16: Local Anesthetics

CHAPTER 16 Local Anesthetics

Local anesthetics are agents that reversibly block nerve conduction when applied to a circumscribed area of the body. Although numerous substances of diverse chemical structure are capable of producing local anesthesia, most drugs of proven clinical usefulness (identified by the suffix -caine) share a fundamental configuration with the first true local anesthetic, cocaine. For centuries, natives of the Peruvian highlands have relied on the leaves of the coca bush to prevent hunger, relieve fatigue, and uplift the spirit. European interest in the psychotropic properties of Erythroxylon coca led to the isolation of cocaine by Niemann in 1859 and to a study of its pharmacology by von Anrep in 1880. Although Niemann and von Anrep reported on the local anesthetic action of cocaine, credit for its introduction into medicine belongs to Karl Koller, a Viennese physician. In 1884, Koller was familiarized with the physiologic effects of cocaine by Sigmund Freud. Koller recognized the drug’s great clinical significance and demonstrated its pain-relieving action in several ophthalmologic procedures. The benefits of cocaine were widely appreciated; within 1 year, local anesthesia had been successfully administered for various medical and dental operations.

Knowledge of cocaine’s potential for adverse reactions soon followed its general acceptance as a local anesthetic. Several deaths attributed to acute cocainization testified to the drug’s low therapeutic index. The abuse liability of cocaine was dramatically illustrated by the self-addiction of William Halsted, a pioneer in regional nerve blockade. A chemical search for safer, nonaddicting local anesthetics was instituted by Einhorn and associates in 1892, culminating 13 years later in the synthesis of procaine. Since then, numerous improvements in the manufacture of local anesthetic solutions have been made, and many useful agents have been introduced into clinical practice. Because no drug is currently devoid of potentially serious toxicity, however, the search for new and better local anesthetic agents continues.


Certain physicochemical characteristics are required of a drug intended for clinical use as a local anesthetic. One prerequisite is that the agent must depress nerve conduction. Because an axon whose cytoplasmic contents have been completely removed can still transmit action potentials, a drug must be able to interact directly with the axolemma to exert local anesthetic activity. A second important consideration is that the agent must have lipophilic and hydrophilic properties to be effective by parenteral injection. Lipid solubility is essential for penetration of the various anatomic barriers existing between an administered drug and its site of action, including the nerve sheath. Water solubility ensures that, when injected in an effective concentration, a drug does not precipitate on exposure to interstitial fluid. These requirements have placed important structural limitations on the clinically useful local anesthetics.

Structure-Activity Relationships

The typical local anesthetic molecule can be divided into three parts: (1) an aromatic group, (2) an intermediate chain, and (3) a secondary or tertiary amino terminus (Figure 16-1). All three components are important determinants of a drug’s local anesthetic activity. The aromatic residue confers lipophilic properties on the molecule, whereas the amino group furnishes water solubility. The intermediate portion is significant in two respects. First, it provides the necessary spatial separation between the lipophilic and hydrophilic ends of the local anesthetic. Second, the chemical link between the central hydrocarbon chain and the aromatic moiety serves as a suitable basis for classification of most local anesthetics into two groups, the esters (–COO–) and the amides (–NHCO–). This distinction is useful because there are marked differences in allergenicity and metabolism between the two drug categories.

Minor modifications of any portion of the local anesthetic molecule can significantly influence drug action. The addition of a chlorine atom to the ortho position on the benzene ring of procaine yields chloroprocaine, a more lipophilic local anesthetic four times as potent as the parent compound yet half as toxic when injected subcutaneously. Table 16-1 lists several important physicochemical properties of local anesthetics and how they correlate with clinical activity.

Influence of pH

By virtue of the substituted amino group, most local anesthetics are weak bases with a negative logarithm of the acid ionization constant (pKa) ranging from 7.5 to 9.0. A local anesthetic intended for injection is usually prepared in salt form by the addition of hydrochloric acid. Not only is water solubility improved, but also stability in aqueous media is increased. When injected, the acidic local anesthetic solution is quickly neutralized by tissue fluid buffers, and a fraction of the cationic form is converted to the nonionized base. As determined by the Henderson-Hasselbalch equation (Figure 16-2), the percentage of drug converted depends primarily on the local anesthetic pKa and the tissue pH. Because only the base form can diffuse rapidly into the nerve, drugs with a high pKa tend to be slower in onset than similar agents with more favorable dissociation constants. Tissue acidity may also impede the development of local anesthesia. Products of inflammation can lower the pH of the affected tissue and limit formation of the free base. Ionic entrapment of the local anesthetic in the extracellular space delays the onset of local anesthesia and may render effective nerve blockade impossible.

Numerous attempts have been made to augment local anesthesia by capitalizing on the influence of pH. Theoretically, alkalization should increase local anesthetic activity by promoting tissue penetration and nerve uptake. Many topical agents are marketed in the base form to improve diffusion across epithelial barriers. Although it has been shown experimentally that alkalization of local anesthetic solutions just before use enhances nerve blockade, practical considerations have limited routine clinical application. Even so, extracellular fluid has in most instances sufficient buffering capacity to negate differences in local anesthetic pH soon after injection.

An alternative approach to modifying drug distribution is through the addition of carbon dioxide. Carbonation of a local anesthetic solution can increase the rate of onset and sometimes the depth of anesthesia. It has been suggested that the hydrocarbonate salt of the local anesthetic penetrates membranes more rapidly than the conventional formulation and that the injected carbon dioxide diffusing into the nerve trunk lowers the internal pH and concentrates local anesthetic molecules by ion trapping.55 There is also evidence that carbon dioxide may potentiate local anesthetic activity by a direct effect on the nerve membrane.15,19 Although promising, carbonated local anesthetic solutions are unavailable in the United States, and a study of carbonated lidocaine used for mandibular anesthesia failed to reveal any significant benefit compared with lidocaine hydrochloride.22


Local anesthetics block the sensation of pain by interfering with the propagation of peripheral nerve impulses. The generation and the conduction of action potentials are inhibited. Electrophysiologic data indicate that local anesthetics do not significantly alter the normal resting potential of the nerve membrane; instead they impair certain dynamic responses to nerve stimulation.

Effects on Ionic Permeability

The quiescent nerve membrane is impermeable to Na+. Excitation of the neuron by an appropriate stimulus temporarily increases Na+ conductance and causes the nerve cell to become less electronegative regarding the outside. If the transmembrane potential is sufficiently depressed, a critical threshold is reached at which the depolarization becomes self-generating. Local electrotonic currents induce a rapid influx of Na+ through activated Na+-selective channels traversing the nerve membrane. The inward Na+ current creates an action potential of approximately +40 mV, which is propagated down the nerve. The action potential is quite transient at any given segment of membrane; loss of Na+ permeability (inactivation of the Na+ channels) and an outward flow of K+ (in nonmyelinated axons) quickly repolarize the membrane. These events are reviewed in Figure 16-3.

Local anesthetics interfere with nerve transmission by blocking the influence of stimulation on Na+ conductance. A developing local anesthetic block is characterized by a progressive reduction in the rate and degree of depolarization and a slowing of conduction. When the depolarization is retarded sufficiently such that repolarization processes develop before the threshold potential can be reached, nerve conduction fails.1

Site of Action

Several sites exist within the nerve membrane where drugs could potentially interfere with Na+ permeability. It was argued that local anesthetics could interact with membrane lipids to impair Na+ channel function, just as had long been proposed for general anesthetics (see Chapter 17).86 In recent years, evidence has accumulated that conventional local anesthetics interact directly with Na+ channels to inhibit nerve conduction.18,88 Each Na+ channel is composed of several subunits. The α subunit is the largest component (260 kDa) and forms the actual channel,20 whereas the smaller β subunits help to stabilize the channel complex within the membrane.56 As depicted in Figure 16-4, the α subunit consists of four homologous domains (I to IV), each of which is composed of six structurally similar helical segments (S1 to S6) that traverse the plasma membrane. Collectively, the S4 segments of each domain constitute the voltage sensor of the “m” or “activation” gate, which opens in response to a depolarizing stimulus. Each S4 segment contains positively charged amino acid residues, specifically arginine and lysine, at every third position of the α helix. In the “helical screw model” of activation,21 depolarization causes the outward conformational rotation of the S4 segments, which can be detected experimentally as the small gating currents that precede the action potential. Local anesthetic blockade of the Na+ channel is characterized by a reduction in the peptide movements responsible for these gating currents.63 Lidocaine tends to trap the S4 segment of domain III in the external, depolarized configuration and to retard movements of the S4 segment of domain IV.77 As a consequence, the Na+ channel remains in an inactivated configuration that precludes normal opening.


FIGURE 16-4 Functional structure of the Na+ channel (linear representation). The four primary domains of the α subunit are indicated by Roman numerals, with the six helical segments (designated S1 through S6, left to right) of each domain shown spanning the membrane. A portion of each of the S5-S6 linkages lines the outer portion of the pore and confers ion selectivity to the channel. The inner portion is lined by the S6 and (to a lesser extent) S5 helices. Outward rotation of the positively charged S4 cylinders and coupled movements of the S6 segments open the pore. Concurrently, portions of the S4-S5 linkages of domains III and IV, which help form the inner mouth of the channel, and the S6 segment of domain IV create a receptor (unlettered circles) for a hydrophobic triad of amino acid residues (isoleucine-phenylalanine-methionine; IFM motif) in the intracellular loop between domains III and IV, which constitutes the inactivation, or h, gate (h). Binding of the h gate to its receptor inactivates the channel within about 1 ms. Each P indicates a phosphorylation site for protein kinase A (circles) and protein kinase C (diamonds). Phosphorylation of the h gate slows inactivation; phosphorylation of other sites reduces channel activation. The ψ symbols indicate glycosylation sites. The β subunits (β1 and β2) modulate Na+ channel electrophysiology and serve as cell adhesion molecules, stabilizing the α subunit in the nerve membrane by interacting with other β subunits and with contactin and ankyrin proteins.

(Adapted from Catterall WA: From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels, Neuron 26:13-25, 2000.)

As the active site for local anesthetics resides within the Na+ channel, access becomes an important issue. In this regard, studies with permanently charged local anesthetics have proved enlightening.44 Conversion of the amino terminus of certain local anesthetics (e.g., lidocaine) to the quaternary form (e.g., QX-314) yields permanently charged cations largely incapable of crossing the nerve membrane. Although ineffective when applied externally to the axolemma, these experimental compounds show full blocking activity on internal administration. They gain access to the receptor by traveling up an aqueous route within the Na+ channel, which must be fully open or at least partially activated to permit their entry from the cytoplasm. Lipophilic molecules, such as benzocaine or the uncharged form of lidocaine, can reach the channel and receptor site by traversing a hydrophobic route, which may include the membrane lipid and hydrophobic portions of the Na+ channel.

Specific mutations of the S6 segment of domain IV of the Na+ channel greatly alter local anesthetic blockade.68 Replacement of the phenylalanine amino acid midway down the S6 helix with an alanine residue reduces by 99% the apparent binding affinity of the local anesthetic etidocaine to open and inactivated channels. A similar, although smaller, effect occurs when the tyrosine located 11 Å and two turns inward on the same side of the S6 helix is replaced with alanine. Because these aromatic amino acids can interact with local anesthetics through hydrophobic and van der Waals interactions, and their spatial separation conforms to the length of the typical local anesthetic molecule (10 Å to 15 Å), they are believed to be part of and to identify the local anesthetic receptor site. Mutation studies have also shown specific amino acid residues on the S6 segments of domains I and III that appear to form part of the receptor site (Figure 16-5).94

As previously mentioned, local anesthetics block nerve conduction by impeding the gating mechanisms that underlie cycling of the Na+ channel. Other actions that could contribute to nerve blockade include a physical occlusion of the channel, an allosterically mediated change in channel conformation, and (at least with local anesthetic cations) a distortion of the local electrical field.57 Some of these actions may be complementary, as binding of a cationic local anesthetic molecule to the putative receptor site places its positive charge adjacent to the most constricted portion of the channel and stabilizes the S4 domain III segment (and to a lesser degree the S4 domain IV segment) in the extruded position.62 Figure 16-6 depicts the Na+ channel as it cycles through its primary configurations in response to a depolarizing stimulus and postulated interactions with neutral and charged local anesthetic species.5


FIGURE 16-6 Normal Na+ channel cycling and local anesthetic blockade. Shown for domains II and IV are the S4 segments (IIS4 and IVS4) surrounding their respective S5-S6 linkages (scalloped lines) and S6 segments (helping to form the activation, or m, gate). A, In the basal resting state, the S4 segments of all domains are fully deactivated, forced inward by the negative resting polarity. The m gate is fully closed. B, With partial depolarization of the membrane, the S4 segments of domains I, II, and III rotate outward independently. The m gate remains closed. Noncharged local anesthetics can gain access to the channel at any stage of the channel cycle by traversing a hydrophobic pathway. C, Conduction begins when the S4 segment of domain IV moves part way out. The steric hindrance on the m gate is relieved, and the gate opens sufficiently for influx of Na+. Charged local anesthetic molecules can reach the receptor only when the channel is in an open configuration. D, Subsequent movement of the S4 domain IV segment allows the channel to open fully. The immediate area assumes a positive polarity as Na+ rushes inward. This movement also exposes the receptor site for the inactivation, or h, gate. E, Inactivation of the channel by docking of the h gate to its receptor automatically follows. The influx of Na+ is terminated. F, As the local internal Na+ concentration dissipates, and the membrane begins to repolarize, the S4 segments of domains I and II return to their resting configurations. At this point, the m and h gates are closed. Return to the normal resting state occurs as the S4 domain returns to its fully resting state, evicting the h gate from its binding site in the process.

(Adapted from Armstrong CM: Na channel inactivation from open and closed states, Proc Natl Acad Sci U S A 103:17991-17996, 2006.)

Similarities in molecular structure among voltage-gated ion channels provide the basis by which local anesthetics influence the movement of ions other than Na+. Inhibition of specific K+ and Ca++ currents may contribute to various local anesthetic effects, including the blockage of nociception.

Use-Dependent Block

Conventional local anesthetics inhibit high-frequency trains of impulses more readily than they do single action potentials. This phenomenon, variously referred to as use-dependent or frequency-dependent conduction block, phasic or transitional block, or Wedensky inhibition, is an important pharmacologic attribute of local anesthetics and one vital to the elucidation of their interaction with the Na+ channel.

It has been stated that quaternary derivatives of local anesthetics retain nerve-blocking activity when they are injected intra-axonally, but are ineffective by external administration. Because these drugs can reach their site of action within the Na+ channel only when the channel is open to the cytoplasm, repetitive stimulation of the nerve should increase exposure of the receptor site to the anesthetic—and lead to increasing drug action—until a steady state is established between the bound drug within the channel and the free drug in the axoplasm. A similar, although less extensive use dependency could be anticipated for lidocaine and related drugs that are partially ionized at physiologic pH.

Numerous studies have proved that high-frequency stimulation increases the magnitude of channel blockade by local anesthetics. Within certain limits, the degree of axonal block is strongly and continuously dependent on the stimulus rate regardless of equilibration time. A concentration of lidocaine that reduces a compound action potential by 40% at a stimulation rate of 1 Hz causes a depression of 80% after 15 seconds at 40 Hz.14 These results, as embodied in the modulated receptor hypothesis of local anesthesia, suggest that stimulation of the nerve membrane not only exposes the site of action to local anesthetic cations, but also increases temporarily the affinity of the channel receptor for them.

As originally proposed by Hille,44 the modulated receptor hypothesis holds that both the charged and neutral forms of local anesthetics bind preferentially to open and inactivated Na+ channels. The binding reciprocally tends to stabilize the channels in the inactivated state. If stimulations are sufficiently infrequent, time is available after each depolarization for the slower-than-normal transition from inactivated to resting channels to take place. This conversion reduces local anesthetic binding and permits a net diffusion of neutral anesthetic molecules out of the channels. The remaining anesthetic bound to closed channels provides a basal or tonic block. Conversely, repeated stimuli do not allow for full recovery between depolarizations; anesthetic binding remains enhanced, Na+ channels in the inactive configuration accumulate, and use-dependent block ensues. Subsequent refinements to the modulated receptor hypothesis include discoveries that the increased affinity state of the receptor caused by depolarization of the membrane is not synonymous with the classically defined open or inactivated forms of the channel but may include closed but partially activated channels and several “slow” inactivated configurations promoted by local anesthetic binding.

Marked differences in use dependency have been recorded for various local anesthetics.24 Benzocaine and related nonionized compounds show little phasic block and then only at very high stimulus rates. Conventional local anesthetics exhibit an approximate 10-fold range in frequency dependence, with phasic block becoming clinically significant at 2.5 Hz for lidocaine and at 0.5 Hz for bupivacaine. Permanently charged local anesthetic derivatives develop use-dependent blocks with stimulus rates of 2.4 per minute (0.04 Hz). Basic knowledge gained by the study of use dependency is increasingly being applied to clinical questions involving local anesthetic efficacy and toxicity and to related classes of drugs, such as various antiarrhythmic and anticonvulsant agents that also exhibit phasic block. Ultimately, new drugs and modes of therapy are expected to arise from the pharmaceutical exploitation of this phenomenon.

Differential Nerve Block

Clinically, neurons vary according to fiber size and type in their susceptibility to local anesthetics. Autonomic functions subserved by preganglionic B and postganglionic C fibers are readily disrupted by local anesthetics, whereas motor control dependent on larger A fibers is not. Sensory neurons are quite heterogeneous in size and exhibit a wide range of sensitivity. Modalities listed in increasing order of resistance to conduction block include the sensations of pain, cold, warmth, touch, and deep pressure. Generally, the more susceptible a fiber is to a local anesthetic agent, the faster it is blocked, and the longer it takes to recover.

Critical length

The clinical observations already described (and best seen after spinal or epidural anesthesia) should not be construed as proof that large myelinated axons are inherently more resistant to local anesthetics than smaller fibers. A careful study of individual axons by Franz and Perry35 revealed that the minimum blocking concentration of procaine is not directly related to fiber diameter. A differential block, in which small C and A fibers were affected but larger A fibers were not, could be obtained but only when the length of compound nerve exposed to procaine was restricted in length. On the basis of these findings, the authors concluded that differential sensitivities of fibers of unequal diameter result from variations in the “critical length” that must be exposed to a local anesthetic for conduction to fail.

In myelinated nerves, action potentials are propagated from one node of Ranvier to the next in a saltatory fashion, with a safety factor sufficient to require at least three consecutive nodes to be completely blocked before impulse transmission is interrupted. Because internodal distance is directly related to fiber diameter, small neurons may seem to be more sensitive clinically than large fibers to conduction block. As a local anesthetic diffuses into the nerve trunk, it reaches an effective concentration over a length required to inhibit small axons (i.e., block three nodes) before it spreads sufficiently to block large fibers. Anatomic barriers to diffusion, nonuniform distribution of drug, or the use of a minimal amount of local anesthetic may preclude some large axons from ever being affected. As local anesthesia fades, small neurons are the last to recover because circumscribed areas of drug concentrations adequate for their inhibition remain along the nerve after the more substantial areas required for large axons have broken up.

When the concentration of local anesthetic is insufficient to block three adjacent nodes completely, anesthesia may still occur if a larger train of nodes is partially blocked.34,69 As long as more than 70% of the Na+ channels in a node are inhibited, the resulting action potential at that node is reduced in size. Progressive declines in the action potentials of partially blocked nodes along the axon ultimately result in failure of conduction if a sufficient length of nerve is exposed to the drug. As shown in Figure 16-7, smaller neurons are again more readily blocked because of the shorter length required for exposure of the requisite number of nodes.69

The critical length hypothesis may also be applied to unmyelinated axons as a group. Differences in modes of impulse transmission preclude direct comparisons based on fiber size between myelinated and unmyelinated axons. Smaller in diameter, C fibers nevertheless have approximately the same apparent critical length as small myelinated axons.

Use-dependent block

In addition to anatomic and physiologic variables, the pattern of impulse traffic normally carried in situ by the different nerve fibers may contribute greatly to a differential nerve block.73 Noxious stimuli and sympathetic nervous system transmissions are encoded in rapid bursts of impulses, whereas motor function usually involves low-frequency discharges. Local anesthetics whose use-dependent characteristics fall within this frequency range tend to block pain sensations and autonomic responses preferentially.


Although primarily used to depress peripheral nerve conduction, local anesthetics are not selective and may interfere with impulse transmission in any excitable tissue. Most prominent of the systemic effects of local anesthetics are effects related to the cardiovascular system and the central nervous system (CNS), but virtually any organ with dependence on nervous or muscular activity may be affected. Local anesthetics may also influence various tissues through actions unrelated to specific disturbances in Na+ conductance.

Central Nervous System

Local anesthetics readily pass from the peripheral circulation into the brain. Because CNS neurons are particularly sensitive to local anesthetics, blood concentrations incapable of altering peripheral nervous activity may profoundly influence CNS function.

Sensitive psychomotor tests and subjective reports of mild drowsiness indicate that systemic effects caused by local anesthetics can occur with plasma concentrations that are achieved in dental patients.6 Analgesic and anticonvulsant effects also occur in subtoxic concentrations. Initial signs and symptoms of a toxic effect are often excitatory in nature and consist of a feeling of lightheadedness and dizziness, followed by visual and auditory disturbances, apprehension, disorientation, and localized involuntary muscular activity. Depressant responses, such as slurred speech, drowsiness, and unconsciousness, may also occur and are especially prominent with certain drugs (e.g., lidocaine). As higher blood concentrations of drug are attained, muscular fasciculations and tremors intensify and develop into generalized tonic-clonic convulsions. On termination, seizure activity is often succeeded by a state of CNS depression identical to general anesthesia. With excessively large doses, respiratory impairment becomes manifest; if untreated, death by asphyxiation may ensue.

The CNS excitation sometimes observed after local anesthesia is intriguing because the sole action ascribed to these agents is one of depression. Studies involving the topical application of local anesthetics to exposed cortical or spinal cord neurons document that the only direct effect of procaine and related drugs is to inhibit electrical activity.26 The apparent stimulation observed clinically may be explained on the basis that inhibitory cortical neurons or synapses are highly susceptible to transmission block. Initial disruption of these pathways results in a disinhibition of excitatory neurons, manifested clinically as stimulation. Electroencephalographic studies indicate that local anesthetic seizures begin in the amygdala.37,76 Disinhibition of this part of the limbic system allows high-voltage discharges to occur, which spread throughout the brain. A more recent finding that local anesthetics can block a family of K+ channels (whose inhibition increases neuronal excitability) raises the possibility that CNS stimulation and cardiac arrhythmias may arise in part from direct neuronal excitation.49

Cardiovascular System

Local anesthetics can exert various effects on the cardiovascular system. Some influences are beneficial and serve as a basis for the use of selected agents in the treatment of cardiac arrhythmias; others are not helpful and merely serve to accentuate systemic toxicity. In almost all instances, however, the observed effects result from the interplay of direct actions of local anesthetics on the myocardium and peripheral vasculature as well as CNS actions indirectly mediated through the autonomic nervous system.


At nontoxic concentrations, local anesthetics differ in their electrophysiologic influences on the heart. Lidocaine shortens the action potential duration and the effective refractory period in Purkinje fibers, whereas procaine acts in the opposite direction. Both drugs increase the effective refractory period relative to the action potential duration, however, and decrease cardiac automaticity, especially in ectopic pacemakers.

Presumably because of their ability to block Ca++ channels and evoked Ca++ release from the sarcoplasmic reticulum and to reduce myofibrillar responsiveness to available Ca++, local anesthetics depress myocardial contractility in a dose-dependent manner.59 With conventional doses of lidocaine, this effect is minor and sympathetic reflexes and direct vascular effects produce a compensatory increase in peripheral resistance, which prevents a decrease in blood pressure. Through a centrally mediated disinhibition of sympathetic nervous activity, heart rate and arterial blood pressure may become elevated coincident with CNS excitation. Conversely, mepivacaine has been reported in moderate doses to decrease peripheral vascular resistance and increase cardiac output,48 which suggests that local anesthetics may exert dissimilar patterns of direct and indirect effects on the heart at subtoxic blood concentrations.

Local anesthetics in doses toxic to the heart are qualitatively similar in action. Membrane excitability and conduction velocity are depressed throughout the heart. Sinus bradycardia and impairment of myocardial contractility contribute to a reduction in cardiac output. These effects are magnified by hypoxia, but even if respiration is supported artificially, circulatory collapse occurs after excessively large doses.

Reports in humans suggest and experiments in several other species confirm that bupivacaine and certain other highly lipophilic local anesthetics are cardiotoxic compared with less lipophilic congeners. Serious ventricular arrhythmias and cardiovascular collapse are more likely to occur, and resuscitation is more problematic. One explanation for these observations involves use-dependent blockade.24 As indicated in Table 16-2, bupivacaine has a high molecular weight for a local anesthetic. That, coupled with its lipophilic tendency and perhaps its high pKa, enables the drug to exert a strong phasic block at normal heart rates. Inhibition of K+ and Ca++ channels/>

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