Basic Pharmacology of Local Anesthetics

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 asso-ciated 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 (Ionization of Weak Acids and Weak Bases). The relative proportions of these two forms are governed by their pK_a and the pH of the body fluids according to the Henderson-Hasselbalch equation, which can be expressed as:

pK_a = pH – log [base]/[conjugate acid]

If the concentration of base and conjugate acid are equal, the second portion of the right side of the equation drops out, as log 1 = 0, leaving:

pK_a = pH (where base = conjugate acid)

Thus, pK_a can be seen as an effective way to consider the ten-dency for compounds to exist in a charged or uncharged form, ie, the lower the pK_a, the greater the percentage of uncharged species at a given pH. Because the pK_a of most local anesthetics is in the range of 7.5–9.0, the charged, cationic form will con-stitute the larger percentage at physiologic pH. A glaring exception is benzocaine, which has a pK_a around 3.5, and thus exists solely as the nonionized base under normal physiologic conditions.This issue of ionization is of critical importance because the cationic form is the most active at the receptor site. However, the story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Thus, the uncharged form is important for cell penetra-tion. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium chan-nel, and hence the production of a clinical effect. Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway (Figure 26–1). As a clinical consequence,local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthet-ic—a strategy sometimes utilized in clinical practice—will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block.

Pharmacokinetics

When local anesthetics are used for local, peripheral, and cen-tral neuraxial anesthesia—their most common clinical applica-tions—systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Thus, classic pharmacokinetics plays a lesser role than with systemic thera-peutics, yet remains important to the anesthetic’s duration and critical to the potential development of adverse reactions, spe-cifically cardiac and central nervous system (CNS) toxicity.Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics has not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute).

A. 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 a vasoconstrictor (eg, epinephrine), and the physicochemical properties of the drug itself. Anesthetics that are more lipid soluble are generally more potent, have a longer duration of action, and take longer to achieve their clinical effect. Extensive protein bind-ing also serves to increase the duration of action.

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 subcutaneous fat. When used for major conduction blocks, the peak serum levels will vary as a function of the specific site of injection,with intercostal blocks among the highest, and sciatic and femoral among the lowest (Figure 26–2). When vasoconstrictors are used with local anesthetics, the resultant reduction in blood flow serves to reduce the rate of systemic absorption and thus diminishes peak serum levels. This effect is generally most evident with the shorter-acting, less potent, and less lipid-soluble anesthetics.

B. Distribution

Localized—As local anesthetic is usually injected directly at thesite of the target organ, distribution within this compartment plays an essential role with respect to achievement of clinical effect. For example, anesthetics delivered into the subarachnoid space will be diluted with cerebrospinal fluid (CSF) and the pattern of distribu-tion will be dependent upon a host of factors, among the most critical being the specific gravity relative to that of CSF and the patient’s position. Solutions are termed hyperbaric, isobaric, and hypobaric, and will respectively descend, remain relatively static, or ascend, within the subarachnoid space due to gravity when the patient sits upright. A review and analysis of relevant literature citedfactors that have been invoked as determinants of spread of local anesthetic in CSF, which can be broadly classified as characteristics of the anesthetic solution, CSF constituents, patient characteristics, and techniques of injection. Somewhat similar considerations apply to epidural and peripheral blocks.

Systemic—The peak blood levels achieved during major con-duction anesthesia will be minimally affected by the concentration of anesthetic or the speed of injection. The disposition of these agents can be well approximated by a two-compartment model. The initial alpha phase reflects rapid distribution in blood and highly perfused organs (eg, brain, liver, heart, kidney), characterized by a steep expo-nential decline in concentration. This is followed by a slower declin-ing beta phase reflecting distribution into less well perfused tissue (eg, muscle, gut), and may assume a nearly linear rate of decline. The potential toxicity of the local anesthetics is affected by the protective effect afforded by uptake by the lungs, which serve to attenuate the arterial concentration, though the time course and magnitude of this effect have not been adequately characterized. 

C. Metabolism and Excretion

The amide local anesthetics are converted to more water-soluble metabolites in the liver (amide type) or in plasma (ester type), 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 to inactive metabolites. For example, the half-lives of procaine and chloroprocaine in plasma are less than a minute. However, excessive concentrations may accumulate in patients with reduced or absent plasma hydro-lysis secondary to atypical plasma cholinesterase.

The amide local anesthetics undergo complex biotransforma-tion in the liver, which includes hydroxylation and N-dealkylation by liver microsomal cytochrome P450 isozymes. There is consid-erable variation in the rate of liver metabolism of individual amide compounds, with prilocaine (fastest) > lidocaine > mepivacaine > ropivacaine ≈ 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_½, Table 26–2) to more than 6 hours in patients with severe liver disease. Many other drugs used in anesthe-sia are metabolized by the same P450 isozymes, and concomitantadministration 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 anesthe-tized with intravenous anesthetic techniques. Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with congestive heart failure.

Pharmacodynamics

A. Mechanism of Action

Membrane potential—The primary mechanism of actionof local anesthetics is blockade of voltage-gated sodium channels (Figure 26–1). The excitable membrane of nerve axons, like the membrane of cardiac muscle  and neuronal cell bodies , maintains a resting transmembrane potential of –90 to –60 mV. During excitation, the sodium chan-nels 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 chan-nels 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.

Sodium channel isoforms—Each sodium channel con-sists of a single alpha subunit containing a central ion-conducting pore associated with accessory beta subunits. The pore-forming alpha subunit is actually sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the beta subunit. A variety of different sodium channels have been characterized by electrophysiologic record-ing, and subsequently isolated and cloned, while mutational analysis has allowed for identification of the essential compo-nents of the local anesthetic binding site. Nine members of a

mammalian family of sodium channels have been so character-ized and classified as Na_v1.1–Na_v1.9, where the chemical sym-bol represents the primary ion, the subscript denotes the physiologic regulator (in this case voltage), the initial number denotes the gene, and the number following the period indi-cates the particular isoform.

Channel blockade— Biologic toxins such as batrachotoxin,aconitine, veratridine, and some scorpion venoms bind to recep-tors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolariza-tion of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin have clinical effects that largely resemble those of local anesthetics (ie, block of conduction without a change in the resting potential). However, in contrast to the local anesthetics, their binding site is located near the extracel-lular surface. The sensitivity of these channels to TTX varies, and subclassification based on this pharmacologic sensitivity has important physiologic and therapeutic implications. Six of the aforementioned channels are sensitive to nanomolar concentra-tion of this biotoxin (TTX-S), while three are resistant (TTX-R). Of the latter, Na_v1.8 and Na_v1.9 appear to be exclusively expressed in dorsal root ganglia nociceptors, which raises the developmental possibility of targeting these specific neuronal subpopulations. Such fine-tuned analgesic therapy has the theo-retical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers.

When progressively increasing concentrations of a local anes-thetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, 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 appears to be 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 poten-tials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which pre-dominate at more positive membrane potentials (see Figure 14–10). 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 14–10). The recovery from drug-induced block is 10–1000 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 action potentials.

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-affin-ity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics.

Other effects—Currently used local anesthetics bind tothe sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clini-cally relevant concentrations, local anesthetics are potentially active at countless other channels (eg, potassium and calcium), enzymes (eg, adenylate cyclase, carnitine-acylcarnitine translocase), and receptors (eg, N-methyl-D-aspartate [NMDA], G protein-coupled, 5-HT₃, neurokinin-1 [substance P receptor]).

The role that such ancillary effects play in achievement of local anesthesia appears to be important but is poorly understood. Further, interactions with these other sites are likely the basis for numerous differences between the local anesthetics with respect to anesthetic effects (eg, differential block) and toxici-ties that do not parallel anesthetic potency, and thus are not adequately accounted for solely by blockade of the voltage-gated sodium channel.

The actions of circulating local anesthetics at such diverse sites exert a multitude of effects, some of which go beyond pain control, including some that are also potentially beneficial. For example, there is evidence to suggest that the blunting of the stress response and improvements in perioperative outcome that may occur with epidural anesthesia derive in part from an action of the anesthetic beyond its sodium channel block. Circulating anesthetics also demonstrate antithrombotic effects having an impact on coagulation, platelet aggregation, and the microcircu-lation, as well as modulation of inflammation.

B. 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. As previously noted, potency is also positively correlated with lipid solubility. 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 R (+) isomer can usually be shown to be slightly more potent than the S(–) isomer (levobupivacaine). 

C. Neuronal Factors Affecting Block

1. Differential block—Since local anesthetics are capable ofblocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. With central neuraxial techniques (spinal or epidural), motor paraly-sis may impair respiratory activity, and autonomic nerve block-ade may promote hypotension. Further, while motor paralysis may be desirable during surgery, it may be disadvantageous in other settings. For example, motor weakness occurring as a consequence of epidural anesthesia during obstetrical labor may limit the ability of the patient to bear down (ie, “push”) during delivery. Similarly, when used for postoperative analgesia, weakness may hamper ability to ambulate without assistance and pose a risk of falling, while residual autonomic blockade may interfere with bladder function, resulting in uri-nary retention and the need for bladder catheterization. These issues are particular problematic in the setting of ambulatory (same-day) surgery, which represents an ever-increasing percentage of surgical caseloads.

2. Intrinsic susceptibility of nerve fibers— Nerve fibersdiffer significantly in their susceptibility to local anesthetic blockade. It has been traditionally taught, and still often cited, that local anesthetics preferentially block smaller diameter fibers first because the distance over which such fibers can pas-sively propagate an electrical impulse is shorter. However, a variable proportion of large fibers are blocked prior to the disappearance of the small fiber component of the compound action potential. Most notably, myelinated nerves tend to be blocked before unmyelinated nerves of the same diameter. For example, preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission (Table 26–3).

Another important factor underlying differential block derives 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 havea high firing rate and relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. As type A delta and C fibers participate in high-frequency pain transmission, this characteristic may favor blockade of these fibers earlier and with lower concentrations of local anesthetics. The potential impact of such effects man-dates cautious interpretation of non-physiologic experiments evaluating intrinsic susceptibility of nerves to conduction block by local anesthetics.

3. Anatomic arrangement—In addition to the effect ofintrinsic vulnerability to local anesthetic block, the anatomic organization of the peripheral nerve bundle may impact the onset and susceptibility of its components. As one would pre-dict based on the necessity of having proximal sensory fibers join the nerve trunk last, the core will contain sensory fibers innervating the most distal sites. Anesthetic placed outside the nerve bundle will thus reach and anesthetize the proximal fibers located at the outer portion of the bundle first, and sen-sory block will occur in sequence from proximal to distal.