Case Study

A 25-year-old woman with a 2-inch superficial laceration on her face is brought by the police to the emergency department after a street brawl. Her wound is still bleeding, but appears clean. After washing and application of pressure, the bleeding stops, and closure of the wound with sutures is planned. What local anesthetic would be appropriate for this relatively short procedure in an area where a good cosmetic result is desirable? Is a vasoconstrictor appropriate?

Local Anesthetics: Introduction

The awareness of pain can be blunted or blocked by drugs that act in the periphery as well as by centrally active analgesics and general anesthetics (as discussed in Chapter 25). Pain awareness, called nociception, is mediated by nerve ending receptors in peripheral tissues and transmitted to the central nervous system (CNS) by primary afferent fibers and relayed by secondary afferent fibers to the brain. Transmission can be reduced by drugs acting on several different neurotransmitter receptors or completely prevented by blocking the sodium channels required for conduction in the afferent neuron axon outside or inside the spinal column (Figure 26–1).

Local anesthetics effectively and reversibly block impulse conduction along nerve axons and other excitable membranes that use sodium channels as the primary means of action potential generation, eg, cardiac muscle. Clinically, local anesthetics are used to block pain sensation from—or sympathetic vasoconstrictor impulses to—specific areas of the body. The first local anesthetic introduced into medical practice, cocaine, was isolated by Niemann in 1860 and introduced into practice by Koller in 1884 as a topical ophthalmic anesthetic. Despite the fact that its chronic use was associated with psychological dependence (addiction), cocaine was used clinically because it was the only local anesthetic drug available for 30 years. In an attempt to improve the clinical properties of cocaine, Einhorn in 1905 synthesized procaine, which became the dominant local anesthetic for the next 50 years. Subsequently, newer local anesthetics were introduced with the goal of reducing local tissue irritation, minimizing systemic cardiac and CNS toxicity, and achieving a faster onset and longer duration of action. Lidocaine, which is still a widely used local anesthetic, was synthesized in 1943 by Löfgren.

The development of newer agents continues because it is relatively easy to synthesize chemicals with local anesthetic properties. Unfortunately, it is difficult to reduce the toxicity of these compounds because the common side effects of local anesthetics represent extensions of their therapeutic effects. New research into the mechanisms of local anesthetic-induced cardiac and spinal toxicity and identification of alternative drug targets for spinal analgesia (eg, opioid receptors, ₂ adrenoceptors, NMDA receptors, N-type calcium channels, and adenosine receptors) suggest that it may be possible to develop safer drugs in the future. To extend the duration of local anesthetic action, a variety of novel delivery systems are in development (eg, polymers, liposomes, and suspensions). A multivesicular liposomal formulation of bupivacaine (DepoBupivacaine), which is in the advanced stages of clinical development, can produce local anesthetic effects lasting up to 72 hours. Transdermal local anesthetic delivery systems have also been successfully introduced into clinical practice for providing topical analgesia.

Basic Pharmacology of Local Anesthetics

Chemistry

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

Local anesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation. The relative proportions of these two forms is governed by their pK_a and the pH of the body fluids according to the Henderson-Hasselbalch equation:

Because the pK_a of most local anesthetics is in the range of 8.0–9.0, the larger percentage in body fluids at physiologic pH will be the charged, cationic form. The cationic form is the most active form at the receptor site because it cannot readily exit from closed channels. However, the uncharged form is important for rapid penetration of biologic membranes and producing a clinical effect, since the local anesthetic receptor is not readily accessible from the external side of the cell membrane. Therefore, local anesthetics are less effective when they are injected into infected (acidic) tissues because a smaller percentage of the local anesthetic is nonionized and available for diffusion across the membrane in an environment with a low extracellular pH.

Pharmacokinetics

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect.

Absorption

Systemic absorption of injected local anesthetic from the site of administration is determined by several factors, including dosage, site of injection, drug-tissue binding, local tissue blood flow, use of vasoconstrictors (eg, epinephrine), and the physicochemical properties of the drug itself. Application of a local anesthetic to a highly vascular area such as the tracheal mucosa or the tissue surrounding intercostal nerves results in more rapid absorption and thus higher blood levels than if the local anesthetic is injected into a poorly perfused tissue such as tendon, dermis, or subcutaneous fat. For regional anesthesia involving block of large nerves, maximum blood levels of local anesthetic decrease according to the site of administration in the following order: intercostal (highest) > caudal > epidural > brachial plexus > sciatic nerve (lowest).

Vasoconstrictor substances such as epinephrine reduce systemic absorption of local anesthetics from the injection site by decreasing blood flow in these areas. This is important for drugs with intermediate or short durations of action such as procaine, lidocaine, and mepivacaine (but not prilocaine).

Since blood levels are lowered up to 30% when vasoconstrictors are added to local anesthetics, localized neuronal uptake is enhanced because of higher local tissue concentrations in the region of drug administration, and the risks of systemic toxic effects are reduced. Furthermore, when used in spinal anesthesia, epinephrine acts directly on the cord to both enhance and prolong local anesthetic-induced spinal anesthesia by acting on ₂ adrenoceptors, which inhibit release of substance P (neurokinin-1) and reduce sensory neuron firing. The recognition of this fact has led to the use of the ₂ agonist-antagonist clonidine and the pure ₂ agonist dexmedetomidine to prolong the local anesthetic effect in the subarachnoid space and on peripheral nerves. The combination of reduced systemic absorption, enhanced local neuronal anesthetic uptake, and ₂ activation by epinephrine is responsible for prolonging the local anesthetic effect by up to 50%. Vasoconstrictors are less effective in prolonging anesthetic action of the more lipid-soluble, long-acting drugs (eg, bupivacaine and ropivacaine), possibly because these molecules are highly tissue-bound. Finally, cocaine is unique among the local anesthetics because it possesses high surface (topical) activity and intrinsic sympathomimetic properties.

Distribution

The amide local anesthetics are widely distributed after intravenous bolus administration. There is also evidence that sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the gastrointestinal tract. As a result of the extremely short plasma half-lives of the ester type agents, their tissue distribution has not been extensively studied.

Metabolism and Excretion

The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination.

Ester-type local anesthetics are hydrolyzed very rapidly in the blood by circulating butyrylcholinesterase (pseudocholinesterase) to inactive metabolites. Therefore, procaine and chloroprocaine have very short plasma half-lives (< 1 minute).

The amide linkage of amide local anesthetics is hydrolyzed by liver microsomal cytochrome P450 isozymes. There is considerable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine Ý bupivacaine and levobupivacaine (slowest). As a result, toxicity from amide-type local anesthetics is more likely to occur in patients with hepatic disease. For example, the average elimination half-life of lidocaine may be increased from 1.6 hours in normal patients (t_1/2, Table 26–2) to more than 6 hours in patients with severe liver disease. Many other drugs used in anesthesia are metabolized by the same P450 isozymes, and concomitant administration of these competing drugs may slow the hepatic metabolism of the local anesthetics.

Decreased hepatic elimination of local anesthetics would also be anticipated in patients with reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous (or balanced) anesthetic techniques.

Pharmacodynamics

Mechanism of Action

The primary mechanism of action of local anesthetics is blockade of voltage-gated sodium channels (Figure 26–2). The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of –90 to –60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about –95 mV); repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues.

The function of sodium channels can be disrupted in several ways. Biologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin block sodium channels by binding to channel receptors near the extracellular surface. Their clinical effects superficially resemble those of local anesthetics (ie, block of conduction without a change in the resting potential) even though their receptor site is quite different. Spinal neurons can be differentiated on the basis of tetrodotoxin effect into TTX-sensitive and TTX-resistant neurons. Some evidence suggests that the TTX-resistant neurons are responsible for pain transmission and are the primary targets for local anesthetics in producing spinal (subarachnoid) anesthesia. Local anesthetics bind to receptors near the intracellular end of the sodium channel and block the channel in a time- and voltage-dependent fashion (see below). The sodium channel has been cloned, its structure has been characterized, and mutational analysis has allowed identification of essential parts of the local anesthetic binding site.

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

The blockade of sodium channels by most local anesthetics is both voltage- and time-dependent: Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials (see Figure 26–2). Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers (Figure 26–3).

Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14–9). The recovery from drug-induced block is 10 to 1000 times slower than the recovery of channels from normal inactivation (as shown for the cardiac membrane in Figure 14–4). As a result, the refractory period is lengthened and the nerve conducts fewer electrical impulses.

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

Several isoforms of the sodium channel have been identified, and they have differing sensitivities to channel-blocking drugs such as tetrodotoxin. There is also evidence that some sodium channels are much more sensitive to local anesthetics than the classic channels associated with axonal transmission.

Local anesthetics have poorly understood effects on inflammation at sites of injury, and these anti-inflammatory effects may contribute to improved pain control in some chronic pain syndromes. At the concentrations used in spinal anesthesia, local anesthetics can inhibit transmission via substance P (neurokinin-1), NMDA, and AMPA receptors in the secondary afferent neurons (Figure 26–1). These effects may contribute to the analgesia achieved by subarachnoid administration. Local anesthetics can also be shown to block a variety of other ion channels, including nicotinic acetylcholine channels in the spinal cord. However, there is no convincing evidence that this mechanism is important in the acute clinical effects of these drugs. High concentrations of local anesthetics in the subarachnoid space can interfere with intra-axonal transport and calcium homeostasis, contributing to potential spinal toxicity.

Structure-Activity Characteristics of Local Anesthetics

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

Other Actions on Nerves

Since local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. Although motor paralysis can be desirable during surgery, it may also limit the ability of the patient to cooperate (ie, push) during obstetric delivery or ambulate without assistance after outpatient surgery. During spinal anesthesia, motor paralysis may impair respiratory activity, and residual autonomic nerve blockade can lead to hypotension upon ambulation. Residual autonomic blockade also interferes with bladder function, resulting in urinary retention and the need for bladder catheterization.

Nerve fibers differ significantly in their susceptibility to local anesthetic blockade on the basis of differences in size and degree of myelination (Table 26–3). Upon direct application of a local anesthetic to a nerve root, the smaller B and C fibers are blocked first, followed by other sensory axons, and motor function is the last to be blocked.

Effect of Fiber Diameter

Local anesthetics preferentially block small fibers because the distance over which such fibers can passively propagate an electrical impulse is shorter. During the onset of local anesthesia, when short sections of a nerve are blocked, the small-diameter fibers are the first to fail to conduct electrical impulses. For myelinated nerves, at least two and preferably three successive nodes of Ranvier must be blocked by the local anesthetic to halt impulse propagation. Therefore, myelinated nerves tend to become blocked before unmyelinated nerves of the same diameter. For this reason, the preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission.

Effect of Firing Frequency

Another important reason for preferential blockade of sensory fibers follows directly from the state- and use-dependent mechanism of action of local anesthetics. Blockade by these drugs is more marked at higher frequencies of depolarization. Sensory (pain) fibers have a high firing rate and a relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. Type A delta and C fibers are smaller-diameter fibers that participate in high-frequency pain transmission. Therefore, these fibers are blocked earlier and with lower concentrations of local anesthetics than are the large A alpha fibers.

Effect of Fiber Position in the Nerve Bundle

An anatomic circumstance that sometimes creates exceptions to the above rules for differential nerve block is the location of the fibers within the peripheral nerve bundle. In large nerve trunks, fibers located circumferentially are the first to be exposed to the local anesthetic when it is administered into the tissue surrounding the nerve. In the extremities, proximal sensory fibers are located in the outer portion of the nerve trunk, whereas the distal sensory innervation is located in the central core of the nerve. Thus, during infiltration block of a large nerve, sensory analgesia first develops proximally and then spreads distally as the drug penetrates deeper into the core of the nerve.

Effects on Other Excitable Membranes

Local anesthetics have weak direct neuromuscular blocking effects that are of little clinical importance. However, their effects on cardiac cell membranes are of major clinical significance, and some local anesthetics are widely used as antiarrhythmic agents (eg, lidocaine) (see Chapter 14) at concentrations lower than those required to produce nerve block. Others of the same amide class (eg, bupivacaine, ropivacaine) can cause lethal arrhythmias if high plasma concentrations are inadvertently achieved.

Clinical Pharmacology of Local Anesthetics

Local anesthetics can provide highly effective analgesia in well-defined regions of the body. The usual routes of administration include topical application (eg, nasal mucosa, wound [incision site] margins), injection in the vicinity of peripheral nerve endings (perineural infiltration) and major nerve trunks (blocks), and injection into the epidural or subarachnoid spaces surrounding the spinal cord (Figure 26–4). Intravenous regional anesthesia (so-called Bier block) is used for short surgical procedures (< 60 minutes) involving the upper and/or lower extremities. This is accomplished by intravenous injection of the anesthetic agent into a distal vein while the circulation of the limb is isolated with a proximally placed tourniquet. Local anesthetic infiltration of autonomic sympathetic fibers can also be used to evaluate the role of sympathetic tone in patients with peripheral vasospastic disorders. Finally, injection of local anesthetics into so-called trigger points can be used for diagnostic and therapeutic purposes in patients with recurrent pain that is triggered by tactile stimulation.

The choice of local anesthetic for infiltration, peripheral nerve blocks, and central neuraxis (spinal/epidural) blockade is usually based on the duration of action required. Procaine and chloroprocaine are short-acting; lidocaine, mepivacaine, and prilocaine have an intermediate duration of action; and tetracaine, bupivacaine, levobupivacaine, and ropivacaine are long-acting local anesthetics (Table 26–1). Articaine has a fast onset and an intermediate duration of action that make it suitable for use in dental procedures.

The anesthetic effect of the agents with short and intermediate durations of action can be prolonged by increasing the dose or adding a vasoconstrictor agent (eg, epinephrine or phenylephrine). The vasoconstrictor slows the removal of the local anesthetic from the injection site. In addition, it decreases the blood level and the probability of cardiovascular and CNS toxicity.

The onset of local anesthesia can be accelerated by the addition of sodium bicarbonate (1–2 mL) to the local anesthetic solution. This maximizes the amount of drug in the more lipid-soluble (unionized) form. Repeated injections of local anesthetics can result in loss of effectiveness (ie, tachyphylaxis) due to extracellular acidosis. Local anesthetics are commonly marketed as hydrochloride salts (pH 4.0–6.0) to maximize aqueous solubility. After injection, the salts are buffered in the tissue to physiologic pH, thereby providing sufficient free base concentration for diffusion through the axonal membrane. However, repeated injections of the local anesthetic can deplete the buffering capacity of the local tissues. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly and results in tachyphylaxis. Tachyphylaxis to local anesthetics is common in areas with a limited buffer capacity (eg, the cerebrospinal fluid).

Pregnancy appears to increase susceptibility to local anesthetic toxicity. Cardiac arrest leading to death following the epidural administration of 0.75% bupivacaine to women in labor resulted in temporary withdrawal of the high concentration of this widely used long-acting local anesthetic. The subsequent introduction of purportedly less cardiotoxic alternatives to bupivacaine (ie, ropivacaine and levobupivacaine) has led to controversy because the evidence supporting enhanced safety is based solely on animal models. It is not clear whether the alleged increased sensitivity to bupivacaine during pregnancy is due to elevated levels of estrogen, progesterone, or factors that contribute to a more rapid vascular uptake of the drug when administered into the epidural space of parturients.

Topical local anesthesia is often used for eye, ear, nose, and throat procedures. Satisfactory topical local anesthesia requires an agent capable of rapid penetration across the skin or mucosa, and with limited tendency to diffuse away from the site of application. Cocaine, because of its excellent penetration and local vasoconstrictor effects, has been used extensively for ear, nose and throat (ENT) procedures. Cocaine is somewhat irritating and is therefore less popular for ophthalmic procedures. Recent concern about its potential cardiotoxicity when combined with epinephrine has led most otolaryngology surgeons to switch to a combination containing lidocaine and epinephrine. Other drugs used for topical anesthesia include lidocaine-bupivacaine combinations, tetracaine, pramoxine, dibucaine, benzocaine, and dyclonine.

Since local anesthetics have membrane-stabilizing effects, both parenteral (eg, intravenous lidocaine) and oral (eg, mexiletine, tocainide) formulations of local anesthetics have been used to treat patients with neuropathic pain syndromes because these syndromes are thought to involve uncontrolled, rapid, sensory fiber firing. Systemic local anesthetic drugs are commonly used as adjuvants to the combination of a tricyclic antidepressant (eg, amitriptyline) and an anticonvulsant (eg, carbamazepine) in chronic pain patients who fail to respond to the combination of antidepressant and anticonvulsant. A period of 1–3 weeks may be required to observe a therapeutic effect after introduction of the local anesthetic in patients with neuropathic pain. Recent studies suggest that intravenous lidocaine may be useful as an adjuvant for reducing acute pain in the perioperative period. As a result of its opioid-sparing effects, use of intravenous lidocaine has been found to facilitate recovery of bowel function and lead to an earlier discharge after abdominal surgery.

Toxicity

The two major forms of local anesthetic toxicity are: (1) systemic effects following absorption of the local anesthetic from their site of administration and (2) direct neurotoxicity from the local effects of these drugs when high concentrations are administered in close proximity to the spinal cord and other major nerve trunks. When blood levels of local anesthetics rise rapidly, adverse effects on several major organ systems may be observed.

Central Nervous System

CNS Toxicity

All local anesthetics have the ability to produce sleepiness, light-headedness, visual and auditory disturbances, and restlessness when high plasma concentrations are produced after rapid absorption or inadvertent intravascular administration. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste. At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions. Local anesthetics apparently cause depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory neuronal pathways. This transitional stage of unbalanced excitation (ie, seizure activity) is then followed by generalized CNS depression.

Convulsions due to excessively high blood levels can be prevented by administering the smallest effective dose of the local anesthetic required for adequate surgical analgesia and by avoiding inadvertent intravascular injection, or injection into highly perfused tissues. When large doses of a local anesthetic are required (eg, for major peripheral nerve block local infiltration for major plastic surgery procedures), premedication with a parenteral benzodiazepine (eg, diazepam or midazolam) provides significant prophylaxis against local anesthetic-induced CNS toxicity by raising the seizure threshold.

If seizures do occur, it is important to prevent hypoxemia and acidosis. Although administration of oxygen does not prevent seizure activity, hyperoxemia may be beneficial after onset of seizures. Hypercapnia and acidosis may lower the seizure threshold, and so hyperventilation is recommended during treatment of seizures. In addition, hyperventilation increases blood pH, which in turn lowers extracellular potassium. This action hyperpolarizes the transmembrane potential of axons, which favors the resting (or low-affinity) state of the sodium channels, resulting in decreased local anesthetic toxicity.

Seizures induced by local anesthetics are usually treated with intravenous anesthetic drugs (eg, thiopental 1–2 mg/kg, propofol 0.5–1 mg/kg, midazolam 0.03–0.06 mg/kg). The muscular manifestations of a seizure can be blocked using a short-acting neuromuscular relaxant drug (eg, succinylcholine, 0.25–0.5 mg/kg IV). It should be emphasized that succinylcholine does not alter the CNS manifestations of local anesthetic-induced seizure activity. Rapid tracheal intubation can prevent pulmonary aspiration of gastric contents and facilitate hyperventilation.

Cocaine

Since prehistoric times, the natives of Peru and Bolivia have chewed the leaves of the indigenous plant Erythroxylon coca, the source of cocaine, to obtain a feeling of well-being and reduce fatigue. The coca leaves are also used to make tea to prevent symptoms of altitude sickness (eg, headaches, nausea). Intense CNS effects can be achieved by sniffing (or "snorting") cocaine powder and smoking cocaine base (or "free basing"). Cocaine has become one of the most widely abused drugs in the world (see Chapter 32). High doses of inhaled and injected cocaine have all of the CNS toxicities described for other local anesthetics. In addition, cocaine can produce severe cardiovascular toxicity, including hypertension, arrhythmias, and acute myocardial failure.

Neurotoxicity

When applied at excessively high concentrations, all local anesthetics can produce direct neural toxicity. Chloroprocaine and lidocaine appear to be more neurotoxic than other local anesthetics when used for spinal anesthesia, with high local concentrations producing so-called transient radicular irritation (or neuropathic symptoms). It has been suggested that this toxicity results from pooling of high concentrations of the local anesthetic in the cauda equina region of the spinal cord (Figure 26–4). Although the precise mechanism of this neurotoxic action has not been established, both interference with axonal transport and disruption of calcium homeostasis have been implicated. Spinal neurotoxicity does not result from excessive sodium channel blockade.

Cardiovascular System

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space.

Cocaine differs from the other local anesthetics with respect to its cardiovascular effects. Cocaine's blockade of norepinephrine reuptake results in vasoconstriction and hypertension, as well as cardiac arrhythmias. The vasoconstriction produced by cocaine can lead to local ischemia and, in chronic abusers who use the nasal route, ulceration of the mucous membrane and damage to the nasal septum have been reported. The vasoconstrictor properties of cocaine can be used clinically to decrease bleeding from mucosal damage or surgical trauma in the nasopharyneal region.

It has been suggested that bupivacaine may be more cardiotoxic than other long-acting local anesthetics (eg, ropivacaine). This reflects the fact that bupivacaine-induced blockade of sodium channels is potentiated by the long action potential duration of cardiac cells compared with nerve fibers. The most common electrocardiographic finding in patients with bupivacaine intoxication is a slow idioventricular rhythm with broad QRS complexes and eventually electromechanical dissociation.

Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult even for experienced clinicians. Recent studies suggest that propofol can be useful in resuscitating patients acutely exposed to toxic levels of bupivacaine. The (S)-isomer, levobupivacaine, appears to have a lower propensity for cardiovascular toxicity than the racemic mixture or the (R)-isomer and has been approved for clinical use. The clinical effects of ropivacaine are similar to those of bupivacaine, but ropivacaine is allegedly associated with a lower potential for cardiovascular toxicity. Ropivacaine is available only as the (S)-stereoisomer, which has inherently less affinity for the cardiac sodium channel. However, both cardiac toxicity and CNS toxicity have been reported when large doses of ropivacaine were used for peripheral nerve blocks.

Hematologic Effects

The administration of large doses (> 10 mg/kg) of prilocaine during regional anesthesia may lead to accumulation of the metabolite o-toluidine, an oxidizing agent capable of converting hemoglobin to methemoglobin. When sufficient methemoglobin is present (3–5 mg/dL), the patient may appear cyanotic and the blood "chocolate-colored." Although moderate levels of methemoglobinemia are well tolerated by healthy individuals, elevated methemoglobinemia may cause decompensation in patients with preexisting cardiac or pulmonary disease. The treatment of methemoglobinemia involves the intravenous administration of a reducing agent (eg, methylene blue or ascorbic acid), which rapidly converts methemoglobin to hemoglobin.

Allergic Reactions

The ester-type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a small percentage of the patient population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide local anesthetics are extremely rare.

Summary: Drugs Used for Local Anesthesia

Preparations Available

References