and all neurons in the central nervous system (CNS). Thus the actions of these compounds can be restricted by administering them locally. Certain practical pharmacokinetic properties make these agents particularly useful in temporarily blocking the sensory transmission of pain impulses. The greatest advantage of local anesthetics is their reversibility—that is, once the drug is eliminated by metabolism, diffusion from its injection site, or excreted, the nerve resumes normal function. There are generally no long-term consequences from the use of local anesthetics. Thus these drugs are highly effective in providing regional or localized reversible pain relief.

The molecular targets for local anesthetics are the voltage-gated sodium channels (VGSCs), which exist in all neurons. These channels are responsible for producing the regenerative action potentials that occur along axons and carry messages from cell bodies to nerve terminals. VGSCs are usually closed at normal resting membrane potentials, which prevents the high concentration of Na⁺ in the extracellular fluid from entering the cell. When membranes are depolarized, these channels open and allow Na⁺ to flow into the cell down its concentration gradient. This influx of positively charged ions leads to further depolarization, causing more channels to open and leading to a self-regenerating action potential. Sustained depolarization causes:

• Spontaneous inactivation of VGSC, which shuts off Na⁺ influx

• Concurrent opening of voltage-gated K⁺ channels

The resultant K⁺ efflux through these and non–voltage-gated K⁺ channels returns the membrane potential to its normal resting value. This mechanism is depicted in Figure 13-1.

FIGURE 13–1 Sequence of events occurring during an action potential.

The cellular physiological mechanism by which local anesthetics block the conduction of nerve impulses is well understood. These drugs bind selectively to VGSCs at the intracellular surface of the channel pore near the pore’s vestibule and thereby block the pathway for Na⁺ and prevent the channels from opening (Fig. 13-2). By blocking Na⁺ influx, these drugs prevent the depolarization necessary for action potential propagation and, at sufficient concentrations, block impulse conduction. Because local anesthetics dissociate from the VGSC very rapidly, once drug administration is stopped, the drug diffuses away from the nerve and/or is absorbed by the local circulation, and impulse activity is restored.

FIGURE 13–2 Transmission of nerve impulses under normal conditions and its prevention in the presence of a local anesthetic agent (producing nerve block).

The ability of local anesthetics to block VGSC is highly dependent on the activity (or state) of the channel. Na⁺ channels exist in three major states (Fig.13-3). In the resting closed state, the channels do not allow Na⁺ influx and are highly sensitive to depolarization-induced opening. In the open state, the channels allow Na⁺ influx, whereas in the inactivated closed state, they do not allow Na⁺ influx and are not opened by depolarization. Local anesthetics have different potencies for binding to these different states. They are much more likely to bind when the channels are active, open, or inactivated and are less likely to bind to the resting state. This modulation of affinity is called activity (or state) dependence and has great practical importance. Because local anesthetics preferentially block nerves in which Na⁺ channels are open or inactivated (activity-dependent), they are more potent in rapidly firing nerves than in nerves in which action potentials occur less frequently. Because sensory neurons fire at greater frequencies in response to more intense noxious stimuli, the effectiveness of impulse blockade is greater under these conditions.

FIGURE 13–3 Unidirectional nature of axonal impulse conduction. Na⁺ channels are depicted in the resting (A), open (B), or inactivated (C) state. The inactivated channels prevent the depolarization from proceeding in more than one direction.

Pharmacokinetics

The structures of the local anesthetics have a direct bearing on their therapeutic actions (Fig. 13-4). All of these agents contain a hydrophobic group linked by either an ester or an amide bond to a relatively hydrophilic group (usually a tertiary or quaternary amine). This hydrophilic group makes the drug H₂O-soluble, enabling the agent to diffuse to the nerve. The hydrophobic group makes the agent lipid soluble and enables the drug to penetrate the lipid membranes (sheath, perineural tissue, and nerve membrane) to reach its binding site on the inner surface of the VGSC. The more hydrophobic local anesthetics bind more tightly to the channel.

FIGURE 13–4 Structures of the two types of local anesthetics depicting sites of hydrolysis (shown with arrows).

Local anesthetics must cross the neuronal cell membrane to reach the VGSC; therefore sufficient amounts of the drugs must be in the unionized form to gain entry to the cell. However, the charged form of the compound is thought to be most active. Thus an important chemical aspect of local anesthetics is that they are weak bases, with pK_a values of 8 to 9. At physiological pH (~7.4), most (80% to 90%) of the drug is in the ionized (charged) form (see Chapter 2). Once inside the cell, the predominant ionized form of the agent binds to the Na⁺ channel proteins.

The rate of onset of clinical local anesthesia is determined by drug concentration and potency, binding to local tissues, the rate of metabolism (for ester type-agents), and the degree of vascularity at the site of drug injection. The last factor is of primary importance, because any diffusion of the agent into blood reduces drug concentration at the nerve fibers. Vasoconstrictors (adrenergic agonists) such as epinephrine (Epi) are frequently combined with local anesthetics to reduce systemic absorption by reducing local blood flow. These vasoconstrictors extend the duration of action of local anesthetics, and they are more effective in prolonging the actions of the less lipid-soluble agents (lidocaine, chloroprocaine, and mepivacaine) than the more lipid-soluble agents (etidocaine and bupivacaine). Combinations of local anesthetics with fixed concentrations of vasoconstrictor drugs are available commercially.

Local anesthetics vary considerably in the rates at which they are converted to inactive metabolites. Because all of these compounds diffuse into the systemic circulation to some extent, metabolism becomes a prominent factor in the potential ability of these agents to produce adverse side effects and toxicity. In addition to drug biotransformation, the binding to plasma proteins (α₁-acid glycoprotein and serum albumin) also causes the concentration of free drug in the circulation to be reduced.

The ester local anesthetics, including procaine and tetracaine (see Fig. 13-4), are rapidly hydrolyzed to inactive products by plasma cholinesterase (butyrylcholinesterase) and liver esterases. Thus these compounds have a very short t_1/2 in the body (Table 13-1). Certain body sites lack esterase activity, including the spinal fluid, which causes the duration of local anesthetic action with “spinal” (intrathecal) anesthesia to be considerably extended. The amide local anesthetics, by contrast, are metabolized by hepatic cytochrome P450s through N-dealkylation, followed by hydrolysis. The relative rates of biotransformation of these local anesthetics vary depending on their specific chemical structure (see Table 13-1).

TABLE 13–1 Pharmacokinetic Parameters

Bupivacaine and etidocaine are bound to plasma proteins extensively, and nonspecific tissue binding also occurs near the injection site. These agents are more likely to cause toxicity in patients with preexisting liver disease as a result of the reduced drug biotransformation and lower plasma protein concentration in these patients (plasma proteins are synthesized in the liver).

Relationship of Mechanisms of Action to Clinical Response

Anatomical, physiological, and chemical factors all play important roles in determining the susceptibility of nerve fibers to blockade by local anesthetics during clinical procedures. Because the Na⁺ channels present in different types of neurons have similar affinities for local anesthetics, these drugs block impulse conduction in all nerve cells, including sensory, motor, autonomic, and CNS neurons. Na⁺ channels also play an important role in other electrically excitable cells. Thus local anesthetics can also have prominent effects on skeletal and cardiac muscle. Their effects on cardiac Na⁺ channels form the basis for their therapeutic use in the treatment of certain cardiac dysrhythmias (see Chapter 22). Their effects on smooth and cardiac muscle also contribute to their toxicity. However, local anesthetics are not equally potent and effective in all cells where Na⁺ channels are present, and they exhibit some selectivity for different neuronal and muscle cell types. This selectivity is determined by the rate of drug penetration, firing rate, and axonal size and location within the nerve bundle and importantly, by the “margin of safety” for nerve impulse transmission. This last factor, a measure of how well transmission can overcome deficits in excitability, differs among different fiber types and also at different zones in a neuron. It is likely to be highest in the trunk region of an axon, lower at distal and central branch regions, and lower also at the impulse generating sites such as the distal terminals of sensory fibers.

It also takes a longer and higher dose of drug to block nerves in a highly vascularized region, a requirement that can be reduced by the coinjection of vasoconstrictors. For peripheral nerve blocks in general, less than 10% of the injected dose actually reaches the nerve to provide impulse blockade. Correspondingly, clinical solutions of local anesthetics (e.g., 1% lidocaine HCl, equal to approximately 40 mM) are far more concentrated than the solutions (approximately 1 mM) that achieve impulse blockade on unmyelinated axons.

Neurons differ substantially in terms of their diameter, degree of myelination, and frequency of firing, and all of these factors influence the ability of local anesthetics to produce blockade. The three major types of nerve fibers are classified as A, B, or C (Fig. 13-5). A fibers are myelinated and have the fastest conduction velocity, B fibers are myelinated with a slower conduction velocity, and C fibers are unmyelinated and have the slowest conduction velocity. Most pain impulses in humans are carried by the Aδ and C fibers. The Aδ fibers, which are distributed primarily in skin and mucous membranes, are the smallest subtype of A fibers (2 to 5 μm diameter) and are associated with a sharp, pricking pain termed “fast pain.” C fibers, which are more widely distributed, are smaller than Aδ fibers (< 1.5 μm diameter) and are associated with a duller, long-lasting, burning pain termed “slow pain.”

FIGURE 13–5 Nerve fibers according to anatomical type.

Local anesthetics block the smaller diameter unmyelinated fibers first, and rapidly firing neurons are generally blocked at lower drug concentrations than the more slowly firing neurons, because these agents exhibit activity-dependence, as discussed. Thus B and Aδ fibers are blocked first, followed by blockade of C fibers. Aγ fibers, which set the length of muscle spindles, are similar in diameter and conduction velocity to Aδ fibers and thus will be blocked along with the Aδ fibers. Blockade of impulses in Aγ fibers produces a flaccid paralysis and probably accounts for the early signs of motor weakness and paralysis. Hence, fast pain fibers (Aδ) are inhibited before a loss of touch or pressure sensations (Aβ fibers), slow pain (C fibers), or motor function (Aα fibers).

The anatomical location of different nerve types also influences the ability of local anesthetics to produce nerve block. For example, peripheral nerves are never affected uniformly by a local anesthetic, because a concentration gradient of the drug from the mantle to the core of the nerve is established during the onset of the block; a steady-state distribution of drug in the nerve is rarely achieved. Thus a dynamic block results from both the rapid influx of the drug into the nerve and a slower efflux from the nerve after injection of a concentrated bolus. Axons in the mantle are generally exposed to higher drug concentrations than are axons in the core, where drug diffusion is more restricted. Although these principles help explain the differential sensitivity of nerve fibers to local anesthetics, it is difficult to predict what will happen in every given situation. Sensory modalities are lost in the following general order: cold, warmth, pain, touch, and deep pressure. As indicated above, motor functions appear to be more resistant to blockade by local anesthetics, but this may result from the relatively complex motor tasks that are tested in the clinical setting, wherein the patient can recruit several different groups of muscles to accomplish a similar movement. Indeed, when simple muscle movements—for example, extensor postural thrust—are isolated in experimental animals during peripheral nerve block, their deficiencies are greater and longer in duration than the loss of pain sensitivity.

Local anesthetics are generally less effective in inflamed tissues than in normal tissues, because inflammation usually results in a local metabolic acidosis, which decreases the pH in surrounding tissues. At an acidic pH, the portion of drug in the nonionized form is reduced markedly, resulting in reduced penetration of cell membranes and reducing the amount of drug reaching its site of action (see Chapter 2).

Local anesthetics are used widely to provide temporary pain relief in localized regions of the body. By varying the drug, its concentration and dose, and the method of administration, a wide range of effects can be obtained. A localized, intensely numb area of skin can be achieved for a short time by infiltrating the area with a short-acting drug. On the other hand, a sensory block can be achieved by administering a dilute solution of a long-acting local anesthetic through an indwelling catheter to the epidural space, providing complete anesthesia while preserving most motor function, including uterine motility. Anesthetics are used to simultaneously provide analgesia and muscle relaxation through spinal or epidural administration, and this route is also used to administer dilute solutions of local anesthetics mixed with opioids for postoperative pain relief (see Chapter 36). These combinations provide effective analgesia and have the advantage of using a lower total dose of the opioid drug than normally would be required alone. Local anesthetics are used as both diagnostic and therapeutic tools in the management of more complicated acute and chronic pain states.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Because termination of local anesthetic action ultimately depends on the movement of the drug into the systemic circulation, side effects and toxicity can result from properly conducted nerve blocks and from accidental intravenous (IV) injection. CNS effects may manifest as depression, stimulation, or both, depending on the neural pathways affected. Accidental brain penetration of local anesthetics can result in tremor and restlessness and culminate in overt clonic convulsions, coma, and respiratory failure (see Clinical Problems Box). However, a variety of signs and symptoms, including general depression and drowsiness, are common clinical consequences. Seizures can be treated or prevented by the IV injection of diazepam along with O₂ administration to protect against hypoxemia in the convulsing patient. An overdose of local anesthetic can result in the reduced transmission of impulses at the neuromuscular junction and at ganglionic synapses, producing weakness or muscle paralysis. Support of respiration is an important component of treatment. Smooth muscle is only minimally affected by local anesthetics.

Local anesthetics have potentially deleterious effects on cardiac pacemaker activity, electrical excitability,

CLINICAL PROBLEMS

CNS seizures and convulsions at high concentrations of agent

Blockade of cardiac Na⁺ channels (also used therapeutically for antiarrhythmic effects; see Chapter 22)

conduction times, and contractile force. Dysrhythmias are possible when high blood concentrations of anesthetic agents are attained. For example, cocaine is a potent local anesthetic and is a prominent drug of abuse, which has extensive adverse effects on the heart and the CNS (see Chapter 37). Bupivacaine is the most cardiotoxic of the local anesthetics, whereas lidocaine is used therapeutically in certain arrhythmias (see Chapter 22).

Local hypersensitivity reactions can result from the use of some ester-type local anesthetics, particularly procaine and related compounds. These can be ameliorated by the systemic administration of antihistamines (H₁ antagonists).

New Horizons

Although the local anesthetics are important therapeutic compounds for pain management, their usefulness is somewhat limited by their potential side effects. The therapeutic profile of these agents would be improved significantly if one were able to:

• Control and predict the duration of block

• Enhance selectivity for pain suppression relative to motor and autonomic blockade

• Improve safety, especially cardiotoxicity

Local anesthetics, at doses below those that block nerve impulse propagation, may have pain-relieving actions via targets other than Na⁺ channels, including neuronal G protein-coupled receptors and binding sites on immune cells. In addition, there are multiple isoforms of the voltage-gated Na⁺ channel α-subunit, and some of these are implicated in neuropathic and inflammatory pain. Specific isoforms are expressed by somatosensory

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Bupivacaine (Marcaine, Sensorcaine)

Chloroprocaine (Nesacaine)

Etidocaine (Duranest)

Levobupivacaine (Chirocaine)

Lidocaine † (Dilocaine, Lidoject, Octocaine, Xylocaine)

Mepivacaine (Carbocaine, Isocaine, Polocaine)

Procaine (Novocain)

Ropivacaine (Naropin)

Tetracaine ‡ (Pontocaine)

primary afferent neurons but not by skeletal or cardiac muscle, suggesting the possibility that isoform-specific drugs might be analgesic without cardiotoxicity and neurotoxicity.

A new development in reversing local anesthetic toxicity, including seizures, electrocardiogram abnormalities, and cardiac arrest, is a lipid emulsion that may act by extracting lipophilic local anesthetics from aqueous plasma or tissues or by counteracting local anesthetic inhibition of myocardial fatty acid oxygenation.