Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e

Chapter 20: Local Anesthetics

William A. Catterall; Kenneth Mackie

INTRODUCTION

Local anesthetics bind reversibly to a specific receptor site within the pore of the Na⁺ channels in nerves and block ion movement through this pore. When applied locally to nerve tissue in appropriate concentrations, local anesthetics can act on any part of the nervous system and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction. Thus, a local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. These effects of clinically relevant concentrations of local anesthetics are reversible with recovery of nerve function and no evidence of damage to nerve fibers or cells in most clinical applications.

History. The first local anesthetic, cocaine, was serendipitously discovered to have anesthetic properties in the late 19th century. Cocaine occurs in abundance in the leaves of the coca shrub (Erythroxylon coca). For centuries, Andean natives have chewed an alkali extract of these leaves for its stimulatory and euphoric actions. Cocaine was first isolated in 1860 by Albert Niemann. He, like many chemists of that era, tasted his newly isolated compound and noted that it caused a numbing of the tongue. Sigmund Freud studied cocaine's physiological actions, and Carl Koller introduced cocaine into clinical practice in 1884 as a topical anesthetic for ophthalmological surgery. Shortly thereafter, Halstead popularized its use in infiltration and conduction block anesthesia.

Chemistry and Structure-Activity Relationship. Cocaine is an ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxy-tropane (Figure 20–1). Because of its toxicity and addictive properties (Chapter 24), a search for synthetic substitutes for cocaine began in 1892 with the work of Einhorn and colleagues, resulting in the synthesis of procaine, which became the prototype for local anesthetics for nearly half a century. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine.

The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage (Figure 20–1). A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, local anesthetics with an ester link are hydrolyzed readily by plasma esterases.

The structure-activity relationship and the physicochemical properties of local anesthetics have been reviewed by Courtney and Strichartz (1987). Hydrophobicity increases both the potency and the duration of action of the local anesthetics; association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na⁺ channels is thought to be hydrophobic (see Mechanism of Action), so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.

Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency- and voltage-dependence of their action.

Figure 20–1

Structural formulas of selected local anesthetics. Most local anesthetics consist of a hydrophobic (aromatic) moiety (black), a linker region (orange), and a substituted amine (hydrophilic region, in red). The structures above are grouped by the nature of the linker region. Procaine is a prototypic ester-type local anesthetic; esters generally are well hydrolyzed by plasma esterases, contributing to the relatively short duration of action of drugs in this group. Lidocaine is a prototypic amide-type local anesthetic; these structures generally are more resistant to clearance and have longer durations of action. There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether linkage. Chloroprocaine has a chlorine atom on C2 of the aromatic ring of procaine.

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Figure 20–2

Structure and function of voltage-gated Na⁺ channels. A. A two-dimensional representation of the α (center), β₁ (left), and β₂ (right) subunits of the voltage-gated Na⁺ channel from mammalian brain. The polypeptide chains are represented by continuous lines with length approximately proportional to the actual length of each segment of the channel protein. Cylinders represent regions of transmembrane α helices. ψ indicates sites of demonstrated N-linked glycosylation. Note the repeated structure of the four homologous domains (I-IV) of the α subunit. Voltage Sensing. The S4 transmembrane segments in each homologous domain of the α subunit serve as voltage sensors. (+) represents the positively charged amino acid residues at every third position within these segments. Electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane; depolarization allows them to move outward. Pore. The S5 and S6 transmembrane segments and the short membrane-associated loop between them (P loop) form the walls of the pore in the center of an approximately symmetrical square array of the four homologous domains (see panel B). The amino acid residues indicated by circles in the P loop are critical for determining the conductance and ion selectivity of the Na⁺ channel and its ability to bind the extracellular pore-blocking toxins tetrodotoxin and saxitoxin. Inactivation. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate of the Na⁺ channel. It is thought to fold into the intracellular mouth of the pore and occlude it within a few milliseconds after the channel opens. Three hydrophobic residues (isoleucine–phenylalanine–methionine; IFM) at the position marked h appear to serve as an inactivation particle, entering the intracellular mouth of the pore and binding therein to an inactivation gate receptor there. Modulation. The gating of the Na⁺ channel can be modulated by protein phosphorylation. Phosphorylation of the inactivation gate between homologous domains III and IV by PKC slows inactivation. Phosphorylation of sites in the intracellular loop between homologous domains I and II by either PKC or PKA reduces Na⁺ channel activation. (Adapted from Catterall, 2000, with permission.Copyright © Elsevier.). B. The four homologous domains of the Na⁺ channel α subunit are illustrated as a square array, as viewed looking down on the membrane. The sequence of conformational changes that the Na⁺ channel undergoes during activation and inactivation is diagrammed. Upon depolarization, each of the four homologous domains sequentially undergoes a conformational change to an activated state. After all four domains have activated, the Na⁺ channel can open. Within a few milliseconds after opening, the inactivation gate between domains III and IV closes over the intracellular mouth of the channel and occludes it, preventing further ion conductance (see Catterall, 2000).

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Mechanism of Action. Local anesthetics act at the cell membrane to prevent the generation and the conduction of nerve impulses. Conduction block can be demonstrated in squid giant axons from which the axoplasm has been removed.

Local anesthetics block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na⁺ that normally is produced by a slight depolarization of the membrane (Chapters 8, 11, 14) (Strichartz and Ritchie, 1987). This action of local anesthetics is due to their direct interaction with voltage-gated Na⁺ channels. As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases. These factors decrease the probability of propagation of the action potential, and nerve conduction eventually fails.

Local anesthetics can bind to other membrane proteins (Butterworth and Strichartz, 1990). In particular, they can block K⁺ channels (Strichartz and Ritchie, 1987). However, since the interaction of local anesthetics with K⁺ channels requires higher concentrations of drug, blockade of conduction is not accompanied by any large or consistent change in resting membrane potential.

Quaternary analogs of local anesthetics block conduction when applied internally to perfused giant axons of squid but are relatively ineffective when applied externally. These observations suggest that the site at which local anesthetics act, at least in their charged form, is accessible only from the inner surface of the membrane (Narahashi and Frazier, 1971; Strichartz and Ritchie, 1987). Therefore, local anesthetics applied externally first must cross the membrane before they can exert a blocking action.

Although a variety of physicochemical models have been proposed to explain how local anesthetics achieve conduction block (Courtney and Strichartz, 1987), it now is generally accepted that the major mechanism of action of these drugs involves their interaction with one or more specific binding sites within the Na⁺ channel (Butterworth and Strichartz, 1990). The Na⁺ channels of the mammalian brain are complexes of glycosylated proteins with an aggregate molecular size in excess of 300,000 Da; the individual subunits are designated α (260,000 Da) and β₁ to β₄ (33,000-38,000 Da). The large α subunit of the Na⁺ channel contains four homologous domains (I-IV); each domain is thought to consist of six transmembrane segments in α-helical conformation (S1-S6; Figure 20–2) and an additional, membrane-reentrant pore (P) loop. The Na⁺-selective transmembrane pore of the channel presumably resides in the center of a nearly symmetrical structure formed by the four homologous domains. The voltage dependence of channel opening is hypothesized to reflect conformational changes that result from the movement of "gating charges" within the voltage-sensor module of the sodium channel in response to changes in the transmembrane potential. The gating charges are located in the S4 transmembrane helix; the S4 helices are both hydrophobic and positively charged, containing lysine or arginine residues at every third position. It is postulated that these residues move perpendicular to the plane of the membrane under the influence of the transmembrane potential, initiating a series of conformational changes in all four domains, which leads to the open state of the channel (Figure 20–2) (Catterall, 2000; Yu et al., 2005).

The transmembrane pore of the Na⁺ channel is thought to be surrounded by the S5 and S6 transmembrane helices and the short membrane-associated segments between them that form the P loop. Amino acid residues in these short segments are the most critical determinants of the ion conductance and selectivity of the channel.

After it opens, the Na⁺ channel inactivates within a few milliseconds due to closure of an inactivation gate. This functional gate is formed by the short intracellular loop of protein that connects homologous domains III and IV (Figure 20–2). This loop folds over the intracellular mouth of the transmembrane pore during the process of inactivation and binds to an inactivation gate "receptor" formed by the intracellular mouth of the pore.

Amino acid residues important for local anesthetic binding are found in the S6 segments in domains I, III, and IV (Ragsdale et al., 1994; Yarov-Yarovoy et al., 2002). Hydrophobic amino acid residues near the center and the intracellular end of the S6 segment may interact directly with bound local anesthetics (Figure 20–3). Experimental mutation of a large hydrophobic amino acid residue (isoleucine) to a smaller one (alanine) near the extracellular end of this segment creates a pathway for access of charged local anesthetic drugs from the extracellular solution to the receptor site. These findings place the local anesthetic receptor site within the intracellular half of the transmembrane pore of the Na⁺ channel, with part of its structure contributed by amino acids in the S6 segments of domains I, III, and IV.

Figure 20–3

The local anesthetic receptor site. A. A drawing of the pore structure of a bacterial K⁺ channel (KcsA), which is related to the sodium channel. The KcsA channel has two transmembrane segments, analogous to the S5 and S6 segments of sodium channels. The S6-like segment forms the walls of the inner pore while the P loop forms the narrow ion selectivity filter at its extracellular (top) end. Four separate KcsA subunits form the pore in their center; only two of the subunits are shown here. B. A structural model of the local anesthetic receptor site. The S6 segments from domains I, III, and IV of the sodium channel α subunit are illustrated, based on the structure of the KcsA channel (panel A). The amino acid residues in these three transmembrane segments that contribute to the local anesthetic receptor site are indicated in single letter code and are presented in space-filling representation (light blue). An etidocaine molecule (black) is illustrated bound in the receptor site. Substitutions of the light blue residues with alanine reduce the affinity for local anesthetic block of sodium channels. It therefore is likely that the side chains of these amino acid residues contact bound local anesthetics in their receptor site. I1760 and I409 likely form the outer boundary of the local anesthetic receptor site. Mutations of I1760 allow drug access to the receptor site from the extracellular side. (This figure was originally published in the Journal of Biological Chemistry. Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA: Role of amino acid resides in transmembrane segments IS6 and IIS6 of the Na⁺ channel alpha subunit in voltage-dependent gating and drug block. J Biol Chem 2002:277, 35393. © the American Society for Biochemistry and Molecular Biology.)

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Frequency- and Voltage-Dependence of Local Anesthetic Action. The degree of block produced by a given concentration of local anesthetic depends on how the nerve has been stimulated and on its resting membrane potential. Thus, a resting nerve is much less sensitive to a local anesthetic than one that is repetitively stimulated; higher frequency of stimulation and more positive membrane potential cause a greater degree of anesthetic block. These frequency- and voltage-dependent effects of local anesthetics occur because the local anesthetic molecule in its charged form gains access to its binding site within the pore only when the Na⁺ channel is in an open state and because the local anesthetic binds more tightly to and stabilizes the inactivated state of the Na⁺ channel (Butterworth and Strichartz, 1990; Courtney and Strichartz, 1987). Local anesthetics exhibit these properties to different extents depending on their pK_a, lipid solubility, and molecular size. In general, the frequency dependence of local anesthetic action depends critically on the rate of dissociation from the receptor site in the pore of the Na⁺ channel. A high frequency of stimulation is required for rapidly dissociating drugs so that drug binding during the action potential exceeds drug dissociation between action potentials. Dissociation of smaller and more hydrophobic drugs is more rapid, so a higher frequency of stimulation is required to yield frequency-dependent block. Frequency-dependent block of ion channels is most important for the actions of antiarrhythmic drugs (Chapter 29).

Differential Sensitivity of Nerve Fibers to Local Anesthetics. Although there is great individual variation, for most patients treatment with local anesthetics causes the sensation of pain to disappear first, followed by loss of the sensations of temperature, touch, deep pressure, and finally motor function (Table 20–1). Classical experiments with intact nerves showed that the λ wave in the compound action potential, which represents slowly conducting, small-diameter myelinated fibers, was reduced more rapidly and at lower concentrations of cocaine than was the α wave, which represents rapidly conducting, large-diameter fibers (Gasser and Erlanger, 1929). In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated Aλ fibers (mediating pain and temperature sensations) are blocked before the larger myelinated Aγ, Aβ, and Aα fibers (mediating postural, touch, pressure, and motor information) (Raymond and Gissen, 1987). The differential rate of block exhibited by fibers mediating different sensations is of considerable practical importance in the use of local anesthetics.

Table 20-1Susceptibility to Block Types of Nerve Fibers

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Table 20-1 Susceptibility to Block Types of Nerve Fibers

CLASSIFICATION

ANATOMIC LOCATION

MYELIN

DIAMETER, (μm)

CONDUCTION VELOCITY, (m/sec)

FUNCTION

CLINICAL SENSITIVITY TO BLOCK

A fibers

A α

Afferent to and efferent

Yes

6–22

10–85

Motor and

A β

from muscles and joints

proprioception

A γ

Efferent to muscle spindles

Yes

3–6

15–35

Muscle tone

A λ

Sensory roots and afferent peripheral nerves

Yes

1–4

5–25

Pain, temperature, touch

+++

B fibers

Preganglionic sympathetic visceromotor, sudomotor, pilomotor

Yes

3–15

Vasomotor,

++++

C fibers

Sympathetic

Postganglionic sympathetic

0.3–1.3

0.7–1.3

Vasomotor, visceromotor sudomotor, pilomotor

++++

Dorsal root

Sensory roots and afferent peripheral nerves

0.4–1.2

0.1–2

Pain, temperature, touch

++++

Source: Adapted from Carpenter and Mackey, 1992, with permission. http://lww.com.

The precise mechanisms responsible for this apparent specificity of local anesthetic action on pain fibers are not known, but several factors may contribute. The initial hypothesis from the classical work on intact nerves was that sensitivity to local anesthetic block increases with decreasing fiber size, consistent with high sensitivity for pain sensation mediated by small fibers and low sensitivity for motor function mediated by large fibers (Gasser and Erlanger, 1929). However, when nerve fibers are dissected from nerves to allow direct measurement of action potential generation, no clear correlation of the concentration dependence of local anesthetic block with fiber diameter is observed (Fink and Cairns, 1984; Franz and Perry, 1974; Huang et al., 1997). Therefore, it is unlikely that the fiber size per se determines the sensitivity to local anesthetic block under steady-state conditions. However, the spacing of nodes of Ranvier increases with the size of nerve fibers. Because a fixed number of nodes must be blocked to prevent conduction, small fibers with closely spaced nodes of Ranvier may be blocked more rapidly during treatment of intact nerves, because the local anesthetic reaches a critical length of nerve more rapidly (Franz and Perry, 1974). Differences in tissue barriers and location of smaller C fibers and Aλ fibers in nerves also may influence the rate of local anesthetic action.

Effect of pH. Local anesthetics tend to be only slightly soluble as unprotonated amines. Therefore, they generally are marketed as water-soluble salts, usually hydrochlorides. Inasmuch as the local anesthetics are weak bases (typical pK_a values range from 8-9), their hydrochloride salts are mildly acidic. This property increases the stability of the local anesthetic esters and the catecholamines added as vasoconstrictors. Under usual conditions of administration, the pH of the local anesthetic solution rapidly equilibrates to that of the extracellular fluids.

Although the unprotonated species of the local anesthetic is necessary for diffusion across cellular membranes, it is the cationic species that interacts preferentially with Na⁺ channels. The results of experiments on anesthetized mammalian nonmyelinated fibers support this conclusion (Ritchie and Greengard, 1966). In these experiments, conduction could be blocked or unblocked merely by adjusting the pH of the bathing medium to 7.2 or 9.6, respectively, without altering the amount of anesthetic present. The primary role of the cationic form also was demonstrated by Narahashi and Frazier, who perfused the extracellular and axoplasmic surface of the giant squid axon with tertiary and quaternary amine local anesthetics and found that the quaternary amines were active (Narahashi and Frazier, 1971). However, the unprotonated molecular forms also possess some anesthetic activity (Butterworth and Strichartz, 1990). Recent reports indicate that quaternary local anesthetics such as QX-314 can gain access to the cytoplasmic surface of the nerve cell membrane via TRPV1 channels (transient receptor potential vanilloid subtype channels) (reviewed by Butterworth and Oxford, 2009). TRP channels, and possibly other ion channels, appear to lose selectivity and permit permeation of molecules like QX-314 in the face of prolonged or intense activation.

Prolongation of Action by Vasoconstrictors. The duration of action of a local anesthetic is proportional to the time of contact with nerve. Consequently, maneuvers that keep the drug at the nerve prolong the period of anesthesia. For example, cocaine inhibits the neuronal membrane transporters for catecholamines, thereby potentiating the effect of NE at α adrenergic receptors in the vasculature, resulting in vasoconstriction and reduced cocaine absorption in vascular beds where α adrenergic effects predominate (Chapters 8 and 12). Ropivacaine and bupivacaine also cause vasoconstriction. In clinical practice, a vasoconstrictor, usually epinephrine, is often added to local anesthetics. The vasoconstrictor performs a dual service. By decreasing the rate of absorption, it not only localizes the anesthetic at the desired site, but also allows the rate at which it is destroyed in the body to keep pace with the rate at which it is absorbed into the circulation. This reduces its systemic toxicity. It should be noted, however, that epinephrine also dilates skeletal muscle vascular beds through actions at β₂ adrenergic receptors, and therefore has the potential to increase systemic toxicity of anesthetic deposited in muscle tissue.

Some of the vasoconstrictor agents may be absorbed systemically, occasionally to an extent sufficient to cause untoward reactions (see the next section). There also may be delayed wound healing, tissue edema, or necrosis after local anesthesia. These effects seem to occur partly because sympathomimetic amines increase the oxygen consumption of the tissue; this, together with the vasoconstriction, leads to hypoxia and local tissue damage. The use of vasoconstrictors in local anesthetic preparations for anatomical regions with limited collateral circulation could produce irreversible hypoxic damage, tissue necrosis, and gangrene, and therefore is contraindicated.

Undesired Effects of Local Anesthetics. In addition to blocking conduction in nerve axons in the peripheral nervous system, local anesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. Thus, they have important effects on the CNS, the autonomic ganglia, the neuromuscular junction, and all forms of muscle (for a review, see Covino, 1987; Garfield and Gugino, 1987; Gintant and Hoffman, 1987). The danger of such adverse reactions is proportional to the concentration of local anesthetic achieved in the circulation. In general, in local anesthetics with chiral centers, the S-enantiomer is less toxic than the R-enantiomer (McClure, 1996).

Central Nervous System. Following absorption, local anesthetics may cause CNS stimulation, producing restlessness and tremor that may progress to clonic convulsions. In general, the more potent the anesthetic, the more readily convulsions may be produced. Alterations of CNS activity are thus predictable from the local anesthetic agent in question and the blood concentration achieved. Central stimulation is followed by depression; death usually is caused by respiratory failure.

The apparent stimulation and subsequent depression produced by applying local anesthetics to the CNS presumably is due solely to depression of neuronal activity; a selective depression of inhibitory neurons is thought to account for the excitatory phase in vivo. Rapid systemic administration of local anesthetics may produce death with no or only transient signs of CNS stimulation. Under these conditions, the concentration of the drug probably rises so rapidly that all neurons are depressed simultaneously. Airway control, along with ventilatory and circulatory support, are essential features of treatment in the late stage of intoxication. Benzodiazepines or rapidly acting barbiturates administered intravenously are the drugs of choice for both the prevention and arrest of convulsions (Chapter 17).

Although drowsiness is the most frequent complaint that results from the CNS actions of local anesthetics, lidocaine may produce dysphoria or euphoria and muscle twitching. Moreover, both lidocaine and procaine may produce a loss of consciousness that is preceded only by symptoms of sedation (Covino, 1987). Whereas other local anesthetics also show the effect, cocaine has a particularly prominent effect on mood and behavior. These effects of cocaine and its potential for abuse are discussed in Chapter 24.

Cardiovascular System. Following systemic absorption, local anesthetics act on the cardiovascular system (Covino, 1987). The primary site of action is the myocardium, where decreases in electrical excitability, conduction rate, and force of contraction occur. In addition, most local anesthetics cause arteriolar dilation. Untoward cardiovascular effects usually are seen only after high systemic concentrations are attained and effects on the CNS are produced. However, on rare occasions, lower doses of some local anesthetics will cause cardiovascular collapse and death, probably due to either an action on the pacemaker or the sudden onset of ventricular fibrillation. Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than bupivacaine. The effects of local anesthetics such as lidocaine and procainamide, which also are used as antiarrhythmic drugs, are discussed in Chapter 29. Finally, it should be stressed that untoward cardiovascular effects of local anesthetic agents may result from their inadvertent intravascular administration, especially if epinephrine also is present.

Smooth Muscle. Local anesthetics depress contractions in the intact bowel and in strips of isolated intestine (Zipf and Dittmann, 1971). They also relax vascular and bronchial smooth muscle, although low concentrations initially may produce contraction (Covino, 1987). Spinal and epidural anesthesia, as well as instillation of local anesthetics into the peritoneal cavity, cause sympathetic nervous system paralysis, which can result in increased tone of GI musculature (described under "Clinical Uses"). Local anesthetics may increase the resting tone and decrease the contractions of isolated human uterine muscle; however, uterine contractions are seldom depressed directly during intrapartum regional anesthesia.

Neuromuscular Junction and Ganglionic Synapse. Local anesthetics also affect transmission at the neuromuscular junction. Procaine, e.g., can block the response of skeletal muscle to maximal motor-nerve volleys and to ACh at concentrations at which the muscle responds normally to direct electrical stimulation. Similar effects occur at autonomic ganglia. These effects are due to block of nicotinic ACh receptors by high concentrations of the local anesthetic (Charnet et al., 1990; Neher and Steinbach, 1978).

Hypersensitivity to Local Anesthetics. Rare individuals are hypersensitive to local anesthetics. The reaction may manifest itself as an allergic dermatitis or a typical asthmatic attack (Covino, 1987). It is important to distinguish allergic reactions from toxic side effects and from the effects of co-administered vasoconstrictors. Hypersensitivity seems to occur more frequently with local anesthetics of the ester type and frequently extends to chemically related compounds. For example, individuals sensitive to procaine also may react to structurally similar compounds (e.g., tetracaine) through reaction to a common metabolite. Although allergic responses to agents of the amide type are uncommon, solutions of such agents may contain preservatives such as methylparaben that may provoke an allergic reaction (Covino, 1987). Local anesthetic preparations containing a vasoconstrictor also may elicit allergic responses due to the sulfite added as an antioxidant for the catecholamine/vasoconstrictor.

Metabolism of Local Anesthetics. The metabolic fate of local anesthetics is of great practical importance, because their toxicity depends largely on the balance between their rates of absorption and elimination. As noted earlier, the rate of absorption of many anesthetics can be reduced considerably by the incorporation of a vasoconstrictor agent in the anesthetic solution. However, the rate of degradation of local anesthetics varies greatly, and this is a major factor in determining the safety of a particular agent. Since toxicity is related to the free concentration of drug, binding of the anesthetic to proteins in the serum and to tissues reduces the concentration of free drug in the systemic circulation, and consequently reduces toxicity. For example, in intravenous regional anesthesia of an extremity, about half of the original anesthetic dose still is tissue-bound 30 minutes after the restoration of normal blood flow (Arthur, 1987).

Some of the common local anesthetics (e.g., tetracaine) are esters. They are hydrolyzed and inactivated primarily by a plasma esterase, probably plasma cholinesterase. The liver also participates in hydrolysis of local anesthetics. Since spinal fluid contains little or no esterase, anesthesia produced by the intrathecal injection of an anesthetic agent will persist until the local anesthetic agent has been absorbed into the circulation.

The amide-linked local anesthetics are, in general, degraded by the hepatic CYPs the initial reactions involving N-dealkylation and subsequent hydrolysis (Arthur, 1987). However, with prilocaine, the initial step is hydrolytic, forming o-toluidine metabolites that can cause methemoglobinemia. The extensive use of amide-linked local anesthetics in patients with severe hepatic disease requires caution. The amide-linked local anesthetics are extensively (55-95%) bound to plasma proteins, particularly α₁-acid glycoprotein. Many factors increase (e.g., cancer, surgery, trauma, myocardial infarction, smoking, and uremia) or decrease (e.g., oral contraceptives) the level of this glycoprotein, thereby changing the amount of anesthetic delivered to the liver for metabolism and thus influencing systemic toxicity. Age-related changes in protein binding of local anesthetics also occur. The neonate is relatively deficient in plasma proteins that bind local anesthetics and thereby is more susceptible to toxicity. Plasma proteins are not the sole determinant of local anesthetic availability. Uptake by the lung also may play an important role in the distribution of amide-linked local anesthetics in the body. Reduced cardiac output slows delivery of the amide compounds to the liver, reducing their metabolism and prolonging their plasma half-lives.

COCAINE

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Chemistry. Cocaine, an ester of benzoic acid and methylecgonine, occurs in abundance in the leaves of the coca shrub. Ecgonine is an amino alcohol base closely related to tropine, the amino alcohol in atropine. It has the same fundamental structure as the synthetic local anesthetics (Figure 20–1).

Pharmacological Actions and Preparations. The clinically desired actions of cocaine are the blockade of nerve impulses, as a consequence of its local anesthetic properties, and local vasoconstriction, secondary to inhibition of local NE reuptake. Toxicity and its potential for abuse have steadily decreased the clinical uses of cocaine. Its high toxicity is due to reduced catecholamine uptake in both the central and peripheral nervous systems. Its euphoric properties are due primarily to inhibition of catecholamine uptake, particularly DA, in the CNS. Other local anesthetics do not block the uptake of NE and do not produce the sensitization to catecholamines, vasoconstriction, or mydriasis characteristic of cocaine. Currently, cocaine is used primarily for topical anesthesia of the upper respiratory tract, where its combination of both vasoconstrictor and local anesthetic properties provide anesthesia and shrinking of the mucosa. Cocaine hydrochloride is provided as a 1%, 4%, or 10% solution for topical application. For most applications, the 1% or 4% preparation is preferred to reduce toxicity. Because of its abuse potential, cocaine is listed as a schedule II controlled substance by the U.S. Drug Enforcement Agency.

LIDOCAINE

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Lidocaine (xylocaine, others), an aminoethylamide (Figure 20–1), is the prototypical amide local anesthetic.

Pharmacological Actions. Lidocaine produces faster, more intense, longer-lasting, and more extensive anesthesia than does an equal concentration of procaine. Lidocaine is an alternative choice for individuals sensitive to ester-type local anesthetics.

Absorption, Fate, and Excretion. Lidocaine is absorbed rapidly after parenteral administration and from the GI and respiratory tracts. Although it is effective when used without any vasoconstrictor, epinephrine decreases the rate of absorption, such that the toxicity is decreased and the duration of action usually is prolonged. In addition to preparations for injection, lidocaine is formulated for topical, opthalmic, mucosal, and transdermal use.

A lidocaine transdermal patch (lidoderm) is used for relief of pain associated with postherpetic neuralgia. An oral patch (dentipatch) is available for application to accessible mucous membranes of the mouth prior to superficial dental procedures. The combination of lidocaine (2.5%) and prilocaine (2.5%) in an occlusive dressing (EMLA, others) is used as an anesthetic prior to venipuncture, skin graft harvesting, and infiltration of anesthetics into genitalia. Lidocaine in combination with tetracaine (pliaglis) in a formulation that generates a "peel" is approved for topical local analgesia prior to superficial dermatological procedures such as filler injections and laser-based treatments. Lidocaine in combination with tetracaine is marketed in a formulation that generates heat upon exposure to air (synera), which is used prior to venous access and superficial dermatological procedures such as excision, electrodessication, and shave biopsy of skin lesions. The mild warming is intended to increase skin temperature by up to 5°C for the purpose of enhancing delivery of local anesthetic into the skin.

Lidocaine is dealkylated in the liver by CYPs to monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. In humans, ~75% of the xylidide is excreted in the urine as the further metabolite 4-hydroxy-2, 6-dimethylaniline (Arthur, 1987).

Toxicity. The side effects of lidocaine seen with increasing dose include drowsiness, tinnitus, dysgeusia, dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest will occur. Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked CNS effects. The metabolites monoethylglycine xylidide and glycine xylidide may contribute to some of these side effects.

Clinical Uses. Lidocaine has a wide range of clinical uses as a local anesthetic; it has utility in almost any application where a local anesthetic of intermediate duration is needed. Lidocaine also is used as an antiarrhythmic agent (Chapter 29).

BUPIVACAINE

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Pharmacological Actions. Bupivacaine (marcaine, sensorcaine, others), is a widely used amide local anesthetic; its structure is similar to that of lidocaine except that the amine-containing group is a butyl piperidine (Figure 20–1). Bupivacaine is a potent agent capable of producing prolonged anesthesia. Its long duration of action plus its tendency to provide more sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period. By taking advantage of indwelling catheters and continuous infusions, bupivacaine can be used to provide several days of effective analgesia.

Toxicity. Bupivacaine is more cardiotoxic than equi-effective doses of lidocaine. Clinically, this is manifested by severe ventricular arrhythmias and myocardial depression after inadvertent intravascular administration. Although lidocaine and bupivacaine both rapidly block cardiac Na⁺channels during systole, bupivacaine dissociates much more slowly than does lidocaine during diastole, so a significant fraction of Na⁺ channels at physiological heart rates remains blocked with bupivacaine at the end of diastole (Clarkson and Hondeghem, 1985). Thus, the block by bupivacaine is cumulative and substantially more than would be predicted by its local anesthetic potency. At least a portion of the cardiac toxicity of bupivacaine may be mediated centrally, as direct injection of small quantities of bupivacaine into the medulla can produce malignant ventricular arrhythmias (Thomas et al., 1986). Bupivacaine-induced cardiac toxicity can be very difficult to treat, and its severity is enhanced by coexisting acidosis, hypercarbia, and hypoxemia.

OTHER SYNTHETIC LOCAL ANESTHETICS

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The number of synthetic local anesthetics is so large that it is impractical to consider them all here. Some local anesthetic agents are too toxic to be given by injection. Their use is restricted to topical application to the eye (Chapter 64), the mucous membranes, or the skin (Chapter 65). Many local anesthetics are suitable, however, for infiltration or injection to produce nerve block; some of these also are useful for topical application. The main categories of local anesthetics are given in the following discussion; agents are listed alphabetically. See Figure 20–1 for their structures.

Local Anesthetics Suitable for Injection

Articaine. Articaine (septocaine) is approved in the U.S. for dental and periodontal procedures. Although it is an amide local anesthetic, it also contains an ester, whose hydrolysis terminates its action. Thus, articaine exhibits a rapid onset (1-6 minutes) and duration of action of ~1 hour.

Chloroprocaine. Chloroprocaine (nesacaine, others) is a chlorinated derivative of procaine. Its major assets are its rapid onset and short duration of action and its reduced acute toxicity due to its rapid metabolism (plasma t_1/2 ~25 seconds). Enthusiasm for its use has been tempered by reports of prolonged sensory and motor block after epidural or subarachnoid administration of large doses. This toxicity appears to have been a consequence of low pH and the use of sodium metabisulfite as a preservative in earlier formulations. There are no reports of neurotoxicity with newer preparations of chloroprocaine, which contain calcium EDTA as the preservative, although these preparations also are not recommended for intrathecal administration. A higher than expected incidence of muscular back pain following epidural anesthesia with 2-chloroprocaine has also been reported (Stevens et al., 1993). This back pain is thought to be due to tetany in the paraspinus muscles, which may be a consequence of Ca²⁺ binding by the EDTA included as a preservative; the incidence of back pain appears to be related to the volume of drug injected and its use for skin infiltration.

Mepivacaine. Mepivacaine (carbocaine, polocaine, others) is an intermediate-acting amino amide. Its pharmacological properties are similar to those of lidocaine. Mepivacaine, however, is more toxic to the neonate and thus is not used in obstetrical anesthesia. The increased toxicity of mepivacaine in the neonate is related to ion trapping of this agent because of the lower pH of neonatal blood and the pK_a of mepivacaine rather than to its slower metabolism in the neonate. It appears to have a slightly higher therapeutic index in adults than does lidocaine. Its onset of action is similar to that of lidocaine and its duration slightly longer (~20%) than that of lidocaine in the absence of a co-administered vasoconstrictor. Mepivacaine is not effective as a topical anesthetic.

Prilocaine. Prilocaine (citanest) is an intermediate-acting amino amide. It has a pharmacological profile similar to that of lidocaine. The primary differences are that it causes little vasodilation and thus can be used without a vasoconstrictor, and its increased volume of distribution reduces its CNS toxicity, making it suitable for intravenous regional blocks (described later). The use of prilocaine is largely limited to dentistry because the drug is unique among the local anesthetics in its propensity to cause methemoglobinemia. This effect is a consequence of the metabolism of the aromatic ring to o-toluidine. Development of methemoglobinemia is dependent on the total dose administered, usually appearing after a dose of 8 mg/kg. If necessary, it can be treated by the intravenous administration of methylene blue (1-2 mg/kg). Methemoglobinemia following prilocaine has limited its use in obstetrical anesthesia, because it complicates evaluation of the newborn. Also, methemoglobinemia is more common in neonates due to decreased resistance of fetal hemoglobin to oxidant stresses and the immaturity of enzymes in the neonate that convert methemoglobin back to the ferrous state.

Ropivacaine. The cardiac toxicity of bupivacaine stimulated interest in developing a less toxic, long-lasting local anesthetic. One result of that search was the development of the amino ethylamide ropivacaine (NAROPIN, others), the S-enantiomer of 1-propyl-2′,6′-pipecoloxylidide. The S-enantiomer was chosen because it has a lower toxicity than the R-isomer (McClure, 1996). Ropivacaine is slightly less potent than bupivacaine in producing anesthesia. In several animal models, it appears to be less cardiotoxic than equi-effective doses of bupivacaine. In clinical studies, ropivacaine appears to be suitable for both epidural and regional anesthesia, with a duration of action similar to that of bupivacaine. Interestingly, it seems to be even more motor-sparing than bupivacaine.

Procaine. Procaine (novocain, others), introduced in 1905, was the first synthetic local anesthetic and is an amino ester. It has been supplanted by newer agents, and its use now is confined to infiltration anesthesia and occasionally for diagnostic nerve blocks. This is because of its low potency, slow onset, and short duration of action. While its toxicity is fairly low, it is hydrolyzed in vivo to produce para-aminobenzoic acid, which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs.

Tetracaine. Tetracaine (pontocaine), is a long-acting amino ester. It is significantly more potent and has a longer duration of action than procaine. Tetracaine may exhibit increased systemic toxicity because it is more slowly metabolized than the other commonly used ester local anesthetics. Currently, it is widely used in spinal anesthesia when a drug of long duration is needed. Tetracaine also is incorporated into several topical anesthetic preparations. With the introduction of bupivacaine, tetracaine is rarely used in peripheral nerve blocks because of the large doses often necessary, its slow onset, and its potential for toxicity.

Local Anesthetics Used Primarily to Anesthetize Mucous Membranes and Skin

Some anesthetics are either too irritating or too ineffective to be applied to the eye. However, they are useful as topical anesthetic agents on the skin and/or mucous membranes. These preparations are effective in the symptomatic relief of anal and genital pruritus, poison ivy rashes, and numerous other acute and chronic dermatoses. They sometimes are combined with a glucocorticoid or antihistamine and are available in a number of proprietary formulations (see Figure 20–1 for structures).

Dibucaine (nupercainal, others) is a quinoline derivative. Its toxicity resulted in its removal from the U.S. market as an injectable preparation; however, it retains wide popularity outside the U.S. as a spinal anesthetic. It currently is available as an over-the-counter ointment for use on the skin.

Dyclonine hydrochloride has a rapid onset of action and duration of effect comparable to that of procaine. It is absorbed through the skin and mucous membranes. The compound has been used as 0.5% or 1% solution for topical anesthesia during endoscopy, for oral mucositis pain following radiation or chemotherapy, and for anogenital procedures; however, marketing of these solutions has been discontinued in the U.S. Dyclonine is an active ingredient in a number of over-the-counter medications including sore throat lozenges (sucrets, others), a patch for cold sores (orajel overnight cold sore patch), and a 0.75% solution (skin shield liquid bandage).

Pramoxine hydrochloride (tronothane, others) is a surface anesthetic agent that is not a benzoate ester. Its distinct chemical structure may help minimize the danger of cross-sensitivity reactions in patients allergic to other local anesthetics. Pramoxine produces satisfactory surface anesthesia and is reasonably well tolerated on the skin and mucous membranes. It is too irritating to be used on the eye or in the nose, but an otic solution containing chloroxylenol is marketed. Various preparations including creams, lotions, sprays, gel, wipes, and foams, usually containing 1% pramoxine, are available for topical application.

Anesthetics of Low Solubility

Some local anesthetics are poorly soluble in water, and consequently are too slowly absorbed to be toxic. They can be applied directly to wounds and ulcerated surfaces, where they remain localized for long periods of time, producing a sustained anesthetic action. Chemically, they are esters of para-aminobenzoic acid lacking the terminal amino group possessed by the previously described local anesthetics. The most important member of the series is benzocaine (ethyl aminobenzoate; hurricaine, others). Benzocaine is structurally similar to procaine, but lacks the terminal diethylamino group (Figure 20–1). It is incorporated into a large number of topical preparations. Benzocaine can cause methemoglobinemia (see the discussion of methemoglobinemia in the "Prilocaine" section); consequently, dosing recommendations must be followed carefully.

Local Anesthetics Largely Restrictedto Ophthalmological Use

Anesthesia of the cornea and conjunctiva can be obtained readily by topical application of local anesthetics. However, most of the local anesthetics that have been described are too irritating for ophthalmological use. The first local anesthetic used in ophthalmology, cocaine, has the severe disadvantages of producing mydriasis and corneal sloughing and has fallen out of favor. The two compounds used most frequently today are proparacaine (alcaine, ophthaine, others) and tetracaine (Figure 20–1). In addition to being less irritating during administration, proparacaine has the added advantage of bearing little antigenic similarity to the other benzoate local anesthetics. Thus, it sometimes can be used in individuals sensitive to the amino ester local anesthetics.

For use in ophthalmology, these local anesthetics are instilled a single drop at a time. If anesthesia is incomplete, successive drops are applied until satisfactory conditions are obtained. The duration of anesthesia is determined chiefly by the vascularity of the tissue; thus it is longest in normal cornea and shortest in inflamed conjunctiva. In the latter case repeated instillations may be necessary to maintain adequate anesthesia for the duration of the procedure. Long-term administration of topical anesthesia to the eye has been associated with retarded healing, pitting, and sloughing of the corneal epithelium, and predisposition of the eye to inadvertent injury. Thus, these drugs should not be prescribed for self-administration. For drug delivery, pharmacokinetics, and toxicity issues unique to drugs for ophthalmic use, see Chapter 64.

BIOLOGICAL TOXINS: TETRODOTOXIN AND SAXITOXIN

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These two biological toxins also block the pore of the Na⁺ channel. Tetrodotoxin is found in the gonads and other visceral tissues of some fish of the order Tetraodontiformes (to which the Japanese fugu, or puffer fish, belongs); it also occurs in the skin of some newts of the family Salamandridae and of the Costa Rican frog Atelopus. Saxitoxin is elaborated by the dinoflagellates Gonyaulax catenella and G. tamarensis and retained in the tissues of clams and other shellfish that eat these organisms. Given the right conditions of temperature and light, the Gonyaulax may multiply so rapidly as to discolor the ocean, causing the condition known as red tide. Shellfish feeding on Gonyaulax at this time become extremely toxic to humans and are responsible for periodic outbreaks of paralytic shellfish poisoning (Stommel and Watters, 2004). Although the toxins are chemically different from each other, their mechanisms of action are similar (Ritchie, 1980). Both toxins, in nanomolar concentrations, specifically block the outer mouth of the pore of Na⁺ channels in the membranes of excitable cells. As a result, the action potential is blocked. The receptor site for these toxins is formed by amino acid residues in the P loop of the Na⁺ channel α subunit (Figure 20–2) in all four domains (Catterall, 2000; Terlau et al., 1991). Not all Na⁺ channels are equally sensitive to tetrodotoxin; some Na⁺ channels in cardiac myocytes and dorsal root ganglion neurons are resistant, and a tetrodotoxin-resistant Na⁺ channel is expressed when skeletal muscle is denervated. Tetrodotoxin and saxitoxin are two of the most potent poisons known; the minimal lethal dose of each in the mouse is ~ 8 μg/kg. Both toxins have caused fatal poisoning in humans due to paralysis of the respiratory muscles; therefore the treatment of severe cases of poisoning requires support of respiration. Blockade of vasomotor nerves, together with a relaxation of vascular smooth muscle, seems to be responsible for the hypotension that is characteristic of tetrodotoxin poisoning. Early gastric lavage and pressor support also are indicated. If the patient survives paralytic shellfish poisoning for 24 hours, the prognosis is good.

CLINICAL USES OF LOCAL ANESTHETICS

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Local anesthesia is the loss of sensation in a body part without the loss of consciousness or the impairment of central control of vital functions. It offers two major advantages. First, physiological perturbations associated with general anesthesia are avoided; second, neurophysiological responses to pain and stress can be modified beneficially. As already discussed, local anesthetics can potentially produce deleterious side effects. Proper choice of a local anesthetic and care in its use are the primary determinants in avoiding toxicity. There is a poor relationship between the amount of local anesthetic injected and peak plasma levels in adults. Furthermore, peak plasma levels vary widely depending on the area of injection. They are highest with interpleural or intercostal blocks and lowest with subcutaneous infiltration. Thus, recommended maximum doses serve only as general guidelines.

This discussion summarizes the pharmacological and physiological consequences of the use of local anesthetics categorized by method of administration. A more comprehensive discussion of their use and administration is presented in textbooks on regional anesthesia (e.g., Cousins et al., 2008).

Topical Anesthesia.

Anesthesia of mucous membranes of the nose, mouth, throat, tracheobronchial tree, esophagus, and genitourinary tract can be produced by direct application of aqueous solutions of salts of many local anesthetics or by suspension of the poorly soluble local anesthetics. Tetracaine (2%), lidocaine (2-10%), and cocaine (1-4%) typically are used. Cocaine is used only in the nose, nasopharynx, mouth, throat, and ear, where it uniquely produces vasoconstriction as well as anesthesia. The shrinking of mucous membranes decreases operative bleeding while improving surgical visualization. Comparable vasoconstriction can be achieved with other local anesthetics by the addition of a low concentration of a vasoconstrictor such as phenylephrine (0.005%). Epinephrine, topically applied, has no significant local effect and does not prolong the duration of action of local anesthetics applied to mucous membranes because of poor penetration. Maximal safe total dosages for topical anesthesia in a healthy 70-kg adult are 300 mg for lidocaine, 150 mg for cocaine, and 50 mg for tetracaine.

Peak anesthetic effect following topical application of cocaine or lidocaine occurs within 2-5 minutes (3-8 minutes with tetracaine), and anesthesia lasts for 30-45 minutes (30-60 minutes with tetracaine). Anesthesia is entirely superficial; it does not extend to submucosal structures. This technique does not alleviate joint pain or discomfort from subdermal inflammation or injury.

Local anesthetics are absorbed rapidly into the circulation following topical application to mucous membranes or denuded skin. Thus, topical anesthesia always carries the risk of systemic toxic reactions. Systemic toxicity has occurred even following the use of local anesthetics to control discomfort associated with severe diaper rash in infants. Absorption is particularly rapid when local anesthetics are applied to the tracheobronchial tree. Concentrations in blood after instillation of local anesthetics into the airway are nearly the same as those following intravenous injection. Surface anesthetics for the skin and cornea have been described earlier in the chapter.

Use of eutectic mixtures of local anesthetics lidocaine (2.5%)/prilocaine (2.5%) (emla) and lidocaine (7%)/tetracaine (7%) (pliagis) bridges the gap between topical and infiltration anesthesia. The efficacy of each of these combinations lies in the fact that the mixture has a melting point less than that of either compound alone, existing at room temperature as an oil that can penetrate intact skin. These creams produce anesthesia to a maximum depth of 5 mm and are applied as a cream on intact skin under an occlusive dressing in advance (~30-60 min) of any procedure. These mixtures are effective for procedures involving skin and superficial subcutaneous structures (e.g., venipuncture and skin graft harvesting). The component local anesthetics will be absorbed into the systemic circulation, potentially producing toxic effects, as described earlier. Guidelines are available to calculate the maximum amount of cream that can be applied and area of skin covered. These mixtures must not be used on mucous membranes or abraded skin, as rapid absorption across these surfaces may result in systemic toxicity.

Infiltration Anesthesia

Infiltration anesthesia is the injection of local anesthetic directly into tissue without taking into consideration the course of cutaneous nerves. Infiltration anesthesia can be so superficial as to include only the skin. It also can include deeper structures, including intra-abdominal organs, when these too are infiltrated.

The duration of infiltration anesthesia can be approximately doubled by the addition of epinephrine (5 μg/mL) to the injection solution; epinephrine also decreases peak concentrations of local anesthetics in blood. Epinephrine-containing solutions should not, however, be injected into tissues supplied by end arteries—for example, fingers and toes, ears, the nose, and the penis. The resulting vasoconstriction may cause gangrene. For the same reason, epinephrine should be avoided in solutions injected intracutaneously. Since epinephrine also is absorbed into the circulation, its use should be avoided in those for whom adrenergic stimulation is undesirable.

The local anesthetics used most frequently for infiltration anesthesia are lidocaine (0.5-1%), procaine (0.5-1%), and bupivacaine (0.125-0.25%). When used without epinephrine, up to 4.5 mg/kg of lidocaine, 7 mg/kg of procaine, or 2 mg/kg of bupivacaine can be employed in adults. When epinephrine is added, these amounts can be increased by one-third.

The advantage of infiltration anesthesia and other regional anesthetic techniques is that it can provide satisfactory anesthesia without disrupting normal bodily functions. The chief disadvantage of infiltration anesthesia is that relatively large amounts of drug must be used to anesthetize relatively small areas. This is no problem with minor surgery. When major surgery is performed, however, the amount of local anesthetic that is required makes systemic toxic reactions likely. The amount of anesthetic required to anesthetize an area can be reduced significantly and the duration of anesthesia increased markedly by specifically blocking the nerves that innervate the area of interest. This can be done at one of several levels: subcutaneously, at major nerves, or at the level of the spinal roots.

Field Block Anesthesia.

Field block anesthesia is produced by subcutaneous injection of a solution of local anesthetic in order to anesthetize the region distal to the injection. For example, subcutaneous infiltration of the proximal portion of the volar surface of the forearm results in an extensive area of cutaneous anesthesia that starts 2-3 cm distal to the site of injection. The same principle can be applied with particular benefit to the scalp, the anterior abdominal wall, and the lower extremity.

The drugs, concentrations, and doses recommended are the same as for infiltration anesthesia. The advantage of field block anesthesia is that less drug can be used to provide a greater area of anesthesia than when infiltration anesthesia is used. Knowledge of the relevant neuroanatomy obviously is essential for successful field block anesthesia.

Nerve Block Anesthesia

Injection of a solution of a local anesthetic into or about individual peripheral nerves or nerve plexuses produces even greater areas of anesthesia than do the techniques already described. Blockade of mixed peripheral nerves and nerve plexuses also usually anesthetizes somatic motor nerves, producing skeletal muscle relaxation, which is essential for some surgical procedures. The areas of sensory and motor block usually start several centimeters distal to the site of injection. Brachial plexus blocks are particularly useful for procedures on the upper extremity and shoulder. Intercostal nerve blocks are effective for anesthesia and relaxation of the anterior abdominal wall. Cervical plexus block is appropriate for surgery of the neck. Sciatic and femoral nerve blocks are useful for surgery distal to the knee. Other useful nerve blocks prior to surgical procedures include blocks of individual nerves at the wrist and at the ankle, blocks of individual nerves such as the median or ulnar at the elbow, and blocks of sensory cranial nerves.

There are four major determinants of the onset of sensory anesthesia following injection near a nerve:

proximity of the injection to the nerve
concentration and volume of drug
degree of ionization of the drug
time

Local anesthetic is never intentionally injected into the nerve, as this would be painful and could cause nerve damage. Instead, the anesthetic agent is deposited as close to the nerve as possible. Thus the local anesthetic must diffuse from the site of injection into the nerve, where it acts. The rate of diffusion is determined chiefly by the concentration of the drug, its degree of ionization (ionized local anesthetic diffuses more slowly), its hydrophobicity, and the physical characteristics of the tissue surrounding the nerve. Higher concentrations of local anesthetic will provide a more rapid onset of peripheral nerve block. The utility of higher concentrations, however, is limited by systemic toxicity and by direct neural toxicity of concentrated local anesthetic solutions. For a given concentration, local anesthetics with lower pK_a values tend to have a more rapid onset of action because more drug is uncharged at neutral pH. For example, the onset of action of lidocaine occurs in ~3 minutes; 35% of lidocaine is in the basic form at pH 7.4. In contrast, the onset of action of bupivacaine requires ~15 minutes; only 5-10% of bupivacaine is uncharged at this pH. Increased hydrophobicity might be expected to speed onset by increased penetration into nerve tissue. However, it also will increase binding in tissue lipids. Furthermore, the more hydrophobic local anesthetics also are more potent (and toxic) and thus must be used at lower concentrations, decreasing the concentration gradient for diffusion. Tissue factors also play a role in determining the rate of onset of anesthetic effects. The amount of connective tissue that must be penetrated can be significant in a nerve plexus compared to isolated nerves and can slow or even prevent adequate diffusion of local anesthetic to the nerve fibers.

Duration of nerve block anesthesia depends on the physical characteristics of the local anesthetic used and the presence or absence of vasoconstrictors. Especially important physical characteristics are lipid solubility and protein binding. Local anesthetics can be broadly divided into three categories:

those with a short (20-45 minutes) duration of action in mixed peripheral nerves, such as procaine
those with an intermediate (60-120 minutes) duration of action, such as lidocaine and mepivacaine
those with a long (400-450 minutes) duration of action, such as bupivacaine, ropivacaine, and tetracaine

Block duration of the intermediate-acting local anesthetics such as lidocaine can be prolonged by the addition of epinephrine (5 μg/mL). The degree of block prolongation in peripheral nerves following the addition of epinephrine appears to be related to the intrinsic vasodilatory properties of the local anesthetic and thus is most pronounced with lidocaine.

The types of nerve fibers that are blocked when a local anesthetic is injected about a mixed peripheral nerve depend on the concentration of drug used, nerve-fiber size, internodal distance, and frequency and pattern of nerve-impulse transmission (see above, sections on Frequency and Voltage-Dependence and Differential Sensitivity). Anatomical factors are similarly important. A mixed peripheral nerve or nerve trunk consists of individual nerves surrounded by an investing epineurium. The vascular supply usually is centrally located. When a local anesthetic is deposited about a peripheral nerve, it diffuses from the outer surface toward the core along a concentration gradient (DeJong, 1994; Winnie et al., 1977). Consequently, nerves in the outer mantle of the mixed nerve are blocked first. These fibers usually are distributed to more proximal anatomical structures than are those situated near the core of the mixed nerve and often are motor. If the volume and concentration of local anesthetic solution deposited about the nerve are adequate, the local anesthetic eventually will diffuse inward in amounts adequate to block even the most centrally located fibers. Lesser amounts of drug will block only nerves in the mantle and the smaller and more sensitive central fibers. Furthermore, since removal of local anesthetics occurs primarily in the core of a mixed nerve or nerve trunk, where the vascular supply is located, the duration of blockade of centrally located nerves is shorter than that of more peripherally situated fibers.

The choice of local anesthetic and the amount and concentration administered are determined by the nerves and the types of fibers to be blocked, the required duration of anesthesia, and the size and health of the patient. For blocks of 2-4 hours, lidocaine (1-1.5%) can be used in the amounts recommended earlier (see "Infiltration Anesthesia"). Mepivacaine (up to 7 mg/kg of a 1-2% solution) provides anesthesia that lasts about as long as that from lidocaine. Bupivacaine (2-3 mg/kg of a 0.25-0.375% solution) can be used when a longer duration of action is required. Addition of 5 μg/mL epinephrine slows systemic absorption and therefore prolongs duration and lowers the plasma concentration of the intermediate-acting local anesthetics.

Peak plasma concentrations of local anesthetics depend on the amount injected, the physical characteristics of the local anesthetic, whether epinephrine is used, the rate of blood flow to the site of injection, and the surface area exposed to local anesthetic. This is of particular importance in the safe application of nerve block anesthesia, since the potential for systemic reactions is related to peak free serum concentrations. For example, peak concentrations of lidocaine in blood following injection of 400 mg without epinephrine for intercostal nerve blocks average 7 μg/mL; the same amount of lidocaine used for block of the brachial plexus results in peak concentrations in blood of ~3 μg/mL (Covino and Vassallo, 1976). Therefore, the amount of local anesthetic that can be injected must be adjusted according to the anatomical site of the nerve(s) to be blocked to minimize untoward effects. Addition of epinephrine can decrease peak plasma concentrations by 20-30%. Multiple nerve blocks (e.g., intercostal block) or blocks performed in vascular regions require reduction in the amount of anesthetic that can be given safely, because the surface area for absorption or the rate of absorption is increased.

Intravenous Regional Anesthesia (Bier's Block)

This technique relies on using the vasculature to bring the local anesthetic solution to the nerve trunks and endings. In this technique, an extremity is exsanguinated with an Esmarch (elastic) bandage, and a proximally located tourniquet is inflated to 100-150 mm Hg above the systolic blood pressure. The Esmarch bandage is removed, and the local anesthetic is injected into a previously cannulated vein. Typically, complete anesthesia of the limb ensues within 5-10 minutes. Pain from the tourniquet and the potential for ischemic nerve injury limits tourniquet inflation to 2 hours or less. However, the tourniquet should remain inflated for at least 15-30 minutes to prevent toxic amounts of local anesthetic from entering the circulation following deflation. Lidocaine, 40-50 mL (0.5 mL/kg in children) of a 0.5% solution without epinephrine is the drug of choice for this technique. For intravenous regional anesthesia in adults using a 0.5% solution without epinephrine, the dose administered should not exceed 4 mg/kg. A few clinicians prefer prilocaine (0.5%) over lidocaine because of its higher therapeutic index. The attractiveness of this technique lies in its simplicity. Its primary disadvantages are that it can be used only for a few anatomical regions, sensation (pain) returns quickly after tourniquet deflation, and premature release or failure of the tourniquet can produce toxic levels of local anesthetic (e.g., 50 mL of 0.5% lidocaine contains 250 mg of lidocaine). For the last reason and because its longer durations of action offer no advantage, the more cardiotoxic local anesthetic, bupivacaine, is not recommended for this technique. Intravenous regional anesthesia is used most often for surgery of the forearm and hand, but can be adapted for the foot and distal leg.

Spinal Anesthesia

Spinal anesthesia follows the injection of local anesthetic into the cerebrospinal fluid (CSF) in the lumbar space. For a number of reasons, including the ability to produce anesthesia of a considerable fraction of the body with a dose of local anesthetic that produces negligible plasma levels, spinal anesthesia remains one of the most popular forms of anesthesia. In most adults, the spinal cord terminates above the second lumbar vertebra; between that point and the termination of the thecal sac in the sacrum, the lumbar and sacral roots are bathed in CSF. Thus, in this region there is a relatively large volume of CSF within which to inject drug, thereby minimizing the potential for direct nerve trauma.

A brief discussion of the physiological effects of spinal anesthesia relating to the pharmacology of the local anesthetics used is presented here. See more specialized texts (e.g., Cousins et al., 2008) for additional details.

Physiological Effects of Spinal Anesthesia. Most of the physiological side effects of spinal anesthesia are a consequence of the sympathetic blockade produced by local anesthetic block of the sympathetic fibers in the spinal nerve roots. A thorough understanding of these physiological effects is necessary for the safe and successful application of spinal anesthesia. Although some of them may be deleterious and require treatment, others can be beneficial for the patient or can improve operating conditions. Most sympathetic fibers leave the spinal cord between T1 and L2 (Chapter 8, Figure 8–1). Although local anesthetic is injected below these levels in the lumbar portion of the dural sac, cephalad spread of the local anesthetic occurs with all but the smallest volumes injected. This cephalad spread is of considerable importance in the practice of spinal anesthesia and potentially is under the control of numerous variables, of which patient position and baricity (density of the drug relative to the density of the CSF) are the most important (Greene, 1983). The degree of sympathetic block is related to the height of sensory anesthesia; often the level of sympathetic blockade is several spinal segments higher, since the preganglionic sympathetic fibers are more sensitive to low concentrations of local anesthetic. The effects of sympathetic blockade involve both the actions (now partially unopposed) of the parasympathetic nervous system and the response of the unblocked portion of the sympathetic nervous system. Thus, as the level of sympathetic block ascends, the actions of the parasympathetic nervous system are increasingly dominant, and the compensatory mechanisms of the unblocked sympathetic nervous system are diminished. As most sympathetic nerve fibers leave the cord at T1 or below, few additional effects of sympathetic blockade are seen with cervical levels of spinal anesthesia. The consequences of sympathetic blockade will vary among patients as a function of age, physical conditioning, and disease state. Interestingly, sympathetic blockade during spinal anesthesia appears to be minimal in healthy children.

Clinically, the most important effects of sympathetic blockade during spinal anesthesia are on the cardiovascular system. At all but the lowest levels of spinal blockade, some vasodilation will occur. Vasodilation is more marked on the venous than on the arterial side of the circulation, resulting in blood pooling in the venous capacitance vessels. This reduction in circulating blood volume is well tolerated at low levels of spinal anesthesia in healthy patients. With an increasing level of block, this effect becomes more marked and venous return becomes gravity-dependent. If venous return decreases too much, cardiac output and organ perfusion decline precipitously. Venous return can be increased by a modest (10-15 degree) head-down tilt or by elevating the legs. At high levels of spinal blockade, the cardiac accelerator fibers, which exit the spinal cord at T1-T4, will be blocked. This is detrimental in patients dependent on elevated sympathetic tone to maintain cardiac output (e.g., during congestive heart failure or hypovolemia), and it also removes one of the compensatory mechanisms available to maintain organ perfusion during vasodilation. Thus, as the level of spinal block ascends, the rate of cardiovascular compromise can accelerate if not carefully observed and treated. Sudden asystole also can occur, presumably because of loss of sympathetic innervation in the continued presence of parasympathetic activity at the sinoatrial node (Caplan et al., 1988). In the usual clinical situation, blood pressure serves as a surrogate marker for cardiac output and organ perfusion. Treatment of hypotension usually is warranted when the blood pressure decreases to ~30% of resting values. Therapy is aimed at maintaining brain and cardiac perfusion and oxygenation. To achieve these goals, administration of oxygen, fluid infusion, manipulation of patient position, and the administration of vasoactive drugs are all options. In practice, patients typically are administered a bolus (500-1000 mL) of fluid prior to the administration of spinal anesthesia in an attempt to prevent some of the deleterious effects of spinal blockade. Since the usual cause of hypotension is decreased venous return, possibly complicated by decreased heart rate, drugs with preferential venoconstrictive and chronotropic properties are preferred. For this reason, ephedrine, 5-10 mg intravenously, often is the drug of choice. In addition to the use of ephedrine to treat deleterious effects of sympathetic blockade, direct-acting α₁ adrenergic receptor agonists such as phenylephrine (Chapter 12) can be administered either by bolus or continuous infusion.

A beneficial effect of spinal anesthesia partially mediated by the sympathetic nervous system is on the intestine. Sympathetic fibers originating from T5-L1 inhibit peristalsis; thus, their blockade produces a small, contracted intestine. This, together with a flaccid abdominal musculature, produces excellent operating conditions for some types of bowel surgery. The effects of spinal anesthesia on the respiratory system mostly are mediated by effects on the skeletal musculature. Paralysis of the intercostal muscles will reduce a patient's ability to cough and clear secretions, which may produce dyspnea in patients with bronchitis or emphysema. Respiratory arrest during spinal anesthesia is seldom due to paralysis of the phrenic nerves or to toxic levels of local anesthetic in the CSF of the fourth ventricle; it is much more likely to be due to medullary ischemia secondary to hypotension.

Pharmacology of Spinal Anesthesia. Currently in the U.S., the drugs most commonly used in spinal anesthesia are lidocaine, tetracaine, and bupivacaine. Procaine occasionally is used for diagnostic blocks when a short duration of action is desired. The choice of local anesthetic is primarily determined by the desired duration of anesthesia. General guidelines are to use lidocaine for short procedures, bupivacaine for intermediate to long procedures, and tetracaine for long procedures. As mentioned earlier, the factors contributing to the distribution of local anesthetics in the CSF have received much attention because of their importance in determining the height of block. The most important pharmacological factors include the amount, and possibly the volume, of drug injected and its baricity. The speed of injection of the local anesthesia solution also may affect the height of the block, just as the position of the patient can influence the rate of distribution of the anesthetic agent and the height of blockade achieved (described in the next section). For a given preparation of local anesthetic, administration of increasing amounts leads to a fairly predictable increase in the level of block attained. For example, 100 mg of lidocaine, 20 mg of bupivacaine, or 12 mg of tetracaine usually will result in a T4 sensory block. More complete tables of these relationships can be found in standard anesthesiology texts. Epinephrine often is added to spinal anesthetics to increase the duration or intensity of block. Epinephrine's effect on duration of block is dependent on the technique used to measure duration. A commonly used measure of block duration is the length of time it takes for the block to recede by two dermatomes from the maximum height of the block, while a second is the duration of block at some specified level, typically L1. In most studies, addition of 200 μg of epinephrine to tetracaine solutions prolongs the duration of block by both measures. However, addition of epinephrine to lidocaine or bupivacaine does not affect the first measure of duration, but does prolong the block at lower levels. In different clinical situations, one or the other measure of anesthesia duration may be more relevant, and this must be kept in mind when deciding whether to add epinephrine to spinal local anesthetics. The mechanism of action of vasoconstrictors in prolonging spinal anesthesia is uncertain. It has been hypothesized that these agents decrease spinal cord blood flow, decreasing clearance of local anesthetic from the CSF, but this has not been convincingly demonstrated. Epinephrine and other α-adrenergic agonists have been shown to decrease nociceptive transmission in the spinal cord, and studies in genetically modified mice suggest that α_2A adrenergic receptors play a principal role in this response (Stone et al., 1997). Such actions may contribute to the beneficial effects of epinephrine, clonidine, and dexmedetomidine when these agents are added to spinal local anesthetics.

Drug Baricity and Patient Position. The baricity of the local anesthetic injected will determine the direction of migration within the dural sac. Hyperbaric solutions will tend to settle in the dependent portions of the sac, while hypobaric solutions will tend to migrate in the opposite direction. Isobaric solutions usually will stay in the vicinity where they were injected, diffusing slowly in all directions. Consideration of the patient position during and after the performance of the block and the choice of a local anesthetic of the appropriate baricity is crucial for a successful block during some surgical procedures. Lidocaine and bupivacaine are marketed in both isobaric and hyperbaric preparations, and if desired, can be diluted with sterile, preservative-free water to make them hypobaric.

Complications of Spinal Anesthesia. Persistent neurological deficits following spinal anesthesia are extremely rare. Thorough evaluation of a suspected deficit should be performed in collaboration with a neurologist. Neurological sequelae can be both immediate and late. Possible causes include introduction of foreign substances (such as disinfectants or talc) into the subarachnoid space, infection, hematoma, or direct mechanical trauma. Aside from drainage of an abscess or hematoma, treatment usually is ineffective; thus, avoidance and careful attention to detail while performing spinal anesthesia are necessary.

High concentrations of local anesthetic can cause irreversible block. After administration, local anesthetic solutions are diluted rapidly, quickly reaching nontoxic concentrations. However, there are several reports of transient or longer-lasting neurological deficits following lidocaine spinal anesthesia, particularly with 5% lidocaine (i.e., 180 mmol) in 7.5% glucose (Zaric and Pace, 2009). Spinal anesthesia sometimes is regarded as contraindicated in patients with pre-existing disease of the spinal cord. No experimental evidence exists to support this hypothesis. Nonetheless, it is prudent to avoid spinal anesthesia in patients with progressive diseases of the spinal cord. However, spinal anesthesia may be very useful in patients with fixed, chronic spinal cord injury.

A more common sequela following any lumbar puncture, including spinal anesthesia, is a postural headache with classic features. The incidence of headache decreases with increasing age of the patient and decreasing needle diameter. Headache following lumbar puncture must be thoroughly evaluated to exclude serious complications such as meningitis. Treatment usually is conservative, with bed rest and analgesics. If this approach fails, an epidural blood patch with the injection of autologous blood can be performed; this procedure usually is successful in alleviating postdural puncture headaches, although a second blood patch may be necessary. If two epidural blood patches are ineffective in relieving the headache, the diagnosis of postdural puncture headache should be reconsidered. Intravenous caffeine (500 mg as the benzoate salt administered over 4 hours) also has been advocated for the treatment of postdural puncture headache; however, the efficacy of caffeine is less than that of a blood patch, and relief usually is transient.

Evaluation of Spinal Anesthesia. Spinal anesthesia is a safe and effective technique, especially during surgery involving the lower abdomen, the lower extremities, and the perineum. It often is combined with intravenous medication to provide sedation and amnesia. The physiological perturbations associated with low spinal anesthesia often have less potential harm than those associated with general anesthesia. The same does not apply for high spinal anesthesia. The sympathetic blockade that accompanies levels of spinal anesthesia adequate for mid- or upper-abdominal surgery, coupled with the difficulty in achieving visceral analgesia, is such that equally satisfactory and safer operating conditions can be realized by combining the spinal anesthetic with a "light" general anesthetic or by the administration of a general anesthetic and a neuromuscular blocking agent.

Epidural Anesthesia

Epidural anesthesia is administered by injecting local anesthetic into the epidural space—the space bounded by the ligamentum flavum posteriorly, the spinal periosteum laterally, and the dura anteriorly. Epidural anesthesia can be performed in the sacral hiatus (caudal anesthesia) or in the lumbar, thoracic, or cervical regions of the spine. Its current popularity arises from the development of catheters that can be placed into the epidural space, allowing either continuous infusions or repeated bolus administration of local anesthetics. The primary site of action of epidurally administered local anesthetics is on the spinal nerve roots. However, epidurally administered local anesthetics also may act on the spinal cord and on the paravertebral nerves.

The selection of drugs available for epidural anesthesia is similar to that for major nerve blocks. As for spinal anesthesia, the choice of drugs to be used during epidural anesthesia is dictated primarily by the duration of anesthesia desired. However, when an epidural catheter is placed, short-acting drugs can be administered repeatedly, providing more control over the duration of block. Bupivacaine, 0.5-0.75%, is used when a long duration of surgical block is desired. Due to enhanced cardiotoxicity in pregnant patients, the 0.75% solution is not approved for obstetrical use. Lower concentrations—0.25%, 0.125%, or 0.0625%—of bupivacaine, often with 2 μg/mL of fentanyl added, frequently are used to provide analgesia during labor. They also are useful preparations for providing postoperative analgesia in certain clinical situations. Lidocaine 2% is the most frequently used intermediate-acting epidural local anesthetic. Chloroprocaine, 2% or 3%, provides rapid onset and a very short duration of anesthetic action. However, its use in epidural anesthesia has been clouded by controversy regarding its potential ability to cause neurological complications if the drug is accidentally injected into the subarachnoid space (discussed earlier). The duration of action of epidurally administered local anesthetics frequently is prolonged, and systemic toxicity decreased, by addition of epinephrine. Addition of epinephrine also makes inadvertent intravascular injection easier to detect and modifies the effect of sympathetic blockade during epidural anesthesia.

For each anesthetic agent, a relationship exists between the volume of local anesthetic injected epidurally and the segmental level of anesthesia achieved. For example, in 20- to 40-year-old, healthy, nonpregnant patients, each 1-1.5 mL of 2% lidocaine will give an additional segment of anesthesia. The amount needed decreases with increasing age and also decreases during pregnancy and in children.

The concentration of local anesthetic used determines the type of nerve fibers blocked. The highest concentrations are used when sympathetic, somatic sensory, and somatic motor blockade are required. Intermediate concentrations allow somatic sensory anesthesia without muscle relaxation. Low concentrations will block only preganglionic sympathetic fibers. As an example, with bupivacaine these effects might be achieved with concentrations of 0.5%, 0.25%, and 0.0625%, respectively. The total amounts of drug that can be injected with safety at one time are approximately those mentioned earlier in the chapter under "Nerve Block Anesthesia" and "Infiltration Anesthesia." Performance of epidural anesthesia requires a greater degree of skill than does spinal anesthesia. The technique of epidural anesthesia and the volumes, concentrations, and types of drugs used are described in detail in standard texts on regional anesthesia (e.g., Cousins et al., 2008).

A significant difference between epidural and spinal anesthesia is that the dose of local anesthetic used can produce high concentrations in blood following absorption from the epidural space. Peak concentrations of lidocaine in blood following injection of 400 mg (without epinephrine) into the lumbar epidural space average 3-4 μg/mL; peak concentrations of bupivacaine in blood average 1 μg/mL after the lumbar epidural injection of 150 mg. Addition of epinephrine (5 μg/mL) decreases peak plasma concentrations by ~25%. Peak blood concentrations are a function of the total dose of drug administered rather than the concentration or volume of solution following epidural injection (Covino and Vassallo, 1976). The risk of inadvertent intravascular injection is increased in epidural anesthesia, as the epidural space contains a rich venous plexus.

Another major difference between epidural and spinal anesthesia is that there is no zone of differential sympathetic blockade with epidural anesthesia; thus, the level of sympathetic block is close to the level of sensory block. Because epidural anesthesia does not result in the zones of differential sympathetic blockade observed during spinal anesthesia, cardiovascular responses to epidural anesthesia might be expected to be less prominent. In practice this is not the case; the potential advantage of epidural anesthesia is offset by the cardiovascular responses to the high concentration of anesthetic in blood that occurs during epidural anesthesia. This is most apparent when, as is often the case, epinephrine is added to the epidural injection. The resulting concentration of epinephrine in blood is sufficient to produce significant β₂ adrenergic receptor-mediated vasodilation. As a consequence, blood pressure decreases, even though cardiac output increases due to the positive inotropic and chronotropic effects of epinephrine (Chapter 12). The result is peripheral hyperperfusion and hypotension. Differences in cardiovascular responses to equal levels of spinal and epidural anesthesia also are observed when a local anesthetic such as lidocaine is used without epinephrine. This may be a consequence of the direct effects of high concentrations of lidocaine on vascular smooth muscle and the heart. The magnitude of the differences in responses to equal sensory levels of spinal and epidural anesthesia varies, however, with the local anesthetic used for the epidural injection (assuming no epinephrine is used). For example, local anesthetics such as bupivacaine, which are highly lipid soluble, are distributed less into the circulation than are less lipid-soluble agents such as lidocaine.

High concentrations of local anesthetics in blood during epidural anesthesia are especially important when this technique is used to control pain during labor and delivery. Local anesthetics cross the placenta, enter the fetal circulation, and at high concentrations may cause depression of the neonate. The extent to which they do so is determined by dosage, acid-base status, the level of protein binding in both maternal and fetal blood, placental blood flow, and solubility of the agent in fetal tissue. These concerns have been lessened by the trend toward using more dilute solutions of bupivacaine for labor analgesia.

Epidural and Intrathecal Opiate Analgesia. Small quantities of opioid injected intrathecally or epidurally produce segmental analgesia (Yaksh and Rudy, 1976). This observation led to the clinical use of spinal and epidural opioids during surgical procedures and for the relief of postoperative and chronic pain (Cousins and Mather, 1984). As with local anesthesia, analgesia is confined to sensory nerves that enter the spinal cord dorsal horn in the vicinity of the injection. Presynaptic opioid receptors inhibit the release of substance P and other neurotransmitters from primary afferents, while postsynaptic opioid receptors decrease the activity of certain dorsal horn neurons in the spinothalamic tracts (Willcockson et al., 1986; see also Chapters 8 and 18). Since conduction in autonomic, sensory, and motor nerves is not affected by the opioids, blood pressure, motor function, and non-nociceptive sensory perception typically are not influenced by spinal opioids. The volume-evoked micturition reflex is inhibited, as manifested by urinary retention. Other side effects include pruritus, nausea, and vomiting in susceptible individuals. Delayed respiratory depression and sedation, presumably from cephalad spread of opioid within the CSF, occur infrequently with the doses of opioids currently used.

Spinally administered opioids by themselves do not provide satisfactory anesthesia for surgical procedures. Thus, opioids have found the greatest use in the treatment of postoperative and chronic pain. In selected patients, spinal or epidural opioids can provide excellent analgesia following thoracic, abdominal, pelvic, or lower extremity surgery without the side effects associated with high doses of systemically administered opioids. For post-operative analgesia, spinally administered morphine, 0.2-0.5 mg, usually will provide 8-16 hours of analgesia. Placement of an epidural catheter and repeated boluses or an infusion of opioid permits an increased duration of analgesia. Many opioids have been used epidurally. Morphine, 2-6 mg, every 6 hours, commonly is used for bolus injections, while fentanyl, 20-50 μg/hour, often combined with bupivacaine, 5-20 mg/hour, is used for infusions. For cancer pain, repeated doses of epidural opioids can provide analgesia of several months' duration. The dose of epidural morphine, e.g., is far less than the dose of systemically administered morphine that would be required to provide similar analgesia. This reduces the complications that usually accompany the administration of high doses of systemic opioids, particularly sedation and constipation. Unfortunately, as with systemic opioids, tolerance will develop to the analgesic effects of epidural opioids, but this usually can be managed by increasing the dose.

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Chapter 20: Local Anesthetics

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INTRODUCTION

Figure 20–1

Figure 20–2

Figure 20–3

COCAINE

LIDOCAINE

BUPIVACAINE

OTHER SYNTHETIC LOCAL ANESTHETICS

BIOLOGICAL TOXINS: TETRODOTOXIN AND SAXITOXIN

CLINICAL USES OF LOCAL ANESTHETICS

BIBLIOGRAPHY

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