Mechanisms of Action of Local Anesthetics

Charles B. Berde, M.D. Boston, Massachusetts

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OBJECTIVES
1. to review local anesthetic actions on initiation and propagation of action potentials in nerves
2. to describe non-impulse-blocking actions of local anesthetics
3. to examine mechanisms of local anesthetic tachyphylaxis and inflammation-induced local
anesthetic failure
4. to understand differential blockade in animal models and in clinical practice
5. to describe PK-PD models relevant to local anesthetic action
6. to review efforts to design safer or longer-duration local anesthetics

CASE PRESENTATION

1. Introduction - Not a solved problem!
My aim in this refresher course is to convince clinicians, clinical researchers, basic
researchers, and translational researchers that local anesthetics and their mechanisms of action
are not solved problems, either from a clinical or research viewpoint. The main focus of the
lecture is not on local anesthetic mechanisms per se from a basic viewpoint, but rather on the
question how might better understanding of local anesthetic mechanisms improve our current
and future clinical uses of these agents for regional anesthesia and for regional and systemic
analgesia?.

2. Local Anesthetics are Extremely Useful
a. They are used widely as sole anesthetic agents, and as postoperative analgesics or
analgesics for labor and delivery. Local anesthetic-based analgesic approaches, both
neuraxial and peripheral, are essential components of a multimodal approach to
postoperative recovery that permits early mobilization and minimizes postoperative
disability [1 ] [2].
b. Systemically-administered local anesthetics are useful analgesics for many forms of
neuropathic pain. Systemic administration of lidocaine (via intravenous or subcutaneous
routes) and oral administration of mexiletine and other analogues relieves neuropathic
pain in some, but not all, patients. Remarkably, in some patients and in animal models,
the duration of pain relief far outlasts the duration of therapeutic drug concentrations in
plasma. [3] Multiple sites of action appear relevant to systemic lidocaines efficacy in
neuropathic pain [4]. In rats with experimental nerve injury, lidocaine suppressed ectopic
discharges in both dorsal root ganglia and at the peripheral sites of nerve injury at doses
lower than those which caused measurable changes in excitability in normal nerves. [5]
Lidocaine reduces c-fiber-evoked activity in the isolated rat spinal cord via reductions in
NMDA and neurokinin receptor-mediated post-synaptic depolarizations. [6] Mexiletines
clinical use is often limited by its high frequency of gastrointestinal and CNS side-effects.
Flecainide showed effectiveness in a trial of patients with postherpetic neuralgia[7].


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3. Current-Generation Local Anesthetics are not Optimized
a. Local anesthetic cardiotoxicity and CNS toxicity (especially seizures) continue to cause
cardiac arrests, neurologic injuries, and deaths on a regular basis. Epidemiologic
information on the incidence of each of these complications is remarkably sparse and
largely retrospective [8]. Pediatric data are available from two prospective studies of
regional anesthesia in France and other French-speaking countries [9] [10], and from a
report of a pediatric cardiac arrest registry. [11] We know even less about the frequency
of complications of local anesthetic administration by general physicians, dentists[12],
surgeons, emergency department physicians and others. Local anesthetic toxicity
appears to be a remarkably frequent cause of morbidity and mortality when used by the
tumescent technique in plastic surgical procedures, such as liposuction, particularly
when recommended doses are exceeded. Mortality estimates for liposuction have ranged
as high as 1:5,000 procedures [13].
b. There is an unmet need for longer duration local anesthetics (see below).
c. Local anesthetics produce concentration-dependent local tissue toxicity in nerves [14]
and muscles [15].
d. Available local anesthetics are not sufficiently selective for nocifensive, sensory,
autonomic, or motor blockade. True differential epidural block is not achievable by
currently available agents.
e. Local anesthetics frequently fail to provide analgesia in sites of infection or
inflammation. This is a substantial problem in dentistry in the setting of a tooth abscess
or severe pulpitis, failure rates of local anesthesia may exceed 70%. Recent evidence
from Cairns and coworkers in our department on roles of PK versus PD mechanisms in
inflammation-induced local anesthetic failure will be presented at the lecture.
f. Repeated administration can sometimes fail due to tachyphylaxis or rapidly-developed
tolerance. Tachyphylaxis may involve both PK [16]and PD [17-19] [20] mechanisms;
PD mechanisms appear to be more important clinically. Tachyphylaxis occurs more
commonly when there is hyperalgesia [17] and unrelieved pain [21] . Co-administration
of systemic or neuraxial opioids with local anesthetics in epidural infusions slows the
development of tachyphylaxis [22]. Studies from our lab in a rat model support the view
that tachyphylaxis can be mediated by sensitization of spinal neurons, and can be
prevented by blockade of spinal NMDA receptors or via blockade of NO synthase [17-
19].
g. Multiple factors reduce the safety margin for local anesthetics and regional anesthesia in
infants and younger children, compared with adults.

4. Local Anesthetics Have Multiple Actions Beyond Blockade of Sodium Channels and
Blockade of Impulse Propagation.
a. Blockade of calcium and potassium [23, 24]channels. Blockade of these other ion channels
may be important to explaining some of the differences among current-day local
anesthetics in their efficacy and toxicity, and may afford directions for targeting new
classes of local anesthetics in the future.
b. Impairment of axoplasmic transport
c. Impairment of leukocyte functioning

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d. Myocyte injury[15]

5. Local Anesthetic Uptake and Distribution into Nerve
Passage of drug from extraneural sites across tissue barriers into nerve is a major factor
limiting local anesthetic effectiveness. The highly simplified diagram in Figure 1 emphasizes the
fact that for local anesthetics, unlike most systemically acting drugs, uptake from the injection
site into the central circulation takes drug away from, rather than towards, the effect site, and
the central circulation is in parallel with, rather than in series with, the path from administration
site to effect site. Less than 1-2% of the injected dose in peripheral nerve blocks ever enters the
nerve. [25] Changes in local blood flow and permeability can dramatically modify local
anesthetic potency and duration of action.

Figure 1 Local Anesthetic Uptake and Clearance Differs from that of Systemic Drugs
a. Most Other Drugs












b. Local Anesthetics

>98% of dose




< 2% of dose







Injection or
absorption
site
Central
circulation
Effect site
Metabolism
and
elimination
Central
Circulation
Metabolism
and
elimination
Effect Site
Injection or
absorption
site

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6. Selected approaches to making a better local anesthetic
a. Use of single enantiomers, rather than racemic mixtures. Ropivacaine and levo-bupivacaine
were developed based on the finding of degrees of stereoselectivity in cardiotoxicity and
degrees of sensory versus motor blockade for these agents in preclinical studies. These
agents produce modest improvement in either sensory selectivity or therapeutic indices
(ratio of effective to toxic doses) compared to the racemic mixtures. The degree of
improvement in sensory selectivity has appeared variable in previous studies[26].
Ropivacaine may have up to a 1.5- 2-fold increase in therapeutic index compared with
bupivacaine in both infant and adult rats[27]. This difference may be clinically important
for infants, since the maximum safe infusion rate for epidural bupivacaine in neonates and
younger infants, roughly 0.2 mg/kg/hr[28], is probably insufficient as the sole agent to
provide epidural analgesia for a substantial fraction of neonates and younger infants, even
with optimal dermatomal placement.
b. Local anesthetics with rapid systemic clearance. Chloroprocaine is unique among available
agents for epidural use in that its clearance by plasma esterases is extremely rapid, even in
preterm neonates[29, 30]. The development of truly preservative-free formulations is a
significant improvement.
c. Sustained-release formulations. Peripheral nerve blocks are useful, but they generally
dont last long enough to influence the overall course of postoperative recovery. One
approach to prolonged-duration local anesthesia is to deliver local anesthetics using a
sustained-release system, such as liposomes[31, 32 ], microspheres [33-35] , or other types
of microparticles. Our group developed some formulations using bupivacaine, small
amounts of the anti-inflammatory steroid, dexamethasone, and a biodegradable polymer,
PLGA, much like that in some types of absorbable suture material[33-35]. Animal studies
showed excellent safety, in terms of very low plasma bupivacaine concentrations, and
nerve blockade lasting 2-7 days, depending on the species, dose, and site of administration.
Initial human studies also showed excellent promise. The commercial development has
stalled in Phase 2 studies, for a complicated series of reasons, but I remain optimistic that
this type of formulation can be effective for prolonged duration infiltration anesthesia for
surgery in the thorax and abdomen.
d. Old molecules previously used for other purposes. Two commonly used systemic drugs
appear promising as local anesthetics: amitriptyline [36] [37] (a tricyclic antidepressant
widely used orally for treatment of neuropathic pain), ketamine[38] (a well-known
sedative-analgesic-anesthetic agent which acts as an antagonist at NMDA receptors and
probably has several other sites of action). Recent animal studies suggest that both agents
produce conduction blockade in vivo, and appear to block sodium channels in vitro. It
remains to be determined whether they will afford clinically important improvements in
duration, safety or sensory selectivity.
e. Site 1 Sodium Channel Toxins Tetrodotoxin (TTX) and saxitoxin (STX) have long been
known to bind to a specific site on sodium channels, designated as site 1, and to have
extremely high potency in blocking some, but not all, sodium channels in isolated cell
bodies or axons. They were rejected as clinically useful local anesthetics because in early
studies there was severe systemic toxicity (diaphragm paralysis and vasodilation) at most
doses sufficient to produce conduction blockade of peripheral nerves. Recent studies by

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Kohane et al. in our group using combinations of site 1 toxins with either vasoconstrictors
or conventional local anesthetics suggest that these and other combinations may
sufficiently improve therapeutic indices to permit use as long-acting local anesthetics[39,
40].
f. Butamben Butamben is a formulation used to provide prolonged analgesia, especially for
patients with terminal malignancy. There remains some controversy about its mechanisms
of action, but it appears to have both aspects of a semi-controlled sustained release system
and actions as a neurolytic agent. [41]

g. New molecules that target sodium channel subtypes. There are a large number of different
sodium channel subtypes in different mammalian tissues. Several groups of investigators
used molecular biologic approaches to identify sodium channels which are expressed
predominantly in smaller sensory neurons[42-45] [46]. Some of these sodium channels,
(denoted as either SNS, PN or NaN subtypes in different publications), are relatively
resistant to blockade by TTX. Rodent models of inflammation and nerve injury have
produce some variability in results; in some studies expression of certain SNS channels is
increased by inflammation and decreased by painful nerve injury [44, 45] [46]. There has
been some drug development activity in targeting these sodium channel subtypes for
development of analgesics, but available information in this regard is too preliminary to
permit conclusions at present.

7. Conclusions
Local anesthetics are extremely useful, but their safety and effectiveness would be improved by
development of agents that produce less systemic and local toxicity, and by better ability to
control duration and to produce sensory-selective blockade.

General Reference
Berde CB and Strichartz GR Local Anesthetics in: Anesthesia, 5
th
edition, R.D. Miller, editor,
Churchill-Livingstone, Philadelphia, PA 2000, pp. 491-521.

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