Anesthetic Toxicity

Treatment of adverse LA reactions depends on their severity. Minor reactions can be allowed to terminate spontaneously. LA-induced seizures should be managed by maintaining a patent airway and by providing oxygen. Seizures may be terminated with intravenous thiopental (1–2 mg/kg), midazolam (0.05–0.10 mg/kg), propofol (0.5–1.5 mg/kg), or a paralytic dose of succinylcholine (0.5–1 mg/kg) followed by mask ventilation or tracheal intubation.4 If LA CV depression is manifested by moderate hypotension, it may be treated by infusion of intravenous fluids and vasopressors (phenylephrine 0.5–5 mcg/kg/min, norepinephrine 0.02–0.2 mcg/kg/min, or vasopressin 40 mcg IV). If myocardial failure is present, epinephrine (1–15 mcg/kg IV bolus) may be required. When toxicity progresses to cardiac arrest, the guidelines for advanced cardiac life support are reasonable;78 however, I suggest that amiodarone and vasopressin be substituted for lidocaine and epinephrine, respectively.79–81 With unresponsive bupivacaine cardiac toxicity, intravenous lipid or cardiopulmonary bypass should be considered.82 Recent animal experiments demonstrate the remarkable ability of lipid infusion to resuscitate animals from bupivacaine overdosage, even after 10 min of unsuccessful “conventional” resuscitative efforts (Figure 6–15).83–85 We now have a report showing that lipid infusion can resuscitate an LA-intoxicated human.86 Given the nearly nontoxic status of lipid infusion, one could not make a convincing argument to withhold this therapy from a patient experiencing difficult resuscitation from LA intoxication.

After nearly 120 years of use in Western medicine, LAs remain important tools for the twenty-first-century physician. Peripheral nerve blocks are almost certainly the result of LA inhibition of voltage-gated Na channels in neuronal membranes. The mechanisms of spinal and epidural anesthesia remain poorly defined. The appropriate and safe dose of LAs is defined by the specific nerve block procedure that is to be undertaken. The mechanisms by which differing LAs produce CV toxicity likely vary: the more potent agents (eg, bupivacaine) may produce arrhythmias through a Na channel action, whereas the less potent agents (eg, lidocaine) may produce myocardial depression through other pathways.