Local Anesthetics

Local Anesthetics

Thomas W. Vickroy


Agents that are classified as local anesthetics act reversibly to prevent transmission of electrical impulses in nerve fibers and other excitable tissues. In most common applications, local anesthetics are administered to animals with the intent to exert actions that are restricted to regions of the body proximal to the site(s) of drug administration. However, as discussed elsewhere in this text, some agents are administered in different ways with the intent to produce broader systemic actions and, in that context, their actions are not classified as local anesthesia. The most widely accepted mechanism by which these drugs are thought to act involves direct binding to, and reversible blockade of, voltage-gated sodium ion (Na+) channels in cell membranes. This singular action prevents Na+ ion entry into nerve cells during periods of intense membrane depolarization, which prevents transmission of nerve impulses. The primary consequence of local anesthetic action is a reversible graded attenuation of sensation to pain and other sensory stimuli within affected body regions. The ability of local anesthetics to produce a selective decrease in pain sensitivity is noteworthy insofar as those effects occur without significant alteration in an animal’s level of consciousness nor any substantial depression of central nervous system (CNS) functions. This combination of desirable properties, including reversibility, anatomically restricted effects, and selective sparing of other neuronal functions, has helped foster the widespread acceptance and use of these agents in both veterinary and human medicine.

Throughout the modern history of drug discovery and development, it has been common for the initial lead compound within many drug classes to be identified and isolated from a natural source, and that is certainly the case for the local anesthetics. For many centuries, native peoples living in the Andes mountains of South America chewed extracts of the leaves from the coca shrub (Erythroxylon coca) for both stimulatory effects and euphoric properties. However, it was not until 19th century that the chemist, Albert Niemann, reported the chemical synthesis of cocaine, the principal active ingredient in coca plant extracts. The local anesthetic properties of this plant alkaloid became known in Western medicine soon thereafter when Niemann reportedly discovered that this newly isolated compound caused numbness in his tongue when he tasted the synthetic cocaine. The ready availability of synthetic cocaine led to studies by Sigmund Freud into the drug’s physiological actions and its eventual introduction into clinical usage for surface analgesia in ophthalmology and eventually for parenteral use to block nerve conduction. As described later in Section Amino-Ester versus Amino-Amide Classes, cocaine is considered to be the archetype for the amino-ester class of local anesthetics and its discovery led to the synthesis and introduction of other amino-ester local anesthetics into clinical use, including benzocaine (1900), procaine (1904), dibucaine (1929), tetracaine (1930), proparacaine (1953), and others. The other broad chemical class of local anesthetics, which are known commonly as amino-amide agents, was brought into clinical use with the introduction of lidocaine in 1948, followed by mepivacaine (1957), prilocaine (1960), bupivacaine (1963), and other agents. The significance of the amino-amide versus amino-ester classifications of local anesthetics is discussed in Section Amino-Ester versus Amino-Amide Classes.

Clinical Uses in Veterinary Medicine

In the clinical setting, most actions of local anesthetics are readily reversible and devoid of any significant effect on an animal’s consciousness or other functions that are associated with the CNS. This combination of properties makes these agents very useful for preventing pain that would normally occur during a wide variety of treatments and procedures. Disruption of neural transmission in sensory afferents with a local anesthetic agent can be accomplished in several distinct ways, including local tissue infiltration, splash blocks, intravenous regional nerve blocks, digital nerve blocks, or by administration of local anesthetics in close proximity to spinal nerve tracts (epidural and intrathecal administration) in order to disrupt pain transmission into higher CNS centers. When these agents are administered correctly with particular attention to anatomical injection site, injection volume, dose, and coadministration of a vasoconstrictor agent, it is possible to produce complete analgesia in a targeted region of the body. In addition, local anesthetics may contribute further to pain management in patients by interfering with the central facilitation (wind up) and sensitization of nociceptive pathways.

Local anesthetic agents are used clinically in many different ways for local or regional blockade of pain in both small and large animal species. The following listing includes some of the more common applications for local anesthetic use, although some specialized applications are not included here.

Topical anesthesia:

In order to be effective for topical anesthesia, the local anesthetic agent must be capable of penetrating through open wounds, skin, or mucous membranes. Penetration of mucous membranes is significant for many local anesthetics and can give rise to significant system absorption, most notably from the respiratory tract. The capacity of most local anesthetics to penetrate intact skin is markedly limited, but certain formulations can be effective for producing superficial dermal anesthesia.

Infiltration anesthesia:

These applications require that a high concentration of agent is injected directly into tissue without particular concern for the anatomical location of nerve tracts in the vicinity of the injection site. In view of the requirement for administering a relatively high amount of drug for infiltration anesthesia, there is a greater risk of systemic absorption and toxicity. Such risks are mitigated commonly by inclusion of a vasoconstrictor agent such as epinephrine along with the local anesthetic.

Splash blocks:

This clinical use refers to direct application of a local anesthetic to a site of interest, such as proximal to the body wall in association with abdominal surgery or adjacent to ovarian ligaments following ovariohysterectomy. Splash blocks are also used in association with oral surgical procedures, including application into tooth extraction sites. Such diffuse applications of local anesthetics have been shown to reduce general anesthetic requirements in some clinical procedures and are therefore considered beneficial.

Field-block anesthesia:

This application commonly involves injection of a local anesthetic immediately adjacent and perpendicular to sensory nerves that innervate a particular region of the body. When performed correctly, local anesthetics used in this manner can effectively ablate all sensations distal to the line of injection sites. In a clinical setting, this particular application requires a detailed knowledge and accurate placement of drug immediately adjacent to sensory nerve tracts that innervate the body region. Nerve block anesthesia represents a more confined application in which the local anesthetic is injected in immediate proximity to a nerve or nerve plexus. The risk of toxicity is considerably less in this application due to more restricted drug placement and the use of limited quantities.

Intravenous regional nerve block (IVRA or Bier block):

These clinical applications provide a rapid and reliable method for evoking short-term anesthesia and muscle relaxation of an animal’s distal extremities. The blood supply to a distal limb is isolated by a tourniquet and the local anesthetic is injected intravenously distal to the tourniquet. The mechanism(s) by which local anesthetics produce IVRA is unknown but may arise from local diffusion of the agent into tissue and action on nerve endings and nerve trunks. Problems associated with this method include systemic toxicity if the tourniquet leaks or is released before the local anesthetic has become bound to tissue. Harmful effects secondary to prolonged disruption of the blood supply with the tourniquet also present some concern with these applications.

Soaker-type catheter:

In this approach, which is commonly referred to as a diffusion or wound catheter, a length of sterile fenestrated tubing is placed surgically at a painful site for the continuous or intermittent administration of local anesthetics. Soaker-type catheters are used in association with limb amputation or large tumor resection or a course of palliative care.

Spinal and epidural anesthesia:

With spinal (subarachnoid) anesthesia, local anesthetic is injected into the lumbar-dura space immediately surrounding the spinal cord where it mixes with the cerebrospinal fluid (CSF). Besides producing the block of sensory innervation, the most notable physiological effect is the sympathetic blockade produced in spinal nerve roots. The degree of spinal anesthesia produced by this method is dependent on the injected volume as well as the drug concentration and the extent of drug diffusion along the spinal cord. Since preganglionic sympathetic fibers are very sensitive to local anesthetic blockade, the sympathetic block typically extends in a rostral direction for one or two additional segments. The movement of anesthetics along the neural axis is determined by volume of injection and by patient position. In epidural anesthesia, drug is injected into the space between the ligamentum flavum and the dura mater that covers the spinal cord. The presumptive site of drug action is spinal nerve roots, although some drug is likely to be absorbed into the epidural space where additional effects could take place.

Mechanisms for Local Anesthetic Action

Multiple lines of evidence indicate that the primary cellular target for local anesthetic action is (are) one or more specific binding sites located within ion-specific channels in the plasma membranes of nerves and other excitable cells (see review by Nau and Wang, 2004). When drug binding sites are occupied by a local anesthetic, the channels are unable to conduct Na+ ions inwardly as normally occurs during periods of intense membrane depolarization. As a consequence of this blockade, the threshold for electrical excitation of the nerve membrane increases, while the rate of rise of the action potential, the speed of impulse conduction, and the safety factor for impulse conduction are collectively reduced. Eventually, as fractional drug occupancy of channel binding sites approaches saturation, the affected regions of nerve cells become incapable of generating or conducting action potentials thereby causing failure of nerve impulse conduction. Results from experimental studies indicate that the locations of local anesthetic binding sites are deep within the Na+ channel complex and appear to be at or near the axoplasmic (inner) surface of the membrane (Butterworth and Strichartz, 1990). This conclusion is based in part on early experimental observations that quaternary analogs of local anesthetics, which are highly charged at physiological pH, selectively block nerve impulse conduction when applied internally to isolated nerve axons, but are relatively ineffective when applied externally. In keeping with this model, it would seem essential that local anesthetic agents must first permeate the nerve membrane in order to access specific binding sites within Na+ channels. This and other observations have led to the hypothesis that the site at which local anesthetics act, at least in their charged form, is accessible only from the inner surface of the membrane (Narahashi and Frazier, 1971). It is well-established that voltage-gated Na+ channels in mammalian neurons are comprised of glycosylated proteins with an aggregate molecular size in excess of 300,000 daltons. The largest of the protein subunits that form the channel complex contains four homologous domains, each containing six alpha-helical transmembrane segments (Figure 15.1). This component of the channel complex is considered to contain the specific binding pocket for local anesthetic agents (Yu et al., 2005). Although several alternative models have been proposed to explain the mechanism for local anesthetic action, including a variety of physicochemical models (Courtney and Strichartz, 1987), none of these hypothetical models are as widely accepted as the Na+ channel binding site model described above.

Image described by caption and surrounding text

Figure 15.1 Theoretical model for sodium channel blockade by local anesthetics. The four homologous transmembrane domains (DI, DII, DIII, and DIV) that form the pore of the Na+ channel are depicted as an array of squares from the perspective of looking at the outer membrane surface. Membrane depolarization causes conformational shifting of voltage-sensing domains and opening of the channel pore (step 1). As sodium ions enter through the open channel, membrane potential (EMEM) becomes positive leading to inactivation of the open channel (step 2). Ultimately, the channel returns to a closed state (step 3) and the cycle repeats. Local anesthetics bind to sites on domains III and IV near the inner membrane surface when channels are in an open or inactivated state (step 4). Once occupied by local anesthetic, the channel becomes incapable of conducting Na+ ions.

Activity-Dependent Blockade

The extent or degree of conduction block that occurs in the presence of a given concentration of local anesthetic depends on several factors, including the resting membrane potential, the degree of nerve stimulation (firing activity), the length of axon in which Na+ channels are blocked, and the duration of exposure to drug. Local anesthetics display an enhanced capacity to block nerve impulse conduction in nerves that are depolarized and actively firing (frequency-dependent blockade), presumably due to an increased capacity for drug to enter channels that are in the open state (ion conducting) versus an inactivated or nonconducting closed state. Once bound to a channel, a local anesthetic stabilizes Na+ channels in an inactivated state that is incapable of conducting Na+ ions (Butterworth and Strichartz, 1990; Courtney and Strichartz, 1987). Some but not all local anesthetic agents exhibit differences in the extent of frequency-dependent nerve blockade owing to differences in the rates of drug dissociation from the channel binding site. For agents that dissociate more rapidly from channel binding sites (small hydrophobic agents), effective channel blockade requires more rapid firing activity in order that the rate of drug binding during the action potential exceeds the rate of drug dissociation from Na+ channels between action potentials. From a clinical perspective, the impact of this frequency-dependent blockade has limited relevance for sodium channel blockade in sensory nerves, but is considered to be important for Na+ channel blockade in myocardial tissues, where the antiarrhythmic actions of these agents can be impacted significantly by the relative rates of drug association and dissociation from channel binding sites.

Differential Effects on Nerve Fibers

By virtue of the pervasive presence of voltage-gated Na+ channels in nearly all nerve cells, it seems likely that local anesthetics would have the capacity to block impulse conduction in most if not all neurons that undergo sodium-dependent firing. Nevertheless, numerous reports from studies in isolated tissues and intact living animals have provided solid evidence for the ability of local anesthetics to exert differential or selective blocking actions on nerve fibers that transmit impulses associated with different sensory modalities or functions. In general, these studies indicate that local anesthetics first cause diminished sensation to pain and temperature along with loss of other sensory modalities (touch and deep pressure), followed by diminished proprioception and motor function. In general, autonomic fibers, small unmyelinated C fibers (mediating pain sensations), and small myelinated A fibers (mediating pain and temperature sensations) are blocked preferentially before larger myelinated fibers that mediate postural, touch, pressure, and motor information. The underlying mechanism(s) that give rise to this differential blockade are incompletely understood, but several factors may contribute, including fiber diameter and extent of axonal myelination. However, the early hypothesis that sensitivity to local anesthetic blockade was inversely correlated to nerve fiber diameter does not fit with all experimental observations (Fink and Cairns, 1984; Franz and Perry, 1974; Huang et al., 1997) and thus it appears unlikely that fiber size per se determines susceptibility to local anesthetic block under steady-state conditions. The spacing between nodes of Ranvier could also contribute to differential sensitivity to local anesthetic action since internodal spacing typically increases in proportion to the diameter of nerve fibers. Because a fixed number of nodes must be blocked in order to prevent impulse conduction, small fibers with closely spaced nodes of Ranvier may be blocked more readily following exposure to local anesthetics. Finally, differences in tissue barriers and the relative locations of smaller C fibers and A fibers within sensory nerve trunks may also contribute to the apparent differences in nerve sensitivities to local anesthetic action. It is important to note that substantial controversy still surrounds the basic premise for differential susceptibility of nerve fibers to local anesthetic action. Since the primary clinical goal of local anesthesia is to alleviate or prevent pain, it would be beneficial if motor functions were spared completely when sensory modalities are attenuated or, at a minimum, that any effect of local anesthetics on motor function and proprioception would dissipate completely before sensory functions were recovered fully. Unfortunately, this is not always the outcome in clinical practice. A practical and important example in veterinary medicine occurs in horses, where limb nerve blocks are performed to assist with certain clinical procedures or diagnostic tests. In such instances, impaired proprioception increases the risk of injury if the horse is permitted to move about without proper restraint. Such heightened risk of injury is one reason why many racing authorities have banned the use of local anesthetics in horses prior to racing. The long-acting local anesthetic etidocaine was withdrawn from the market owing to problems associated with persistent motor deficits in horses and some other species.

Chemical Properties

Amino-Ester versus Amino-Amide Classes

Local anesthetics are organic bases, but are classified as amphipathic substances since nearly all agents contain both lipophilic (aromatic) and hydrophilic (substituted amine) moieties. These chemically diverse regions of the molecule are linked by an intermediate-length carbon chain that contains either an amide bond or ester bond, which gives rise to the frequent subclassification of local anesthetics into amino-amide and amino-ester classes of agents (Figure 15.2). The distinction between amino-amide and amino-ester local anesthetic agents represents far more than some arcane chemical classification insofar as enzyme-catalyzed disruption of these bonds within the linker regions renders agents incapable of producing a local anesthetic effect and, in many cases, represents a significant route for inactivation. In general, ester-linked agents are highly susceptible to enzyme-catalyzed hydrolysis of the ester bond by different families of esterase enzymes and, as a consequence, tend to have much shorter durations of action as compared with amide-linked agents. This is an important consideration in animals that have a diminished overall level of esterase enzyme activities secondary to disease processes, genetic abnormalities, or, perhaps most importantly, prior exposure to agents that cause reversible or irreversible inhibition of esterase enzymes. By comparison, the amino-amide link is more resistant to enzymatic degradation and is highly stable under temperature extremes, including heat sterilization.

Diagram shows lipophilic domain linking hydrophilic domain leading to ester-type linkage and amide-type linkage.

Figure 15.2 Representation of the core structural elements for two major classes of local anesthetic agents. Chemical structures for archetype representatives of the ester-linked agents (procaine) and amide-linked agents (lidocaine) are shown with the carboxylic acid ester and amide chemical bonds, respectively, highlighted within the shaded region.

Effect of Local pH

The physical chemical properties and structure–activity relationships for local anesthetic agents have been reviewed in detail previously (Courtney and Strichartz, 1987). Most local anesthetics contain a tertiary amine as the hydrophilic group and an unsaturated aromatic ring as the lipophilic group. In general, tertiary amines are poorly soluble in water and, accordingly, many local anesthetics are prepared as hydrochloride salts in order to improve water solubility and facilitate their formulation as injectable aqueous solutions. Since local anesthetics are weak organic bases (B), with typical pKa values ranging from 8 to 9, the hydrochloride salts form mildly acidic solutions in water, which tends to enhance the chemical stability of catecholamines, such as epinephrine, that are sometimes included for their vasoconstrictor action. Under usual conditions of administration, it is likely that the pH of the local anesthetic solution rapidly equilibrates with that of the extracellular fluid environment. Experimental studies support a model (Figure 15.3) wherein the unprotonated species of the local anesthetic (B0) is the predominant form that is able to diffuse across cellular membranes, whereas the less permeable cationic species (BH+) is the predominant form that interacts preferentially with Na+ channels. In consideration of this model, wherein the unprotonated form of drug provides improved access to the target site and the protonated form has greater affinity for blocking Na+ channels, it is evident that pH of extracellular fluid can influence the actions of local anesthetics. The relative concentrations of uncharged (B0) and cationic forms (BH+) of drug at equilibrium are related to the pKa of the ionizable group as well as the local pH and can be estimated mathematically by the Henderson–Hasselbalch relationship as follows:

(15.1) numbered Display Equation

Diagram shows nerve axon and blood vessel linked together with B0 along with plasma proteins.

Figure 15.3 Principal routes for local anesthetic movement following subcutaneous injection. Passive diffusion (thick striped arrows) is likely to be the primary process by which the unprotonated (B0) forms of local anesthetics enter either nerve axons or blood vessels. In addition, the cationic form (BH+) may enter neurons via transient receptor potential vanilloid subtype-1 channels (TRPV-1), if present, and allow for blockade of sodium channels from the axoplasmic side.

When solution pH is equivalent to the pKa of a local anesthetic, the relative concentrations of [B0] and [BH+] are equal. However, in situations where the extracellular fluid becomes mildly acidified (reduced pH), such as in association with localized tissue inflammatory reactions, the relative ratio of [B0]/[BH+] decreases in accordance with the above relationship and the cationic form becomes the predominant species. A modest shift in the pH of extracellular fluid can cause a significant shift in the equilibrium between cationic and neutral forms and thereby affect the rate at which drug is able to diffuse through the nerve cell membrane and reach the target binding site. Another situation where the equilibrium concentrations of charged species could be important is with regard to local anesthetic diffusion across the maternal–fetal barrier in the placenta, where fetal blood is slightly acidic (lower pH) relative to maternal blood. However, it is important to recognize that the impact from shifts in the acid–base equilibrium can be influenced by other factors for certain agents, including differences in drug–protein binding, differences in the membrane permeability of neutral and cationic species, as well as differences in the Na+ channel blocking activity for the neutral and cationic species. For example, it has been reported that the unprotonated (B0) form of some local anesthetics can exhibit significant channel-blocking activity, whereas the uncharged form of other agents are nearly devoid of activity. In addition, the capacity for the charged cationic form of local anesthetics to gain access to the cytoplasmic surface of the nerve cell membrane by passage appears to not be limited by transmembrane diffusion of the unprotonated neutral form as commonly proposed. For example, research studies have demonstrated that a permanently charged derivative of lidocaine has the ability to permeate neuronal membranes by passage through a family of nonselective cation channels known as transient receptor potential vanilloid subtype 1 or TRPV1 channels (Binshtok et al., 2009). These and related membrane channels are expressed primarily within sensory neurons and, when activated by membrane depolarization, permit influx of inorganic cations, primarily Ca2+ and Na+.

However, in light of the selective expression of TRPV1 channels in a subset of sensory neurons, this alternate pathway for local anesthetic entry and blockade of axonal Na+ channels (Figure 15.3) raises the potential to achieve greater pharmacological selectivity and thereby avoid unwanted effects on motor nerves and possibly other nonnociceptive modalities (Blumberg, 2007). In addition to being the responsive element for changes in molecular charge under different conditions of pH, the hydrophilic moiety is considered crucial for influencing drug binding affinity to target sites within Na+ channels. Structure–activity studies indicate that the intermediate linking chain is likely to be important for proper alignment of the lipophilic and hydrophilic ends of the drug, with a length of three to seven carbon atoms being optimal for channel blocking activity. In general, detailed studies of the structure–activity relationship for local anesthetics have revealed that: (i) highly lipophilic agents exhibit higher potencies, which may reflect an increased binding affinity for target sites as well as enhanced partitioning into the membrane microenvironment; (ii) highly lipophilic agents exhibit longer durations of action possibly due to enhanced distribution into nerve cell membranes plus reduced accessibility to degradative enzymes in plasma and liver; (iii) higher lipophilicity is associated with a greater propensity for toxicity and a smaller therapeutic index; and (iv) agents that are smaller in size exhibit faster rates for dissociation from target receptor sites and, accordingly, display a greater extent of frequency- and voltage-dependent actions in rapidly firing neurons.


Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Local Anesthetics
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