Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 20
Local Anesthetics

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.

CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine (Figure 20–1). These agents were synthesized as substitutes for cocaine, preserving the local anesthetic effect of cocaine but avoiding its toxicity and addictive properties. The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage. 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. 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, 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.

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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). 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. Figure 20–1 in 12th edition of the parent text shows additional variations on the basic structure.

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.

MECHANISM OF ACTION. Local anesthetics act at the cell membrane to prevent the generation and the conduction of nerve impulses. The major mechanism of action of local anesthetics involves their interaction with 1 or more specific binding sites within the Na+ channel (see Figure 14–1A).

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 membrane depolarization. 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 nerve conduction fails. Local anesthetics can block K+ channels but this interaction requires higher concentrations of drug; thus, blockade of conduction is not accompanied by any large change in resting membrane potential.

FREQUENCY- AND VOLTAGE-DEPENDENCE OF LOCAL ANESTHETIC ACTION. A 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. 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.

DIFFERENTIAL SENSITIVITY OF NERVE FIBERS TO LOCAL ANESTHETICS. 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).

Table 20–1

Susceptibility of Nerve Fibers to Local Anesthetics

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In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated Aδ fibers (mediating pain and temperature sensations) are blocked before the larger myelinated Aγ, Aβ, and Aα fibers (mediating postural, touch, pressure, and motor information) The precise mechanisms responsible for this apparent specificity of local anesthetic action on pain fibers are not known.The differential rate of block exhibited by fibers mediating different sensations is of considerable practical importance in the use of local anesthetics.

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 pKa 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.

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. In clinical practice, a vasoconstrictor, usually epinephrine, is often added to local anesthetics. The vasoconstrictor, by decreasing the rate of absorption, localizes the anesthetic at the desired site, and reduces systemic toxicity by allowing metabolism to keep pace with the rate at which it is absorbed into the circulation. 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.

UNDESIRED EFFECTS OF LOCAL ANESTHETICS. 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.

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.

CNS. Following absorption, local anesthetics may cause CNS stimulation, producing restlessness and tremor that may progress to clonic convulsions. Central stimulation is followed by depression; death usually is caused by respiratory failure. Benzodiazepines or rapidly acting barbiturates administered intravenously are the drugs of choice for both the prevention and arrest of convulsions (see Chapter 17). 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.

Cardiovascular System. Following systemic absorption, local anesthetics act on the cardiovascular system, primarily on 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; on rare occasions, lower doses of some local anesthetics will cause cardiovascular collapse and death. Ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than bupivacaine. 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 bowel. They also relax vascular and bronchial smooth muscle, although low concentrations initially may produce contraction. Spinal and epidural anesthesia and instillation of local anesthetics into the peritoneal cavity cause sympathetic nervous system paralysis, which can result in increased tone of GI musculature. Local anesthetics seldom depress uterine contractions 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 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.

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. Hypersensitivity seems to occur more frequently with local anesthetics of the ester type and frequently extends to chemically related compounds. 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. 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. Because toxicity is related to the concentration of free 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.

Some of the common local anesthetics (e.g., tetracaine) are esters; they are inactivated primarily by a plasma esterase. The liver also participates in hydrolysis of local anesthetics. Because 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. 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. 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

Cocaine, an ester of benzoic acid and methylecgonine, occurs in abundance in the leaves of the coca shrub.

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. Cocaine’s 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. 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. Because of its abuse potential, cocaine is listed as a schedule II controlled substance by the U.S. Drug Enforcement Agency.

LIDOCAINE

Lidocaine (XYLOCAINE, others), an aminoethylamide, is the prototypical amide local anesthetic.

PHARMACOLOGICAL ACTIONS; PREPARATIONS. 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. 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, ophthalmic, 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 and metabolized to monoethylglycine and xylidide. Both metabolites retain local anesthetic activity.

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 utility in almost any application where a local anesthetic of intermediate duration is needed. Lidocaine also is used as an anti-arrhythmic agent (see Chapter 29).

BUPIVACAINE

PHARMACOLOGICAL ACTIONS; PREPARATIONS. Bupivacaine (MARCAINE, SENSORCAINE, others), is a widely used amide local anesthetic. 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 make it popular for providing prolonged analgesia during labor or the postoperative period. With 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. 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

LOCAL ANESTHETICS SUITABLE FOR INJECTION

ARTICAINE. Articaine (SEPTOCAINE) is an amide local anesthetic approved in the U.S. for dental and periodontal procedures. Articaine exhibits a rapid onset (1-6 min) and duration of action of ~1 h.

CHLOROPROCAINE. Chloroprocaine (NESACAINE, others) is a chlorinated derivative of procaine. It has rapid onset and short duration of action and reduced acute toxicity due to its rapid metabolism (plasma t1/2 ~25 seconds). A higher than expected incidence of muscular back pain following epidural anesthesia with 2-chloroprocaine has also been reported. This back pain is thought to be due to tetany in the paraspinous 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 is more toxic to the neonate and thus is not used in obstetrical anesthesia. 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. 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. The use of prilocaine is largely limited to dentistry because the drug can 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.

ROPIVACAINE. Ropivacaine (NAROPIN, others), an amino ethylamide, is slightly less potent than bupivacaine in producing anesthesia. In clinical studies, ropivacaine appears to be suitable for both epidural and regional anesthesia, with a duration of action similar to that of bupivacaine.

PROCAINE. Procaine (NOVOCAIN, others) is an amino ester. It is 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. 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. It is widely used in spinal anesthesia when a drug of long duration is needed. Tetracaine also is incorporated into several topical anesthetic preparations. 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.

DIBUCAINE. Dibucaine (NUPERCAINAL, others) is a quinoline derivative. Its toxicity resulted in its removal from the U.S. market as an injectable preparation; 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. 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. 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 SHIELDLIQUID BANDAGE).

PRAMOXINE. 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.

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. The most important member of the series is benzocaine (ethyl aminobenzoate; HURRICAINE, others). Benzocaine is incorporated into a large number of topical preparations. Benzocaine can cause methemoglobinemia; consequently, dosing recommendations must be followed carefully.

LOCAL ANESTHETICS LARGELY RESTRICTED TO OPHTHALMOLOGICAL USE

Most of the local anesthetics that have been described are too irritating for ophthalmological use. The 2 compounds used most frequently today are proparacaine (ALCAINE, OPHTHAINE, others) and tetracaine (see 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. 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; see Chapter 64.

CLINICAL USES OF LOCAL ANESTHETICS

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 2 major advantages. First, physiological perturbations associated with general anesthesia are avoided; second, neurophysiological responses to pain and stress can be modified beneficially. There is a poor relationship between the amount of local anesthetic injected and peak plasma levels in adults. Peak plasma levels vary widely depending on the area of injection. Thus, recommended maximum doses serve only as general guidelines.

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%). 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 min (3-8 min with tetracaine), and anesthesia lasts for 30-45 min (30-60 min with tetracaine).

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.

Use of eutectic mixtures of local anesthetics lidocaine (2.5%)/prilocaine (2.5%) (EMLA) and lidocaine (7%)/tetracaine (7%) (PLIAGLIS) 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). 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-containing solutions should not, however, be injected into tissues supplied by end arteries (e.g., fingers and toes, ears, the nose, and the penis). The resulting vasoconstriction may cause gangrene. 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. 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.

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 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 peripheral nerves or nerve plexuses produces 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.

Major determinants of the onset of sensory anesthesia following injection near a nerve are:

• 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 into the nerve where it acts. The rate of diffusion is determined 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. Local anesthetics with lower pKa values tend to have a more rapid onset of action because more drug is uncharged at neutral pH. Increased hydrophobicity might be expected to speed onset by increased penetration into nerve tissue. However, it also will increase binding in tissue lipids. The amount of connective tissue that must be penetrated 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. It is useful to think of 3 categories:

• Those with a short (20-45 min) duration of action in mixed peripheral nerves, such as procaine

• Those with an intermediate (60-120 min) duration of action, such as lidocaine and mepivacaine

• Those with a long (400-450 min) 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 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. Anatomical factors are similarly important. 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 h, lidocaine (1-1.5%) can be used in the amounts recommended earlier. 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. 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.

INTRAVENOUS REGIONAL ANESTHESIA (BIER 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 min. Pain from the tourniquet and the potential for ischemic nerve injury limits tourniquet inflation to 2 h or less. However, the tourniquet should remain inflated for at least 15-30 min 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). 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 is popular. 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.

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. The consequences of sympathetic blockade 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. 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. This reduction in circulating blood volume is well tolerated at low levels of spinal anesthesia in healthy patients. As the level of spinal block ascends, the rate of cardiovascular compromise can accelerate if not carefully observed and treated. 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. Because 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, direct-acting α1 adrenergic receptor agonists such as phenylephrine (seeChapter 12) can be administered either by bolus or continuous infusion.

PHARMACOLOGY OF SPINAL ANESTHESIA. In the U.S., lidocaine, tetracaine, and bupivacaine are most commonly used in spinal anesthesia. Procaine occasionally is used for diagnostic blocks when a short duration of action is desired. General guidelines are to use lidocaine for short procedures, bupivacaine for intermediate to long procedures, and tetracaine for long procedures.

The factors contributing to the distribution of local anesthetics in the CSF determine the height of block. The most important pharmacological factors include the amount, and possibly the volume, of drug injected and its baricity. 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. Vasoconstrictors may prolong spinal anesthesia by decreasing spinal cord blood flow and thus decreasing clearance of local anesthetic from the CSF. Epinephrine and other α adrenergic agonists decrease nociceptive transmission in the spinal cord, an effect that may involve activation of α2A adrenergic receptors. 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.

COMPLICATIONS OF SPINAL ANESTHESIA. Persistent neurological deficits following spinal anesthesia are extremely rare. Possible causes include introduction of foreign substances into the subarachnoid space, infection, hematoma, or direct mechanical trauma. Aside from drainage of an abscess or hematoma, treatment usually is ineffective. High concentrations of local anesthetic can cause irreversible block. After administration, local anesthetic solutions are diluted rapidly, quickly reaching nontoxic concentrations. 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 evaluated to exclude serious complications such as meningitis. Treatment usually is with bed rest and analgesics. If this approach fails, an epidural blood patch with the injection of autologous blood can be performed.

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. 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. 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. 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 is on the spinal nerve roots. However, epidurally administered local anesthetics also may act on the spinal cord and on the paravertebral nerves.

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. 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. Lidocaine 2% is the most frequently used intermediate-acting epidural local anesthetic. Addition of epinephrine prolongs duration of action, decreases systemic toxicity, and also makes inadvertent intravascular injection easier to detect and modifies the effect of sympathetic blockade during epidural anesthesia. 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.

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 blood concentrations are a function of the total dose of drug administered rather than the concentration or volume of solution following epidural injection. 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. Cardiovascular responses to epidural anesthesia might be expected to be less prominent; however, in practice 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 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 (see Chapter 12).

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. 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. The 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 (see Chapter 18). Because 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. Side effects include urinary retention, pruritus, nausea, and vomiting.

Spinally administered opioids by themselves do not provide satisfactory anesthesia for surgical procedures but are used during surgical procedures and for the relief 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 cancer pain, repeated doses of epidural opioids can provide analgesia of several months’ duration. Unfortunately, as with systemic opioids, tolerance will develop to the analgesic effects of epidural opioids.