Basic and Clinical Pharmacology, 13th Ed.

Local Anesthetics

Kenneth Drasner, MD*

CASE STUDY

A 67-year-old woman is scheduled for elective total knee arthroplasty. What local anesthetic agents would be most appropriate if surgical anesthesia were to be administered using a spinal or an epidural technique, and what potential complications might arise from their use? What anesthetics would be most appropriate for providing postoperative analgesia via an indwelling epidural or peripheral nerve catheter?

Simply stated, local anesthesia refers to loss of sensation in a limited region of the body. This is accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation. Such blockade may bring with it other physiologic changes such as muscle paralysis and suppression of somatic or visceral reflexes, and these effects might be desirable or undesirable depending on the particular circumstances. Nonetheless, in most cases, it is the loss of sensation, or at least the achievement of localized analgesia, that is the primary goal.

Although local anesthetics are often used as analgesics, it is their ability to provide complete loss of all sensory modalities that is their distinguishing characteristic. The contrast with general anesthesia should be obvious, but it is perhaps worthwhile to emphasize that with local anesthesia the drug is delivered directly to the target organ, and the systemic circulation serves only to diminish or terminate its effect. Local anesthesia can also be produced by various chemical or physical means. However, in routine clinical practice, it is achieved with a rather narrow spectrum of compounds, and recovery is normally spontaneous, predictable, and without residual effects. The development of these compounds has a rich history (see Box: Historical Development of Local Anesthesia), punctuated by serendipitous observations, delayed starts, and an evolution driven more by concerns for safety than improvements in efficacy.

image BASIC PHARMACOLOGY OF LOCAL ANESTHETICS

Chemistry

Most local anesthetic agents consist of a lipophilic group (eg, an aromatic ring) connected by an intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine) (Table 26–1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action.

TABLE 26–1 Structure and properties of some ester and amide local anesthetics.1

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Local anesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation (see Chapter 1, Ionization of Weak Acids and Weak Bases). The relative proportions of these two forms are governed by their pKa and the pH of the body fluids according to the Henderson-Hasselbalch equation, which can be expressed as:

pKa = pH – log [base]/[conjugate acid]

If the concentration of base and conjugate acid are equal, the second portion of the right side of the equation drops out, as log 1 = 0, leaving:

pKa = pH (when base concentration = conjugate acid concentration)

Historical Development of Local Anesthesia

Although the numbing properties of cocaine were recognized for centuries, one might consider September 15, 1884, to mark the “birth of local anesthesia.” Based on work performed by Carl Koller, cocaine’s numbing effect on the cornea was demonstrated before the Ophthalmological Congress in Heidelberg, ushering in the era of surgical local anesthesia. Unfortunately, with widespread use came recognition of cocaine’s significant CNS and cardiac toxicity, which along with its addiction potential, tempered enthusiasm for this application. As the early investigator Mattison commented, “the risk of untoward results have robbed this peerless drug of much favor in the minds of many surgeons, and so deprived them of a most valued ally.” As cocaine was known to be a benzoic acid ester, the search for alternative local anesthetics focused on this class of compounds, resulting in the identification of benzocaine shortly before the turn of the last century. However, benzocaine proved to have limited utility due to its marked hydrophobicity, and was thus relegated to topical anesthesia, a use for which it still finds limited application in current clinical practice. The first useful injectable local anesthetic, procaine, was introduced shortly thereafter by Einhorn, and its structure has served as the template for the development of the most commonly used modern local anesthetics. The three basic structural elements of these compounds can be appreciated by review of Table 26–1: an aromatic ring, conferring lipophilicity, an ionizable tertiary amine, conferring hydrophilicity, and an intermediate chain connecting these via an ester or amide linkage.

One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of tetracaine in 1928. Unfortunately, tetracaine demonstrated significant toxicity when employed for high-volume peripheral blocks, ultimately reducing its common usage to spinal anesthesia. Both procaine and tetracaine shared another drawback: their ester linkage conferred instability, and particularly in the case of procaine, the free aromatic acid released during ester hydrolysis of the parent compound was believed to be the source of relatively frequent allergic reactions.

Löfgren and Lundqvist circumvented the problem of instability with the introduction of lidocaine in 1948. Lidocaine was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a more favorable duration of action than procaine, and less systemic toxicity than tetracaine. To this day, it remains one of the most versatile and widely used anesthetics. Nonetheless, some applications required more prolonged block than that afforded by lidocaine, a pharmacologic void that was filled with the introduction of bupivacaine, a more lipophilic and more potent anesthetic. Unfortunately, bupivacaine was found to have greater propensity for significant effects on cardiac conduction and function, which at times proved lethal. Recognition of this potential for cardiac toxicity led to changes in anesthetic practice, and significant toxicity became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental work leading to the introduction of two recent additions to the anesthetic armamentarium, levobupivacaine and ropivacaine. The former is the S(–) enantiomer of bupivacaine, which has less affinity for cardiac sodium channels than its R(+) counterpart. Ropivacaine, another S(–) enantiomer, shares this reduced affinity for cardiac sodium channels, while being slightly less potent than bupivacaine or levobupivacaine.

Thus, pKa can be seen as an effective way to consider the tendency for compounds to exist in a charged or uncharged form, ie, the lower the pKa, the greater the percentage of uncharged weak bases at a given pH. Because the pKaof most local anesthetics is in the range of 7.5–9.0, the charged, cationic form will constitute the larger percentage at physiologic pH. A glaring exception is benzocaine, which has a pKaaround 3.5, and thus exists solely as the nonionized base under normal physiologic conditions.

This issue of ionization is of critical importance because the cationic form is the most active at the receptor site. However, the story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Thus, the uncharged form is important for cell penetration. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel, and hence the production of a clinical effect (Figure 26–1). Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway. As a clinical consequence, local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic—a strategy sometimes utilized in clinical practice—will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block.

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FIGURE 26–1 Schematic diagram depicting paths of local anesthetic (LA) to receptor sites. Extracellular anesthetic exists in equilibrium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway).

Pharmacokinetics

When local anesthetics are used for local, peripheral, and central neuraxial anesthesia—their most common clinical applications—systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Thus, classic pharmacokinetics plays a lesser role than with systemic therapeutics, yet remains important to the anesthetic’s duration and critical to the potential development of adverse reactions, specifically cardiac and central nervous system (CNS) toxicity.

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics has not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute).

TABLE 26–2 Pharmacokinetic properties of several amide local anesthetics.

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A. Absorption

Systemic absorption of injected local anesthetic from the site of administration is determined by several factors, including dosage, site of injection, drug-tissue binding, local tissue blood flow, use of a vasoconstrictor (eg, epinephrine), and the physicochemical properties of the drug itself. Anesthetics that are more lipid soluble are generally more potent, have a longer duration of action, and take longer to achieve their clinical effect. Extensive protein binding also serves to increase the duration of action.

Application of a local anesthetic to a highly vascular area such as the tracheal mucosa or the tissue surrounding intercostal nerves results in more rapid absorption and thus higher blood levels than if the local anesthetic is injected into a poorly perfused tissue such as subcutaneous fat. When used for major conduction blocks, the peak serum levels will vary as a function of the specific site of injection, with intercostal blocks among the highest, and sciatic and femoral among the lowest (Figure 26–2). When vasoconstrictors are used with local anesthetics, the resultant reduction in blood flow serves to reduce the rate of systemic absorption and thus diminishes peak serum levels. This effect is generally most evident with the shorter-acting, less potent, and less lipid-soluble anesthetics.

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FIGURE 26–2 Comparative peak blood levels of several local anesthetic agents following administration into various anatomic sites. (Adapted, with permission, from Covino BD, Vassals HG: Local Anesthetics: Mechanism of Action in Clinical Use. Grune & Stratton, 1976. Copyright Elsevier.)

B. Distribution

1. LocalizedAs local anesthetic is usually injected directly at the site of the target organ, distribution within this compartment plays an essential role with respect to achievement of clinical effect. For example, anesthetics delivered into the subarachnoid space will be diluted with cerebrospinal fluid (CSF) and the pattern of distribution will be dependent upon a host of factors, among the most critical being the specific gravity relative to that of CSF and the patient’s position. Solutions are termed hyperbaric, isobaric, and hypobaric, and will respectively descend, remain relatively static, or ascend, within the subarachnoid space due to gravity when the patient sits upright. A review and analysis of relevant literature cited 25 factors that have been invoked as determinants of spread of local anesthetic in CSF, which can be broadly classified as characteristics of the anesthetic solution, CSF constituents, patient characteristics, and techniques of injection. Somewhat similar considerations apply to epidural and peripheral blocks.

2. SystemicThe peak blood levels achieved during major conduction anesthesia will be minimally affected by the concentration of anesthetic or the speed of injection. The disposition of these agents can be well approximated by a two-compartment model. The initial alpha phase reflects rapid distribution in blood and highly perfused organs (eg, brain, liver, heart, kidney), characterized by a steep exponential decline in concentration. This is followed by a slower declining beta phase reflecting distribution into less well perfused tissue (eg, muscle, gut), and may assume a nearly linear rate of decline. The potential toxicity of the local anesthetics is affected by the protective effect afforded by uptake by the lungs, which serve to attenuate the arterial concentration, though the time course and magnitude of this effect have not been adequately characterized.

C. Metabolism and Excretion

The local anesthetics are converted to more water-soluble metabolites in the liver (amide type) or in plasma (ester type), which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. Ester-type local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase to inactive metabolites. For example, the half-lives of procaine and chloroprocaine in plasma are less than a minute. However, excessive concentrations may accumulate in patients with reduced or absent plasma hydrolysis secondary to atypical plasma cholinesterase.

The amide local anesthetics undergo complex biotransformation in the liver, which includes hydroxylation and N-dealkylation by liver microsomal cytochrome P450 isozymes. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine ≈ bupivacaine and levobupivacaine (slowest). As a result, toxicity from amide-type local anesthetics is more likely to occur in patients with hepatic disease. For example, the average elimination half-life of lidocaine may be increased from 1.6 hours in normal patients (t½Table 26–2) to more than 6 hours in patients with severe liver disease. Many other drugs used in anesthesia are metabolized by the same P450 isozymes, and concomitant administration of these competing drugs may slow the hepatic metabolism of the local anesthetics. Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous anesthetic techniques. Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with congestive heart failure.

Pharmacodynamics

A. Mechanism of Action

1. Membrane potentialThe primary mechanism of action of local anesthetics is blockade of voltage-gated sodium channels (Figure 26–1). The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of –90 to –60 mV. During excitation, the sodium channels open, and a fast, inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about –95 mV); repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues.

2. Sodium channel isoformsEach sodium channel consists of a single alpha subunit containing a central ion-conducting pore associated with accessory beta subunits. The pore-forming alpha subunit is actually sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the beta subunit. A variety of different sodium channels have been characterized by electrophysiologic recording, and subsequently isolated and cloned, while mutational analysis has allowed for identification of the essential components of the local anesthetic binding site. Nine members of a mammalian family of sodium channels have been so characterized and classified as Nav1.1–Nav1.9, where the chemical symbol represents the primary ion, the subscript denotes the physiologic regulator (in this case voltage), the initial number denotes the gene, and the number following the period indicates the particular isoform.

3. Channel blockadeBiologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin have clinical effects that largely resemble those of local anesthetics (ie, block of conduction without a change in the resting potential). However, in contrast to the local anesthetics, their binding site is located near the extracellular surface. The sensitivity of these channels to TTX varies, and subclassification based on this pharmacologic sensitivity has important physiologic and therapeutic implications. Six of the aforementioned channels are sensitive to nanomolar concentration of this biotoxin (TTX-S), while three are resistant (TTX-R). Of the latter, Nav1.8 and Nav1.9 appear to be exclusively expressed in dorsal root ganglia nociceptors, which raises the developmental possibility of targeting these specific neuronal subpopulations. Such fine-tuned analgesic therapy has the theoretical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers.

When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. These progressive effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible. In myelinated nerves, the critical length appears to be two to three nodes of Ranvier. At the minimum dose required to block propagation, the resting potential is not significantly altered.

The blockade of sodium channels by most local anesthetics is both voltage and time dependent: Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials (see Figure 14–10). Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers (Figure 26–3). Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14–10). The recovery from drug-induced block is 10–1000 times slower than the recovery of channels from normal inactivation (as shown for the cardiac membrane in Figure 14–4). As a result, the refractory period is lengthened and the nerve conducts fewer action potentials.

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FIGURE 26–3 Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Adapted, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther 1975;195:225.)

Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.

4. Other effectsCurrently used local anesthetics bind to the sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clinically relevant concentrations, local anesthetics are potentially active at countless other channels (eg, potassium and calcium), enzymes (eg, adenylyl cyclase, carnitine-acylcarnitine translocase), and receptors (eg, N-methyl-D-aspartate [NMDA], G protein-coupled, 5-HT3, neurokinin-1 [substance P receptor]). The role that such ancillary effects play in achievement of local anesthesia appears to be important but is poorly understood. Further, interactions with these other sites are likely the basis for numerous differences between the local anesthetics with respect to anesthetic effects (eg, differential block) and toxicities that do not parallel anesthetic potency, and thus are not adequately accounted for solely by blockade of the voltage-gated sodium channel.

The actions of circulating local anesthetics at such diverse sites exert a multitude of effects, some of which go beyond pain control, including some that are also potentially beneficial. For example, there is evidence to suggest that the blunting of the stress response and improvements in perioperative outcome that may occur with epidural anesthesia derive in part from an action of the anesthetic beyond its sodium channel block. Circulating anesthetics also demonstrate antithrombotic effects having an impact on coagulation, platelet aggregation, and the microcirculation, as well as modulation of inflammation.

B. Structure-Activity Characteristics of Local Anesthetics

The smaller and more highly lipophilic local anesthetics have a faster rate of interaction with the sodium channel receptor. As previously noted, potency is also positively correlated with lipid solubility. Lidocaine, procaine, and mepivacaine are more water soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the R(+) isomer can usually be shown to be slightly more potent than the S(–) isomer (levobupivacaine).

C. Neuronal Factors Affecting Block

1. Differential blockSince local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. With central neuraxial techniques (spinal or epidural), motor paralysis may impair respiratory activity, and autonomic nerve blockade may promote hypotension. Further, while motor paralysis may be desirable during surgery, it may be a disadvantage in other settings. For example, motor weakness occurring as a consequence of epidural anesthesia during obstetrical labor may limit the ability of the patient to bear down (ie, “push”) during delivery. Similarly, when used for postoperative analgesia, weakness may hamper ability to ambulate without assistance and pose a risk of falling, while residual autonomic blockade may interfere with bladder function, resulting in urinary retention and the need for bladder catheterization. These issues are particularly problematic in the setting of ambulatory (same-day) surgery, which represents an ever-increasing percentage of surgical caseloads.

2. Intrinsic susceptibility of nerve fibersNerve fibers differ significantly in their susceptibility to local anesthetic blockade. It has been traditionally taught, and still often cited, that local anesthetics preferentially block smaller diameter fibers first because the distance over which such fibers can passively propagate an electrical impulse is shorter. However, a variable proportion of large fibers are blocked prior to the disappearance of the small fiber component of the compound action potential. Most notably, myelinated nerves tend to be blocked before unmyelinated nerves of the same diameter. For example, preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission (Table 26–3).

TABLE 26–3 Relative size and susceptibility of different types of nerve fibers to local anesthetics.

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Another important factor underlying differential block derives from the state- and use-dependent mechanism of action of local anesthetics. Blockade by these drugs is more marked at higher frequencies of depolarization. Sensory (pain) fibers have a high firing rate and relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. As type A delta and C fibers participate in high-frequency pain transmission, this characteristic may favor blockade of these fibers earlier and with lower concentrations of local anesthetics. The potential impact of such effects mandates cautious interpretation of non-physiologic experiments evaluating intrinsic susceptibility of nerves to conduction block by local anesthetics.

3. Anatomic arrangementIn addition to the effect of intrinsic vulnerability to local anesthetic block, the anatomic organization of the peripheral nerve bundle may impact the onset and susceptibility of its components. As one would predict based on the necessity of having proximal sensory fibers join the nerve trunk last, the core will contain sensory fibers innervating the most distal sites. Anesthetic placed outside the nerve bundle will thus reach and anesthetize the proximal fibers located at the outer portion of the bundle first, and sensory block will occur in sequence from proximal to distal.

image CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS

Local anesthetics can provide highly effective analgesia in well-defined regions of the body. The usual routes of administration include topical application (eg, nasal mucosa, wound [incision site] margins), injection in the vicinity of peripheral nerve endings (perineural infiltration) and major nerve trunks (blocks), and injection into the epidural or subarachnoid spaces surrounding the spinal cord (Figure 26–4).

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FIGURE 26–4 Schematic diagram of the typical sites of injection of local anesthetics in and around the spinal canal. When local anesthetics are injected extradurally, it is referred to as an epidural block. A caudal block is a specific type of epidural block in which a needle is inserted into the caudal canal via the sacral hiatus. Injections around peripheral nerves are known as perineural blocks (eg, paravertebral block). Finally, injection into cerebrospinal fluid in the subarachnoid (intrathecal) space is referred to as a spinal block.

Clinical Block Characteristics

In clinical practice, there is generally an orderly evolution of block components beginning with sympathetic transmission and progressing to temperature, pain, light touch, and finally motor block. This is most readily appreciated during onset of spinal anesthesia, where a spatial discrepancy can be detected in modalities, the most vulnerable components achieving greater dermatomal (cephalad) spread. Thus, loss of the sensation of cold (often assessed by a wet alcohol sponge) will be roughly two segments above the analgesic level for pinprick, which in turn will be roughly two segments rostral to loss of light touch recognition. However, because of the anatomic considerations noted earlier for peripheral nerve trunks, onset with peripheral blocks is more variable, and proximal motor weakness may precede onset of more distal sensory loss. Additionally, anesthetic solution is not generally deposited evenly around a nerve bundle, and longitudinal spread and radial penetration into the nerve trunk are far from uniform.

With respect to differential block, it is worth noting that “successful” surgical anesthesia may require loss of touch, not just ablation of pain, as some patients will find even the sensation of touch distressing during surgery, often fearing that the procedure may become painful. Further, while differences may exist in modalities, it is not possible with conventional techniques to produce surgical anesthesia without some loss of motor function.

A. Effect of Added Vasoconstrictors

Several benefits may be derived from addition of a vasoconstrictor to a local anesthetic. First, localized neuronal uptake is enhanced because of higher sustained local tissue concentrations that can translate clinically into a longer duration block. This may enable adequate anesthesia for more prolonged procedures, extended duration of postoperative pain control, and lower total anesthetic requirement. Second, peak blood levels will be lowered as absorption is more closely matched to metabolism and elimination, and the risk of systemic toxic effects is reduced. Moreover, when incorporated into a spinal anesthetic, epinephrine may not only contribute to prolongation of the local anesthetic effect via its vasoconstrictor properties, but also exert a direct analgesic effect mediated by postsynaptic α2 adrenoceptors within the spinal cord. Recognition of this potential has led to the clinical use of the α2 agonist clonidine as a local anesthetic adjuvant for spinal anesthesia.

Conversely, inclusion of epinephrine may have untoward effects. The addition of epinephrine to anesthetic solutions can potentiate the neurotoxicity of local anesthetics used for peripheral nerve blocks or spinal anesthesia. Further, the use of a vasoconstrictor agent in an area that lacks adequate collateral flow (eg, digital block) is generally avoided, though some have questioned the validity of this proscription.

B. Intentional Use of Systemic Local Anesthetics

Although the principal use of local anesthetics is to achieve anesthesia in a restricted area, these agents are sometimes deliberately administered systemically to take advantage of suppressive effects on pain processing. In addition to documented reductions in anesthetic requirement and postoperative pain, systemic administration of local anesthetics has been used with some success in the treatment of chronic pain, and this effect may outlast the duration of anesthetic exposure. The achievement of pain control by systemic administration of local anesthetics is thought to derive, at least in part, from the suppression of abnormal ectopic discharge, an effect observed at concentrations of local anesthetic an order of magnitude lower than those required for blockade of propagation of action potentials in normal nerves. Consequently, these effects can be achieved without the adverse effects that would derive from failure of normal nerve conduction. Escalating doses of anesthetic appear to exert the following systemic actions: (1) low concentrations may preferentially suppress ectopic impulse generation in chronically injured peripheral nerves; (2) moderate concentrations may suppress central sensitization, which would explain therapeutic benefit that may extend beyond the anesthetic exposure; and (3) higher concentrations will produce general analgesic effects and may culminate in serious toxicity.

Toxicity

Local anesthetic toxicity derives from two distinct processes: (1) systemic effects following inadvertent intravascular injection or absorption of the local anesthetic from the site of administration; and (2) neurotoxicity resulting from local effects produced by direct contact with neural elements.

A. Systemic Toxicity

The dose of local anesthetic used for epidural anesthesia or high-volume peripheral blocks is sufficient to produce major clinical toxicity, even death. To minimize risk, maximum recommended doses for each drug for each general application have been promulgated. The concept underlying this approach is that absorption from the site of injection should appropriately match metabolism, thereby preventing toxic serum levels. However, these recommendations do not consider patient characteristics or concomitant risk factors, nor do they take into account the specific peripheral nerve block performed, which has a significant impact on the rate of systemic uptake (Figure 26–2). Most importantly, they fail to afford protection from toxicity induced by inadvertent intravascular injection (occasionally into an artery, but more commonly a vein).

1. CNS toxicityAll local anesthetics have the ability to produce sedation, light-headedness, visual and auditory disturbances, and restlessness when high plasma concentrations result from rapid absorption or inadvertent intravascular administration. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste. At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions. Local anesthetics apparently cause depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory neuronal pathways. This transitional stage of unbalanced excitation (ie, seizure activity) is then followed by generalized CNS depression. However, this classic pattern of evolving toxicity has been largely characterized in human volunteer studies (which are ethically constrained to low doses), and by graded administration in animal models. Deviations from such classic progression are common in clinical toxicity and will be influenced by a host of factors, including patient vulnerability, the particular anesthetic administered, concurrent drugs, and rate of rise of serum drug levels. A recent literature review of reported clinical cases of local anesthetic cardiac toxicity found prodromal signs of CNS toxicity in only 18% of cases.

When large doses of a local anesthetic are required (eg, for major peripheral nerve block or local infiltration for major plastic surgery), premedication with a parenteral benzodiazepine (eg, diazepam or midazolam) will provide some prophylaxis against local anesthetic-induced CNS toxicity. However, such premedication will have little, if any, effect on cardiovascular toxicity, potentially delaying recognition of a life-threatening overdose. Of note, administration of a propofol infusion or general anesthesia accounted for 5 of the 10 cases presenting with isolated cardiovascular toxicity in the aforementioned literature review of reported clinical cases.

If seizures do occur, it is critical to prevent hypoxemia and acidosis, which potentiate anesthetic toxicity. Rapid tracheal intubation can facilitate adequate ventilation and oxygenation, and is essential to prevent pulmonary aspiration of gastric contents in patients at risk. The effect of hyperventilation is complex, and its role in resuscitation following anesthetic overdose is somewhat controversial, but it likely offers distinct benefit if used to counteract metabolic acidosis. Seizures induced by local anesthetics should be rapidly controlled to prevent patient harm and exacerbation of acidosis. A recent practice advisory from the American Society of Regional Anesthesia advocates benzodiazepines as first-line drugs (eg, midazolam, 0.03–0.06 mg/kg) because of their hemodynamic stability, but small doses of propofol (eg, 0.25–0.5 mg/kg) were considered acceptable alternatives, as they are often more immediately available in the setting of local anesthetic administration. The motor activity of the seizure can be effectively terminated by administration of a neuromuscular blocker, though this will not diminish the CNS manifestations, and efforts must include therapy directed at the underlying seizure activity.

2. CardiotoxicityThe most feared complications associated with local anesthetic administration result from the profound effects these agents can have on cardiac conduction and function. In 1979, an editorial by Albright reviewed the circumstances of six deaths associated with the use of bupivacaine and etidocaine. This seminal publication suggested that these relatively new lipophilic and potent anesthetics had greater potential cardiotoxicity, and that cardiac arrest could occur concurrently or immediately following seizures and, most importantly, in the absence of hypoxia or acidosis. Although this suggestion was sharply criticized, subsequent clinical experience unfortunately reinforced Albright’s concern—within 4 years the FDA had received reports of 12 cases of cardiac arrest associated with the use of 0.75% bupivacaine for epidural anesthesia in obstetrics. Further support for enhanced cardiotoxicity of these anesthetics came from animal studies demonstrating that doses of bupivacaine and etidocaine as low as two thirds those producing convulsions could induce arrhythmias, while the margin between CNS and cardiac toxicity was less than half that for lidocaine. In response, the FDA banned the use of 0.75% bupivacaine in obstetrics. In addition, incorporation of a test dose became ingrained as a standard of anesthetic practice, along with the practice of fractionated administration of local anesthetic.

Although reduction in bupivacaine’s anesthetic concentration and changes in anesthetic practice did much to reduce the risk of cardiotoxicity, the recognized differences in the toxicity of the stereoisomers comprising bupivacaine created an opportunity for the development of potentially safer anesthetics (see Chapter 1). Investigations demonstrated that the enantiomers of the racemic mixture bupivacaine were not equivalent with respect to cardiotoxicity, the S(–) enantiomer having better therapeutic advantage, leading to the subsequent marketing of levobupivacaine. This was followed shortly thereafter by ropivacaine, a slightly less potent anesthetic than bupivacaine. It should be noted, however, that the reduction in toxicity afforded by these compounds is only modest, and that risk of significant cardiotoxicity remains a very real concern when these anesthetics are administered for high-volume blocks.

3. Reversal of bupivacaine toxicityRecently, a series of clinical events, serendipitous observations, systematic experimentation, and astute clinical decisions have identified a relatively simple, practical and apparently effective therapy for resistant bupivacaine cardiotoxicity using intravenous infusion of lipid. Furthermore, this therapy appears to have applications that extend beyond bupivacaine cardiotoxicity to the cardiac or CNS toxicity induced by an overdose of any lipid-soluble drug (see Box: Lipid Resuscitation).

B. Localized Toxicity

1. Neural injuryFrom the early introduction of spinal anesthesia into clinical practice, sporadic reports of neurologic injury associated with this technique raised concern that local anesthetic agents were potentially neurotoxic. Following injuries associated with Durocaine—a spinal anesthetic formulation containing procaine—initial attention focused on the vehicle components. However, experimental studies found 10% procaine alone induced similar injuries in cats, whereas the vehicle did not. Concern for anesthetic neurotoxicity reemerged in the early 1980s with a series of reports of major neurologic injury occurring with the use of chloroprocaine for epidural anesthesia. In these cases, there was evidence that anesthetic intended for the epidural space was inadvertently administered intrathecally. As the dose required for spinal anesthesia is roughly an order of magnitude less than for epidural anesthesia, injury was apparently the result of excessive exposure of the more vulnerable subarachnoid neural elements.

With changes in vehicle formulation and in clinical practice, concern for toxicity again subsided, only to reemerge a decade later with reports of cauda equina syndrome associated with continuous spinal anesthesia (CSA). In contrast to the more common single-injection technique, CSA involves placing a catheter in the subarachnoid space to permit repetitive dosing to facilitate adequate anesthesia and maintenance of block for extended periods. In these cases the local anesthetic was evidently administered to a relatively restricted area of the subarachnoid space; in order to extend the block to achieve adequate surgical anesthesia, multiple repetitive doses of anesthetic were then administered. By the time the block was adequate, neurotoxic concentrations had accumulated in a restricted area of the caudal region of the subarachnoid space. Most notably, the anesthetic involved in the majority of these cases was lidocaine, a drug most clinicians considered to be the least toxic of agents. This was followed by reports of neurotoxic injury occurring with lidocaine intended for epidural administration that had inadvertently been administered intrathecally, similar to the cases involving chloroprocaine a decade earlier. The occurrence of neurotoxic injury with CSA and subarachnoid administration of epidural doses of lidocaine served to establish vulnerability whenever excessive anesthetic was administered intrathecally, regardless of the specific anesthetic used. Of even more concern, subsequent reports provided evidence for injury with spinal lidocaine administered at the high end of the recommended clinical dosage, prompting recommendations for a reduction in maximum dose. These clinical reports (as well as concurrent experimental studies) served to dispel the concept that modern local anesthetics administered at clinically relevant doses and concentrations were incapable of inducing neurotoxic injury.

The mechanism of local anesthetic neurotoxicity has been extensively investigated in cell culture, isolated axons, and in vivo models. These studies have demonstrated myriad deleterious effects including conduction failure, membrane damage, enzyme leakage, cytoskeletal disruption, accumulation of intracellular calcium, disruption of axonal transport, growth cone collapse, and apoptosis. It is not clear what role these factors or others play in clinical injury. It is clear, however, that injury does not result from blockade of the voltage-gated sodium channel per se, and thus clinical effect and toxicity are not tightly linked.

Lipid Resuscitation

Based on a case of apparent cardiotoxicity from a very low dose of bupivacaine in a patient with carnitine deficiency, Weinberg postulated that this metabolic derangement led to enhanced toxicity due to the accumulation of fatty acids within the cardiac myocyte. He hypothesized that administration of lipid would similarly potentiate bupivacaine cardiotoxicity, but experiments performed to test this hypothesis demonstrated exactly the opposite effect. Accordingly, he began systematic laboratory investigations, which clearly demonstrated the potential efficacy of an intravenous lipid emulsion (ILE) for resuscitation from bupivacaine cardiotoxicity. Clinical confirmation came 8 years later with the report of the successful resuscitation of a patient who sustained an anesthetic-induced (bupivacaine plus mepivacaine) cardiac arrest refractory to standard advanced cardiac life support procedures (ACLS). Numerous similar reports of successful resuscitations soon followed, extending this clinical experience to other anesthetics including levobupivacaine and ropivacaine, anesthetic-induced CNS toxicity, as well as toxicity induced by other classes of compounds, eg, bupropion-induced cardiovascular collapse and multiform ventricular tachycardia provoked by haloperidol. Laboratory investigations have likewise provided evidence of efficacy for treatment of diverse toxic challenges (eg, verapamil, clomipramine, and propranolol).

The mechanism by which lipid is effective is incompletely understood, but almost certainly some of its effect is related to its ability to extract a lipophilic drug from aqueous plasma and thus reducing its effective concentration at tissue targets, a mechanism termed “lipid sink.” However, the extent of this extraction does not appear adequate to account for the magnitude of clinical effect, suggesting that other mechanisms at least contribute to the efficacy of lipid rescue. For example, bupivacaine has been shown to inhibit fatty acid transport at the inner mitochondrial membrane, and lipid might act by overcoming this inhibition serving to restore energy to the myocardium or derive benefit via elevation of intramyocyte calcium concentration. Although numerous questions remain, the evolving evidence is sufficient to warrant administration of lipid in cases of systemic anesthetic toxicity. Its use has been promulgated by a task force of the American Society of Regional Anesthesia, and administration of lipid has been incorporated into the most recent revision of ACLS guidelines for Cardiac Arrest in Special Situations. Importantly, propofol cannot be administered for this purpose, as the relatively enormous volume of this solution required for lipid therapy would deliver lethal quantities of propofol.

2. Transient neurologic symptoms (TNS)In addition to the very rare but devastating neural complications that can occur with neuraxial (spinal and epidural) administration of local anesthetics, a syndrome of transient pain or dysesthesia, or both, has been recently linked to use of lidocaine for spinal anesthesia. Although these symptoms are not associated with sensory loss, motor weakness, or bowel and bladder dysfunction, the pain can be quite severe, often exceeding that induced by the surgical procedure. TNS occurs even at modest doses of anesthetic, and has been documented in as many as one third of patients receiving lidocaine, with increased risk associated with certain patient positions during surgery (eg, lithotomy), and with ambulatory anesthesia. Risk with other anesthetics varies considerably. For example, the incidence is only slightly reduced with procaine or mepivacaine but appears to be negligible with bupivacaine, prilocaine, and chloroprocaine. The etiology and significance of TNS remain to be established, but differences between factors affecting TNS and experimental animal toxicity argue strongly against a common mechanism mediating these symptoms and persistent or permanent neurologic deficits. Nonetheless, the high incidence of TNS has greatly contributed to dissatisfaction with lidocaine as a spinal anesthetic, leading to its near abandonment for this technique (although it remains a popular and appropriate anesthetic for all other applications, including epidural anesthesia). Chloroprocaine, once considered a more toxic anesthetic, is now being explored for short-duration spinal anesthesia as an alternative to lidocaine, a compound that has been used for well over 50 million spinal anesthetic procedures.

image COMMONLY USED LOCAL ANESTHETICS & THEIR APPLICATIONS

ARTICAINE

Approved for use in the USA as a dental anesthetic in April 2000, articaine is unique among the amino-amide anesthetics in having a thiophene, rather than a benzene ring, as well as an additional ester group that is subject to metabolism by plasma esterases (Table 26–1). The modification of the ring serves to enhance lipophilicity, and thus improve tissue penetration, while inclusion of the ester leads to a shorter plasma half-life (approximately 20 minutes) potentially imparting a better therapeutic index with respect to systemic toxicity. These characteristics have led to widespread popularity in dental anesthesia, where it is generally considered to be more effective, and possibly safer, than lidocaine, the prior standard. Balanced against these positive attributes are concerns that development of persistent paresthesias, while rare, may be three times more common with articaine. However, prilocaine has been associated with an even higher relative incidence (twice that of articaine). Importantly, these are the only two dental anesthetics that are formulated as 4% solutions; the others are all marketed at lower concentrations (eg, the maximum concentration of lidocaine used for dental anesthesia is 2%), and it is well established that anesthetic neurotoxicity is, to some extent, concentration-dependent. Thus, it is quite possible that enhanced risk derives from the formulation rather than from an intrinsic property of the anesthetic. In a recent survey of US and Canadian Dental Schools, over half of respondents indicated that 4% articaine is no longer used for mandibular nerve block.

BENZOCAINE

As previously noted, benzocaine’s pronounced lipophilicity has relegated its application to topical anesthesia. However, despite over a century of use for this purpose, its popularity has recently diminished owing to increasing concerns regarding its potential to induce methemoglobinemia. Elevated levels can be due to inborn errors, or can occur with exposure to an oxidizing agent, and such is the case with significant exposure to benzocaine (or nitrites, see Chapter 12). Because methemoglobin does not transport oxygen, elevated levels pose serious risk, with severity obviously paralleling blood levels.

BUPIVACAINE

Based on concerns for cardiotoxicity, bupivacaine is often avoided for techniques that demand high volumes of concentrated anesthetic, such as epidural or peripheral nerve blocks performed for surgical anesthesia. In contrast, relatively low concentrations (≤ 0.25%) are frequently used to achieve prolonged peripheral anesthesia and analgesia for postoperative pain control, and the drug enjoys similar popularity where anesthetic infiltration is used to control pain from a surgical incision. It is often the agent of choice for epidural infusions used for postoperative pain control and for labor analgesia. Finally, it has a comparatively unblemished record as a spinal anesthetic, with a relatively favorable therapeutic index with respect to neurotoxicity, and little, if any, risk of TNS. However, spinal bupivacaine is not well suited for outpatient or ambulatory surgery, because its relatively long duration of action can delay recovery, resulting in a longer stay prior to discharge to home.

CHLOROPROCAINE

The introduction of chloroprocaine into clinical practice in 1951 represented a reversion to the earlier amino-ester template. Chloroprocaine gained widespread use as an epidural agent in obstetrical anesthesia where its rapid hydrolysis served to minimize risk of systemic toxicity or fetal exposure. The unfortunate reports of neurologic injury associated with apparent intrathecal misplacement of large doses intended for the epidural space led to its near abandonment. However, the frequent occurrence of TNS with lidocaine administered as a spinal anesthetic has created an anesthetic void that chloroprocaine appears well suited to fill. The onset and duration of action of spinal chloroprocaine are even shorter than those of lidocaine, while presenting little, if any, risk of TNS. Although never exonerated with respect to the early neurologic injuries associated with epidural anesthesia, it is now appreciated that high doses of any local anesthetic are capable of inducing neurotoxic injury. A formulation is now marketed in Europe specifically for spinal anesthesia, and there is considerable off-label use of a preservative-free solution in the USA. Nonetheless, documented use as a spinal anesthetic is relatively limited, and additional experience will be required to firmly establish safety. In addition to chloroprocaine’s emerging use for spinal anesthesia, it still finds some current use as an epidural anesthetic, particularly in circumstances where there is an indwelling catheter and the need for quick attainment of surgical anesthesia, such as caesarian section for a laboring parturient with a compromised fetus.

COCAINE

Current clinical use of cocaine is largely restricted to topical anesthesia for ear, nose, and throat procedures, where its intense vasoconstriction can serve to reduce bleeding. Even here, use has diminished in favor of other anesthetics combined with vasoconstrictors because of concerns about systemic toxicity, as well as the inconvenience of dispensing and handling this controlled substance.

ETIDOCAINE

Introduced along with bupivacaine, etidocaine has had limited application due to its poor block characteristics. It has a tendency to produce an inverse differential block (ie, compared with other anesthetics such as bupivacaine, it produces excessive motor relative to sensory block), which is rarely a favorable attribute.

LEVOBUPIVACAINE

As previously discussed, this S(–) enantiomer of bupivacaine is somewhat less cardiotoxic than the racemic mixture. It is also less potent, and tends to have a longer duration of action, though the magnitude of these effects is too small to have any substantial clinical significance. Interestingly, recent work with lipid resuscitation suggests a potential advantage of levobupivacaine over ropivacaine, as the former is more effectively sequestered into a so-called lipid sink, implying greater ability to reverse toxic effects should they occur.

LIDOCAINE

Aside from the issue of a high incidence of TNS with spinal administration, lidocaine has had an excellent record as an intermediate duration anesthetic, and remains the reference standard against which most anesthetics are compared.

MEPIVACAINE

Although structurally similar to bupivacaine and ropivacaine (Table 26–1), mepivacaine displays clinical properties that are comparable to lidocaine. However, it differs from lidocaine with respect to vasoactivity, as it has a tendency toward vasoconstriction rather than vasodilation. This characteristic likely accounts for its slightly longer duration of action, which has made it a popular choice for major peripheral blocks. Lidocaine has retained its dominance over mepivacaine for epidural anesthesia, where the routine placement of a catheter negates the importance of a longer duration. More importantly, mepivacaine is slowly metabolized by the fetus, making it a poor choice for epidural anesthesia in the parturient. When used for spinal anesthesia, mepivacaine has a slightly lower incidence of TNS than lidocaine.

PRILOCAINE

Prilocaine has the highest clearance of the amino-amide anesthetics, imparting reduced risk of systemic toxicity. Unfortunately, this is somewhat offset by its propensity to induce methemoglobinemia, which results from accumulation of one its metabolites, ortho-toluidine, an oxidizing agent. As a spinal anesthetic, prilocaine’s duration of action is slightly longer than that of lidocaine, and the limited data suggest it carries a low risk of TNS. It is gaining increasing use for spinal anesthesia in Europe, where it has been marketed specifically for this purpose. No approved formulation exists in the USA, and there is no formulation that would be appropriate to use for spinal anesthesia as an off-label indication.

ROPIVACAINE

Ropivacaine is an S(–) enantiomer in a homologous series that includes bupivacaine and mepivacaine, distinguished by its chirality, and the propyl group off the piperidine ring (Table 26–1). Its perceived reduced cardiotoxicity has led to widespread use for high-volume peripheral blocks. It is also a popular choice for epidural infusions for control of labor and postoperative pain. Although there is some evidence to suggest that ropivacaine might produce a more favorable differential block than bupivacaine, the lack of equivalent clinical potency adds complexity to such comparisons.

EMLA

The term eutectic is applied to mixtures in which the combination of elements has a lower melting temperature than its component elements. Lidocaine and prilocaine can combine to form such a mixture, which is marketed as EMLA (Eutectic Mixture of Local Anesthetics). This formulation, containing 2.5% of lidocaine and 2.5% prilocaine, permits anesthetic penetration of the keratinized layer of skin, producing localized numbness. It is commonly used in pediatrics to anesthetize the skin prior to venipuncture for intravenous catheter placement.

FUTURE DEVELOPMENTS

Sustained-Release Formulations

The provision of prolonged analgesia or anesthesia, as in the case of postoperative pain management, has traditionally been accomplished by placement of a catheter to permit continuous administration of anesthetic. More recently, efforts have focused on drug delivery systems that can slowly release anesthetic, thereby providing extended duration without the drawbacks of a catheter. Sustained-release delivery has the potential added advantage of reducing risk of systemic toxicity. Preliminary work encapsulating local anesthetic into microspheres, liposomes, and other microparticles has established proof of concept, although significant developmental problems, as well as questions regarding potential tissue toxicity, remain to be resolved.

Less Toxic Agents; More Selective Agents

It has been clearly demonstrated that anesthetic neurotoxicity does not result from blockade of the voltage-gated sodium channel. Thus, effect and tissue toxicity are not mediated by a common mechanism, establishing the possibility of developing compounds with considerably better therapeutic indexes.

As previously discussed, the identification and subclassification of families of neuronal sodium channels has spurred research aimed at development of more selective sodium channel blockers. The variable neuronal distribution of these isoforms and the unique role that some play in pain signaling suggests that selective blockade of these channels is feasible, and may greatly improve the therapeutic index of sodium channel modulators.

SUMMARY Drugs Used for Local Anesthesia

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PREPARATIONS AVAILABLE

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*The author thanks Bertram G. Katzung, MD, PhD, and Paul F. White, PhD, MD, for contributions to this chapter in previous editions.

CASE STUDY ANSWER

If a spinal anesthetic technique were selected, bupivacaine would be an excellent choice. It has an adequately long duration of action and a relatively unblemished record with respect to neurotoxic injury and transient neurologic symptoms, which are the complications of most concern with spinal anesthetic technique. Although bupivacaine has greater potential for cardiotoxicity, this is not a concern when the drug is used for spinal anesthesia because of the extremely low doses required for intrathecal administration. If an epidural technique were chosen for the surgical procedure, the potential for systemic toxicity would need to be considered, making lidocaine or mepivacaine (generally with epinephrine) preferable to bupivacaine (or even ropivacaine or levobupivacaine) because of their better therapeutic indexes with respect to cardiotoxicity. However, this does not apply to epidural administration for postoperative pain control, which involves administration of more dilute anesthetic at a slower rate. The most common agents used for this indication are bupivacaine, ropivacaine, and levobupivacaine.