LOCAL ANESTHETICS: AGENTS, ACTIONS AND MISCONCEPTIONS

LOCAL ANESTHETICS: AGENTS, ACTIONS AND MISCONCEPTIONS
John Butterworth, M.D. Indianapolis, Indiana

refresher course lectures 2001



Early History of Local Anesthesia
Local and regional anesthesia date from the
red-letter year 1884 when Koller reported topical
cocaine anesthesia of the eye and Halsted
injected cocaine under direct vision to produce
mandibular nerve and brachial plexus blocks.1-3
Nevertheless, both the stimulating and anesthetic
properties of cocaine were widely recognized the
Incas long before the compound made its way to
Europe where its effects could be “discovered.”
Cocaine was used to produce spinal and epidural
anesthesias by 1900. 4 Procaine and other less-toxic,
synthetic local anesthetics (LAs) were
soon developed.3
All LAs contain an aromatic ring and an
amine, separated by a hydrocarbon chain (Figure
1).2,3,5,6 There are two families of LAs, esters or
amides, named by the chemical link between the
aromatic moiety and the hydrocarbon chain.
Ropivacaine and levobupivacaine exist as single
(S-) enantiomers. Other LAs either exist as
racemates or have no asymmetric carbons.
Electrophysiology of Na Channels and LAs
LAs bind to voltage-gated Na channels. Na
channels are integral membrane proteins that
initiate and propagate action potentials in axons,
dendrites, and muscle tissue, initiate and
maintain membrane potential oscillations in
specialized heart and brain cells, and shape and
filter synaptic inputs. Na channels contain 1
larger á -subunit and 1 or 2 smaller â -subunits. The á -subunit, the site of ion conduction and LA binding,
has 4 homologous domains each having 6 á -helical, membrane-spanning segments.7,8
There are 10 human Na channel genes on 4 chromosomes. Defined genes contribute specific Na
channel forms to each of unmyelinated axons, nodes of Ranvier, and small dorsal root ganglion
nociceptors.9 Na channel mutations lead to muscle, cardiac, and neural diseases.10 During development,
Na channels cluster at nodes of Ranvier in myelinated axons. This nodal clustering is essential for high-speed
signal transmission.11
Na channels exists in at least 3 native conformations: “resting,” “open,” and “inactivated,” first
described by Hodgkin and Huxley.12 During an action potential, neuronal Na channels “open” briefly,
allowing extracellular Na ions to flow into the cell, depolarizing the plasma membrane. After only a few
milliseconds, Na channels “inactivate” (whereupon the Na current ceases). Na channels return to the
“resting” conformation with membrane repolarization. In mammalian myelinated fibers, membrane
repolarization requires no contribution from K currents.5,12 The process by which voltage-gated channels
gate may involve movements of paddle-shaped voltage sensors within the channel’s outer perimeter.13,14
Local anesthesia results when LAs bind Na channels and inhibit the Na permeability that underlies
action potentials in neurons.5,12 LA binding has been localized to the D4 S6 region of the á -subunit.15
Figure 1




Membrane potential influences both Na channel conformation and Na channel affinity for LAs. LA
inhibition of Na currents increases with repetitive depolarizations, often called “use-dependent” block.
Repetitive trains of depolarizations increase the likelihood that a LA will encounter a Na channel that is
“open" or "inactivated,” both of which forms have greater LA affinity than “resting” channels.5,12,16
Other types of chemicals will also bind and inhibit Na channels, including general anesthetics,
substance P inhibitors, á 2 agonists, tricyclic antidepressants, and nerve toxins.5,17-19 The latter two
chemical classes have undergone animal testing in the hope that they might be safer, more prolonged, or
more effective than conventional LAs.
LA Pharmacodynamics
In clinical use a LA may be described by its potency, duration of action, speed of onset and tendency
for differential sensory nerve block. These properties do not sort independently.
LA Potency and Duration
Nerve-blocking potency of LAs increases with increasing molecular weight and increasing lipid
solubility.20,21 Larger, more lipophilic LAs permeate nerve membranes more readily and bind Na
channels with greater affinity. More lipid-soluble LAs are relatively water-insoluble, highly protein-bound
in blood, less readily removed by the blood stream from nerve membranes, and more slowly
“washed out” from isolated nerves in vitro. Thus, increased lipid solubility associates with increased
protein binding in blood, increased potency, longer duration of action, and an increased tendency for
severe cardiac toxicity. Extent and duration of anesthesia can be correlated with LA content of nerves in
animal experiments.22-24
LA Speed of Onset
In general, the onset of anesthesia in isolated nerves slows with increasing LA lipid solubility. At
any pH, the percentage of LA molecules present in the uncharged form, largely responsible for
membrane permeability, decreases with increasing pKa.20,21 However, of the two LAs of fastest onset,
etidocaine is highly lipid soluble and chloroprocaine has a high pKa, minimizing the value of
generalizations about pKa and speed of onset.
Differential Sensory Nerve Block
Sensory anesthesia sufficient for skin incision usually cannot be obtained without motor
impairment.2,3,5 All LAs will block smaller diameter fibers at lower concentrations than are required to
block larger fibers of the same type.25 Bupivacaine and ropivacaine are relatively selective for sensory
fibers. Bupivacaine produces more rapid onset of sensory than motor block whereas the closely related
chemical mepivacaine demonstrates no differential onset during regional nerve blocks.26 Specific Na
channel gene products are found in unmyelinated nerves, motor nerves, and dorsal root ganglia, offering
the tantalizing possibility that specific antagonists may some day be produced for these specific Na
channel forms.27,28
Other Factors Influencing LA Activity
Many factors influence the ability of a given LA to produce adequate regional anesthesia, including
the dose, site of administration, additives, temperature, and pregnancy. As the LA dose increases, the
likelihood of success and the duration of anesthesia increase, while the delay of onset and tendency for
differential block decrease. In general, the fastest onset and shortest duration of anesthesia occur with
spinal or subcutaneous injections; a slow onset and long duration are obtained with plexus blocks.29
Epinephrine is frequently added to LA solutions to cause vasoconstriction and to serve as a marker for
intravascular injection.3,6 Epinephrine increases LA duration largely by prolonging and increasing intra-

neural concentrations of LAs.23 Other popular LA
additives include clonidine, NaHCO3, opioids, and
hyaluronidase.
LAs have greater apparent potency at basic pH,
where an increased fraction of LA molecules are
uncharged, than at more acidic pH (Figure 2).30
Uncharged LA bases diffuse across nerve sheaths
and membranes more readily than charged LAs,
hastening onset of anesthesia. Not surprisingly,
some clinical studies show that the addition of
sodium bicarbonate to LAs speeds the onset of
nerve blocks.3,6 Curiously, once LAs gain access to
the cytoplasmic side of the Na channel, H + ions
potentiate use-dependent block.5,12 Spread of
neuraxial anesthesia likely increases during
pregnancy due to decreases in thoraco-lumbar CSF
volume and an increased neural susceptibility to
LAs.31,32
Many texts and review articles persist in
referring to “maximal” doses of LAs. Nevertheless,
the maximal tolerable dose depends on many
factors, including the site of administration, the
presence of absence of such additives as clonidine
or epinephrine, patient characteristics (such as body
habitus), pregnancy, and the presence of certain diseases. The maximal tolerable dose is infnitessimally
small when given into the vertebral artery! With the same LA dose, intercostal blocks consistently
produce greater peak LA concentrations than plexus or epidural blocks.3,6,29,33 Thus it is illogical to speak
of one maximal “safe” dose of LA.34
LA Blood Concentrations, Protein Binding, Metabolism, and Pharmacokinetics
In blood, all LAs are partially protein-bound, primarily to á 1-acid glycoprotein (AGP) and
secondarily to albumin.2,3,6 Affinity for AGP correlates with LA hydrophobicity and decreases with
protonation.35 Extent of protein binding is influenced by the concentration of AGP. Both protein binding
and protein concentration decline during pregnancy.36 During longer-term infusion of LA and LA-opioid
combinations concentrations of serum binding proteins progressively increase.37 There is considerable
first-pass uptake of LAs by lung.38
Esters undergo rapid hydrolysis in blood, catalyzed by pseudocholinesterase.2,3,6 Procaine and
benzocaine are metabolized to para-aminobenzoic acid (PABA), the species underlying anaphylaxis to
these agents.3 The amides undergo metabolism in the liver. Lidocaine undergoes oxidative N-dealkylation
(by cytochrome P450IIIA4).2,3,6 Prilocaine is hydroxylized to o-toluidine, which (directly or
indirectly through hydroxylation products) causes methemoglobinemia.3,21 Amide LA clearance is highly
dependent on hepatic blood flow, hepatic extraction, and enzyme function, and is reduced by factors
which decrease hepatic blood flow, such as â -adrenergic receptor or H2-receptor blockers, and by heart
or liver failure.2,3,6
Toxic Side Effects of LAs
Aside from Na channels, LAs will bind many other targets, including voltage-gated K and Ca
channels, KATP channels, enzymes, NMDA receptors, â -adrenergic receptors, G-protein-mediated
Figure 2. Effect of pH on potency
of procaine in isolated nerves
(from reference 32).

modulation of K and Ca channels, and nicotinic acetylcholine receptors.5,39,40 LA binding to these other
sites could underlie LA production of spinal or epidural analgesia, and could contribute to toxic side
effects.5,12,41 And, it is a mistake to assume that all adverse LA effects are the result of binding to Na
channels.
Central Nervous System (CNS) Side Effects
LA CNS toxicity results from inhibition of excitatory pathways in the CNS, producing a
stereotypical sequence of signs and symptoms.2,3,6,29 As the LA dose increases, seizures may arise in the
amygdala.2,3 With further LA dosing, CNS excitation progresses to CNS depression, and eventual
respiratory arrest. More potent LAs produce seizures at lower blood concentrations and lower doses than
less potent LAs. Both metabolic and respiratory acidosis decrease the convulsive dose.42
Cardiovascular (CV) Toxicity
LAs bind and inhibit cardiac Na channels.2,12 Bupivacaine binds more avidly and longer than
lidocaine to cardiac Na channels.43 Certain R(+) isomers bind cardiac Na channels more avidly than S(-)
isomers. This led to the development of levobupivacaine and ropivacaine. LAs inhibit conduction in the
heart with the same rank order of potency as for nerve block.44,45 LAs produce dose-dependent
myocardial depression, possibly from interference with Ca signaling mechanisms within cardiac
muscle.44 In the heart, LAs bind and inhibit Ca and K channels at concentrations greater than those at
which binding to Na channels is maximal.5,12,46 LAs bind â -adrenergic receptors and inhibit epinephrine-stimulated
cyclic AMP formation, either of which could underlie the refractoriness of bupivacaine CV
toxicity to standard resuscitation measures.47,48
In animals, most LAs will not produce CV toxicity until the blood concentration exceeds 3 times that
which produces seizures; however, there are clinical reports of simultaneous CNS and CV toxicity with
bupivacaine.2,3,6 In dogs, supraconvulsant doses of bupivacaine more commonly produce arrhythmias
than supraconvulsant doses of ropivacaine or lidocaine.49 LAs produce CV signs of CNS excitation
(increased heart rate, arterial blood pressure, and cardiac output) at lower concentrations than those
associated with cardiac depression.
In rats, the rank order for cardiac toxicity appears to be bupivacaine > levobupivacaine >
ropivacaine.50-52 In dogs, both programmed electrical stimulation and epinephrine resuscitation elicited
more arrhythmias with bupivacaine and levobupivacaine than with lidocaine or ropivacaine.53-55 When
LAs were given to the point of extreme hypotension, dogs receiving lidocaine could be resuscitated, but
required continuing infusion of epinephrine to counteract LA-induced myocardial depression.
Conversely, many dogs receiving bupivacaine or levobupivacaine to the point of extreme hypotension
could not be resuscitated. After bupivacaine, levobupivacaine, or ropivacaine, dogs that could be
defibrillated often required no additional therapy.53-55 Studies in pigs also show that bupivacaine may
have a greater propensity than lidocaine for arrhythmogenesis. The ratio of potency (lidocaine:
bupivacaine) for myocardial depression was 1:4; whereas that for arrhythmogenesis was 1:16. 56 A
common clinical question is whether all LA cardiovascular toxicity arises from the same mechanism.
Given that the potent LAs (such as bupivacaine) seem much more prone to arrhythmogenesis than less
potent agents (such as lidocaine), it seems likely that the mechanism of cardiovascular toxicity depends
on which LA has been administered.
Neurotoxic Effects of LAs
During the 1980s, 2-chloroprocaine (formulated with Na metabisulfite at an acidic pH) occasionally
produced cauda equina syndrome after accidental intrathecal injection of large doses.3,5,57-59 Reports of
neurotoxicity virtually disappeared when the compound was reformulated, but have now returned
following the introduction of generic products containing the original metabisulfite and pH.59 Whether
the toxin is 2-chloroprocaine or metabisulfite remains unsettled: 2-chloroprocaine is now being tested as

a substitute for lidocaine in human spinal anesthesia.60 At the same time, other investigators have linked
neurotoxic reactions to the LA rather than to metabisulfite.61 Presently, there is controversy about
transient neurologic symptoms and persisting sacral deficits after lidocaine spinal anesthesia. Unlike
other spinal LA solutions, lidocaine 5% permanently interrupts conduction when applied to isolated
nerves or to isolated neurons.62 This may be the result of lidocaine-induced increases in intracellular
calcium, and does not appear to involve Na channel blockade.63
Treatment of LA Toxicity
Treatment of adverse LA reactions depends on their severity. Minor reactions can be allowed to
terminate spontaneously. LA-induced seizures should be managed by maintaining the airway and
providing oxygen. Seizures may be terminated with intravenous thiopental (1-2 mg/kg), midazolam
(0.05-0.10 mg/kg), or propofol (0.5-1.5 mg/kg).3 If LA intoxication produces CV depression,
hypotension may be treated by infusion of intravenous fluids and vasopressors (phenylephrine 0.5-5
ì g/kg/min, norepinephrine 0.02-0.2 ì g/kg/min, or vasopressin 2-20 units IV). If myocardial failure is
present, epinephrine (1-15 ì g/kg IV bolus) may be required. When toxicity progresses to cardiac arrest,
the guidelines for Advanced Cardiac Life Support are reasonable;64 however, I suggest that amiodarone
and vasopressin be substituted for lidocaine and epinephrine, respectively.65-67 With unresponsive
bupivacaine cardiac toxicity, intravenous lipid or cardiopulmonary bypass should be considered.68
Recent animal experiments demonstrate the remarkable ability of lipid infusion to resuscitate animals
from bupivacaine over dosage, even after 10 min of unsuccessful "conventional" resuscitative efforts.69-71
Summary
After 120 years of medical use, LAs remain versatile and important tools for the physician. Some
features of local anesthesia are well understood. Peripheral nerve blocks are almost certainly the result of
LA inhibition of Na channels in neuronal membranes. Conversely, the mechanisms of spinal and
epidural anesthesia remain poorly defined. The mechanisms by which LAs produce CV toxicity likely
vary with the more potent agents (e.g., bupivacaine) producing arrhythmias through (likely) a Na channel
action, and with the less potent agents (e.g., lidocaine) producing myocardial depression via other
pathways.