Local Anesthetics

Local anesthetics are drugs that produce reversible conduc- sa lts. These hydrochloride salt solutions are acidic (pH 6),
tion blockade of impulses along centra l and peripheral contrib uting to the stability of the loca l anesth etic. An
nerve pathways after regional anesthesia. With progressive acidic pH is also important if epinephrine is present in the
increases in concentrations of local anesthetics, the trans- local anesthetic solution, because this catecho lamin e is
mission of autonomic, somatic sensory, and somatic unstable at an alka line pH. Sodium bisulfite, which is
motor impulses is interrupted, producing autonomic ner- strongly acidic, may be added to commercially prepared
vous system blockade, sensory anesthesia, and ske leta l local anesthetic-epinephrine solutions (pH 4) to prevent
muscle paralysis in the area innervated by the affected oxidative decomposition of epinephrine.
I nerve. Removal of the local anesthetic is followed by spon-
taneous and complete return of nerve conduction, with no
Liposomal Local Anesthetics
evidence of structural damage to nerve fibers as a result of
the drug's effects. Drugs such as lid ocaine, tetracaine, and bupivacaine have
Cocaine was introduced as the first local anesthetic in been incorporated into lip osomes to prolong the dura-
1884, by Kollar, for use in ophthalmology. Halsted recog- tion of action and decrease toxicity (Mowat et a!., 1996).
nized the ability of injected cocaine to interrupt nerve Liposomes are vesicles consisting of bilayers of phospho-
impulse conduction, leading to the introduction of periph- lipid surrounding an aqueous phase. The phospholipid
era l nerve block anesthesia and spinal anesthesia. As an can act as a barrier to drug diffusion from the liposome,
ester of benzoic acid, cocaine is present in large amounts in effectively providing a slow-release preparation with a
the leaves of Erythroxylon coca, a plant growing in the Andes prolonged duration of action (Duncan and Wildsmith,
mountains, where its cerebral-stimulating qualities are 1995). Extended-duration local anesthetics could have
well known. Another unique feature of cocaine is its abi lity clinical use for prolonged postoperative analgesia and
to produce localized vasoconstriction, making it useful to treatment of chron ic pain when infiltrated or app li ed top-
shrink the nasal mucosa in rhinolaryngologic procedures ically. Unlike systemic ana lgesics, lo ca l anesthetics reli-
and nasotracheal intubation. The abuse potential of ab ly relieve pain without associated systemic side effects
cocaine limits its legitimate medical uses, whereas irritant characteristic of opioids. Bupivacaine incorporated into
properties of cocaine preclude its use for topical anesthesia biodegradable microcapsules provided analgesia for 96
of the cornea or any form of injection to produce anesthe- hours after subcutaneous infiltration (Pedersen et aI. ,
sia (see the section on Cocaine Toxicity). 2004) .
The first synthetic local anesthetic was the ester deriva-
tive procaine, introduced by Einhorn in 1905. Lidocaine
Alkalinization of Local Anesthetic Solutions
was synthesized as an amide local anesthetic by Lofgren in
1943. It produces more rapid, intense, and longer- lasting Alka linization of local anesthetic solutions shortens the
conduction blockade than procaine. Unlike procaine, lido- onset of neural blockade, enhances the depth of sensory
caine is effective topically and is a highly efficacious car- and motor blockade, and increases the spread of epidural
diac antidysrhythmic drug. For these reasons, lidocaine is blockade (Curatolo et aI., 1998) . The pH of commercial
the standard to which all other anesthetics are compared. preparations of local anesthetic solutions ranges from 3.9 to
6.5 and is especially acidic if prepackaged with epineph-
rine (increased acidity prolongs the shelf life of epineph-
COMMERCIAL PREPARATIONS rine). The pKa of local anesthetics used clinically is near 8,
so that on ly a small fraction (about 3%) of the local
Local anesthetics are poorly soluble in water and therefore anesthetic exists in the lipid-soluble form. Alkalinization
are marketed most often as water-solub le hydrochloride increases the percentage of loca l anesthetic existing in the
180 Section I: Pharmacology

lipid-soluble form that is avai lable to diffuse across lipid

cellular barriers. Adding sodium bicarbonate will speed the
onset of peripheral nerve block and epidural block by 3 to
5 minutes. Procaine

H3 CO, /p
STRUCTURE-ACTIVITY RELATIONSHIPS HC' NV- 0
g 4
~ ~ C 'r-7<..N-CH 3
H/ '" I ~OCH CH N / CH3 0-co~
2 2 ' CH
3
H
Local anesthetics consist of a lipophilic and a hydrophilic Tetracaine Cocaine
portion separated by a connecting hydrocarbon chain

~NH8 -(~~3
(Fig. 7-1). The hydrophi lic group is usually a tertiary
amine, such as diethylamine, whereas the lipophili c por-
tion is usually an unsaturated aromatic ring, such as VCH3 V
Mepivacaine
paraaminobenzoic acid . The lipophilic portion is essen-
tial for anesthetic activity, and therapeutically useful
local anesthetics require a delicate balance between lipid
solubility and water so lub ility. In almost all instances, an
ester (-CO-) or an amide (-NHC-) bond lin ks the Bupivacaine
hydrocarbon chain to the lipop hilic aromatic ring. The
nature of this bond is the basis for classifying drugs that
produce conduction blockade of nerve impulses as ester
local anesthetics or amide local anesthetics (Fig. 7-2).
The important differences between ester and amide local
anesthetics relate to the site of metabolism and the Prilocaine
potential to produce allergic reactions.
Figure 7-2. Ester and amide local anesthetics. Mepivacaine,
bupivacaine, and ropivacaine are chiral drugs because the mole-
cules possess an asymmetric carbon atom.
Modification of Chemical Structure
Modifying the chemica l structure of a loca l anesthetic
alters its pharmacologic effects. For examp le, lengthening hydrolysis rate of ch loroprocaine limits the duration of
the connecting hydrocarbon chain or increasing the action and system ic toxicity of this loca l anesthetic.
number of carbon atoms on the tertiary amine or aro- Etidocaine resem bl es lidocaine, but substituting a propyl
matic ring often results in a loca l anesthetic with a differ- gro up for an ethyl group at the amine end and add ing an
ent lipid so lubility, pote ncy, rate of metabolism, and ethyl group o n the alpha carbon of the connecting
duration of action (Table 7-1). Indeed, substitutin g a hydrocarbon chain produces a 50-fold increase in lipid
butyl group for the amine group on the benzene ring of so lubility and a two- to threefold increase in the dura-
procaine results in tetracaine. Compared with procaine, tion of action.
tetracaine is more lipid so lubl e, is ten times more potent, Mep ivaca in e, bupivacaine, and ropivacaine are charac-
and has a longer duration of action corresponding to a terized as pipecoloxylidides (see Fig. 7-2). Mepivacaine h as
four- to fivefold decrease in the rate of metabolism. a methyl group on the piperidine nitrogen atom (amine
Halogenation of procaine to chloroprocaine results in a end) of the molecule. Addition of a butyl group to the
three- to fourfold in crease in the hydrolysis rate of piperidine nitrogen of mepivacaine results in bupivacaine,
ch lo roprocaine by plasma cholin esterase. This rapid which is 35 times more lipid soluble and has a potency
and duration of action three to four times that of mepiva-
caine. Ropivacaine structurally resembles bupivacaine and
mepivacaine, with a propyl group on the piperidine nitro-
gen atom of the molecule.

Racemic Mixtures or Pure Isomers

Lipophilic Hydrocarbon Hydrophilic The pipecoloxylidide local anesthetics (mepivacaine,

Chain bupivacaine, ropivacaine, levobupivacaine) are ch ira l
drugs because their molecules possess an asymmetric
Figure 7-1. Local anesthetics consist of a lipophilic and carbon atom (see Fig. 7-2). As such, these drugs may
hydrophilic portion separated by a connecting hydrocarbon chain. have a left- (S) or right- (R) handed configuration .
 Chapter 7: Local Anesthetics 181

TABLE 7-1.
COMPARATIVE PHARMACOLOGY OF LOCAL ANESTHETICS
Duration after Maximum Single Toxic Plasma
Infiltration Dose for Concentration Protein
Classification Potency Onset (mins) Infiltration (mg) (~g/ml) pK Binding (%)

Esters
Procaine 1 Slow 45-60 500 8.9 6
Chloroprocaine 4 Rapid 30-45 600 8.7
Tetraca ine 16 Slow 60-180 100 (topical) 8.5 76
Amides
Lidoca ine Rapid 60-120 300 >5 7.9 70
Etidocaine 4 Slow 240-480 300 - 2 7.7 94
Prilocaine Slow 60-120 400 >5 7.9 55
Mepivacaine 1 Slow 90-180 300 >5 7.6 77
Bupivacaine 4 Slow 240-480 175 >3 8.1 95
, Levobupivacaine 4 Slow 240-480 175 8.1 > 97
Ropivacaine 4 Slow 240-480 200 >4 8.1 94

Fraction Fraction Fraction Volume of Elimination

Nonionized Nonionized Nonionized Lipid Distribution Clearance Half-Time
Classification (%) at pH 7.2 (%) at pH 7.4 (%) at pH 7.6 Solubility (liters) (liters/min) (mins)

Esters
~ 65 9
Procaine 2 3 5 0.6
Chloroprocaine 3 5 7 35 7
Tetracaine 5 7 11 80
Amides
Lidocaine 17 25 33 2.9 91 0 .95 96
Etidocaine 24 33 44 141 133 1.22 156
Prilocaine 17 24 33 0.9 191 96
Mepivacaine 28 39 50 1 84 9.78 114
Bupivacaine 11 17 24 28 73 0.47 210
Levobupivacai ne 11 17 24 55 156
Ropivacaine 17 59 0.44 108

Adapted from Denson DD. Physiology and pharmacology of local anesthetics. In: Sinatra RS, Herd AH, Ginsberg
B, Preble LM (eds): Acute pain. Mechanisms and management. St Louis, Mosby Year Book, 1992:124; and
Burm AG, van der Meer AD, va n Kleef JW, et al. Pharmacokinetics of the enantiom ers of bupivacaine following
intravenous administration of the racemate. Br J Clin Pharmaco/1994; 38: 125-129.

Mepivacaine and bupivaca in e are available for clinical decreased potency at sodium ion channels (Vladimirov
use as racem ic mixtures (50:50 mixtu re) of the enan- et al., 2000) .
tiomers. The enantiomers of a chira l drug m ay vary in
their pharmacokinetics, pharmacodynamics, and toxic-
ity. Administering a racemic drug mi xture is, in reality, MECHANISM OF ACTION
the administration of two different drugs ( Ehrlich,
1992). These differences in pharmacologic activity refl ect Local anesthetics prevent transmission of nerve impulses
the fact that individual enantiomers bind to recepto rs or (conduction blod<ade) by inhibiting passage of sodium ions
enzymes that are chiral amino acids with stereoselective through ion-selective sodium channels in nerve membranes
properties. The S enantiom ers of bupivacaine and mepi- (Butterworth and Strichartz, 1990). The sodium channel
vacai ne appea r to be less toxic than the commercially itself is a specific receptor for local anesthetic molecules.
available race mic mixtures of these local anesthetics Ocdusion of open sodium channels by local anesthetic mol-
(Burm et aI., 1997) . In contrast to m epivacaine and bupi- ecules contributes little to overall inhibition of sodium per-
vacaine, ropivacaine and levo bupivacai ne have bee n meab ility. Failure of sodium ion channel permeab ility to
developed as a pure S enantiomers (McClure, 1996). ina-ease slows tll e rate of depolalization SUdl that threshold
These S enantiomers are considered to produce less neu - potential is not reached and thus an action potential is not
rotoxicity and cardiotoxicity than race mic mixtures or propagated (Fig. 7-3). Local anesthetics do not alter the rest-
th e R enantiomers of local anesthetics, perhaps refl ecting ing transmembrane potential or threshold potential.
182 Section I: Pharmacology

30 time sodium chan n els open during an action potential

> ( frequency-dependent b lockade). Therefore, local anes-
.s thetic molecules can gain access to receptors only when
]Q 0
c
Ol
sodium cl1annels are in activated-open states. For this rea-
'0 so n, selective conduction blockade of nerve fibers by local
c-
Ol -30 anesthetics may be related to the nerve's characteristic fre-
c:
~ quencies of activity as well as to its anatomic properties,
.D
E
Q)
such as diameter. Indeed, a resting nerve is less sensitive to
E -60
en
loca l anesthetic-ind uced conduction blockade than is a
c: Threshold Potential
nerve that has been repetitively stimulated. Etidoca ine
~ cha racteristically blocks motor n erves before sensory
-90 nerves because of frequency-dependent blockade (Bromage
Local Anesthetic et aI., 1974) . The pharmacologic effects of other drugs,
Figure 7-3 . . Local an~sthetics slow the rate of depolarization of including anticonvulsants and barbiturates in addition to
the nerve action potentia l such that the threshold potential is not loca l anesthetics, may reflect frequency-dependent blockade.
reached. As a result, an act ion potential cannot be propagated in
the presence of local anest hetic, and conduction blockade resu lts.
Other Site of Action Targets
Sodium Channels In addition to sodium ion channels, local anesthetics block
The sodium channel consists of the large sodium-conducting vo ltage-dependent potassium ion channels. Compared
pore (alpha-subunit) and valying numbers of adjacent with sodium ion channels, local anesthetics exhibit a
smaller beta subunits. The large polypeptide that forms the mucl1 lower affi ni ty. However, blocl<ade of potassium ion
alpha-subunit is further divided into four subunits (Dl-IV). channels might exp lain broadening of the action potential
H is the alpha subunit that all ows ion conduction and in the presence of local anesthetics. Considering the stmc-
binds to local anesthetics. However, beta subunits may mod- tural simi larity between vo ltage-dependent calcium ion
ulate loca l anesthetic binding to the alpha subunit. Bindi ng chan nels and sodium ion cl1annels, it is not surprising that
affinities of local anesthetics to the sodium ion channels are calcium ion currents (L-type most sensitive) may also be
stereospecific and depend on the conformation al state of blocked by local anesthetics (Sugiyama and Muteki, 1994) .
the sodium channel (Lee-Son et aI., 1992). Sod ium chan- Although local anesthetics are cons idered principally ion
nels exist in activated-open, inactivated-closed, and rested- ch annel blockers, there is evidence these dmgs may also act
closed states during various phases of the action potential. on G-protein coup led receptors (Hollmann et aI., 2001a).
[n the resting nerve membrane, sodium channels are distrib-
uted in equilibrium between the rested-closed and inacti-
vated-closed states. By selectively binding to sodium chan- MINIMUM CONCENTRATION
nels in inactivated-closed states, local anesthetic molecules
stabi lize these cl1annels in this configuration and prevent The minimum concentration of loca l anesthetic necessary
their cl1ange to the rested-closed and activated-open states to produce conduction blockade of nerve impulses is
in response to nerve impulses. Sod ium cl1annels in the inac- termed the On. The Cm is analogous to the minimum
tivated-closed state are not permeable to sodium, and thus alveolar concentration (MAC) for inhaled anesthetics.
conduction of nerve impulses in the form of propagated Nerve fiber diameter influences Cm, with larger nerve
action potentials cannot occur. It is speculated that loca l fibers requiring hi gher co ncentrations of loca l anesthetic
anesthetics bind to specific sites located on the inner por- for production of conduction blockade. An increased tissue
tion of sodium channels (intemal gate or H gate) as well as pH or high frequency of nerve stimulation decreases Cm.
obsuucting sodium channels near their extemal openings to Each local anesthetic has a unique Cm, reflecting differ-
maintain these channels in inactivated-closed states ing potencies of each dmg. The Cm of motor fibers is
(Butterworth and Strichartz, 1990). This binding appears to approximately twice that of sensory fibers; thus, sensory
be weak and to reflect a relatively poor fit of the local anes- anesthesia may not always b e accompanied by skeletal
thetic molecule with the receptor. This is consistent with the muscle paralysis. Despite an unchanged Cm, less local
broad variety of cl1emical structures that exhibit local anes- anesthetic is needed for subarachnoid anesthesia than for
thetic activity on sodium channels (Lee-Son et al., 1992). ep idural anesthesia, reflecting greater access of local anes-
thetics to unprotected nelves in the subarachnoid space.
Peripheral nerves are comprised of myelinated A and B
Frequency-Dependent Blockade
fibers and unmyelinated C fibers (see Chapter 41). A mini-
Sodium ion channels tend to recover from local anesthetic- mal length of myelinated nerve fiber must be exposed to an
induced conduction blockade between action potentials adequate concentration of local anesthetic for conduction
and to develop additional conduction blockade each blockade of nerve impulses to occur. For example, if only
 Chapte r 7: Loca l Anesthetics 183

one node of Ranvier is b locked (site of change in sodium Intrinsic vasod ilator activity will also influence appar-
permeability), the nerve impulse can jump (skip) across this ent potency and duration of action. For example, th e
node and conduction blod<ade does not occur. For conduc- enhanced vasodilator action of lidocaine compared with
tion bl od<ade to occur in an A fib er, it is necessalY to expose m epivaca in e res ults in th e greater systemic absorption and
at least two and preferably three successive nodes of Ranvier shorter duration of action of lidocaine. Bupivacaine and
(approximately 1 cm) to an adequate concenu'ation of local etidocaine produce similar vasodi lation, but plasma con-
anesthetic. Both ty pes of pain-conducting fibers (myelinated centrations of bupivacain e after epidural placement exceed
A-delta and nonmyelinated C fibers) are b locked by similar those of etidocaine. Presumably, the greater lipid solubility
concentrations of loca l anesthetics, despite the differences in of etidocaine results in tissue sequestration and less avail-
the diameters of these fibers . Preganglionic B fibers are more able drug for systemic absorption. Occasional prolonged
readi ly blocked by local anesthetics than any fib er, even sensOlY blockade after injection of e tidocaine h as been
though these fib ers are myelinated . attributed to tissue sequestration.

Differential Conduction Blockade Absorption and Distribution

Differential conduction blockade is illustrated by selective Absorption of a local anesthetic from its site of inj ection
blockad e of prega n glionic sympathetic n ervous system B into the systemic circulation is influenced by th e site of
fibers using low concentrations of lo ca l an es th etics. inj ection and dosage, use of epinephrine, and pharmaco-
Slightly higher concentrations of local an es thetics interrupt logic characteristics of the drug (Fig. 7-4) (Covino and
conduction in sm all C fibers and small- and medium-sized Vassa ll o, 1976) . The ultimate p lasma concentration of a
A fibers, with loss of sensation for pain and temperature. local anesthetic is determin ed by the rate of tissue distribu-
Nevertheless, touch, proprioception , and motor function tion and the rate of dearan ce of the drug. For example, the
are still present such that th e patient will sense press ure infus ion of lidocaine for 1 minute is followed by a rapid
but not pain with surgical stimulation. In an anxious
decrease in th e drug's plasma concentration that is paral-
patient, however, any sensation may b e misinterpreted as
leled by an initial high uptake into the lungs and distribu-
failure of the local a nesthetic.
tion of the lo ca l anesthetic to highl y perfused tissues

Changes during Pregnancy

In creased sens itivity (more rapid onset of conduction
blockad e) may b e present during pregnan cy (Datta et aL, Intercostal
, ,
1983). Alterations in prote in-binding ch aracteristi cs of Caudal
bupivaca ine may result in increased co n centrations of
Mepivacaine
500 mg Epidural
,
pharmacologically active unbound drug in the parturient's Brachial Plexus ,
plasma (Denson et a I., 1984). Nevertheless, progestero ne, Sciatic Femoral ,
which binds to th e same alphal-acid glycoprotein as bup i-
vaca ine, does not influence protein binding of this local Intercostal
, I
anesthetic (D enson et al., 1984). This evid ence suggests Lidocaine Epidural
that bupivacaine and progeste rone bind to discre te but 400 mg J Brachial Plexus
separate sites on protein mol ecules. , Sciatic Femoral

Pri locaine
Intercostal ,
PHARMACOKINETICS I
400 mg Caudal ,
Epidural
Local anesthetics are weak bases that have pI( values some-
what above physio logic pH (see Table 7-1) . As a result, Intercostal ,
<50% of the local anesthetic exists in a lipid-solub le non- Etidocaine Caudal'
ionized form at physiologic pH. For example, at pH 7.4, only 300 mg ~IEPidural
5% ofteu'acaine exists in a nonionized form . Acidosis in the Brachial Plexus
enviro nment into whid1 th e loca l anesthetic is injected (as is
present with tissue infection) further increases the ionized I I I I
fraction of drug. This is consistent with th e poor quality of 2 4 6 8
local anesthesia that often results when a local anesthetic is Blood Levels (ug/ml)
inj ected into an aci dic infected area . Local anesthetics with Figure 7-4 . Peak p lasma concentratio ns of loca l anest hetic are
pKs n earest to physiologic pH have the most rapid onset of influenced by the site of injection fo r accomp lishment of regiona l
anesthesia. (From Covi no BG, Vassa ll o HL. Local anesthetics:
action, reflectin g th e presence of an optimal ratio of ionized
mechanisms of action and clinical use. New York: Grune & Stratton,
to non ionized drug fraction (see Table 7-1). 1976; with permission.)
184 Section I: Pharmacology

100 100

80 80

OJ
Q) ::>

0
(J)
0 0 Bupivacaine
60 "0 60
"C c
.S! ::>
0 0
co
.~ 0
E
Q)
Q)
OJ
e
Q)
40
<1l
C 40
a.. Q) Mepivacaine
~
Q)
0..
Lidocaine

20 20

o
2 4 8 16 32 64 128 256 o 4 8 12 16 20
T ime (minutes ) Total Drug Concentration (l1g/ml- ' )

Figure 7-5. Perfusion model for the distribution of lidocaine in Figure 7-6. The percent age of local anesthetic bound to pro-
various tissues and its elimination after an intravenous infusion for tein is inversely re lated to the plasm a concentration of drug . (From
1 minute. (RET, rapidly equilibrating [highly perfused] tissues .) Tucker GT, Boyes RN , Bridenbaugh PO, et al. Binding of anilide-
(From Benowitz N, Forsyth RP, Melmon KL, et al. Lidocaine disposi- t ype local anesthetics in human p lasma : I. Rel ationships between
tion kinet ics in monkey and man . I: Prediction by a perfusion binding , physiochemical properties, and anestheti c activity.
model. elin Pharmacol Ther 1974;16: 87-92; with permission.) Anesthesiology 1970;33 :287-293; with permission .)

(b ra in , hea rt, and kidn eys ) (Fig. 7-5 ) (Be nowitz et aI. , (lOl'feldt et al., 1980). After rapid entry of local anesth etics
19 74). Lipid solubili ty of the local anesthetic is imp0l1ant into the venous circul ation, this pulmonalY extraction will
in this redistribution, as well as being a prim ary determi- limit the co ncentratio n of drug that reaches th e systemic ci r-
nant of intrinsic local anesth etic potency. After distributio n cul atio n for distribution to the coro nary and cerebral circula-
to highly perfused tissues, th e local anesthetic is redistrib- tio ns. For bupivacaine, this first-pass pulm onary extraction is
uted to less well perfused tissues, including skeletal muscl es dose dependent, suggesting that the uptake process beco mes
and fa t. Considerati o n of ca rdiac o utput is important fo r saturated ra pidly (Rothstein et aI. , 1984) . Proprano lol
describing th e overall tissue distributi o n of local anesthet- impairs bupivaca ine extraction by the lungs, perhaps refl ect-
ics a nd pres umably th e ir intercomp artmental clea ra nce ing a comm o n receptor site for th e two drugs (Rothstein and
(Kuipers et a I., 2001) . Ultima tely, th e loca l a nesth eti c is Pitt, 1983 ) . Furth ermo re, propranolol decreases plas m a
elimin ated fro m the p lasma by metabo lism and excretio n . cl ea rance of lidocaine and bupivacaine, presumably refl ect-
In addition to the tissue blood flow and lipid solubili ty ing propranol o l-induced decreases in h epatic blood fl ow o r
of the local anesthetic. pati ent-related facto rs such as age, inhibition of hepatic metabolism (Bowdle et al., 1987 ).
cardiovascular status, and hepatic fu nction will also influ-
ence the absorption and resultant pl asma concentratio ns of Placental Transfer
local a nestheti cs. Protein binding o f local anesthetics will
influence th eir distributi o n and excretion . In this regard, There m ay be clinically significant transpl acental transfer
protein binding parallels lipid solubil ity of the local anes- of local an esth eti cs between th e m other and fetus. Plasma
thetic and is inversely related to the pl asma co ncentrati on of protein binding influences the rate and degree of diffusion
drug (see Table 7-1) (Fig. 7-6) (Tucker et aI., 1970). Overall, of local an es thetics across the pl acenta (see Tabl e 7-1) .
after systemic absorptio n, amide local anesthetics are more Bupivaca in e, w hich is highly p rot ein bo und (ap proxi-
widely distributed in tissues than ester local anesthetics. mately 95%), has an umbilical ve in-maternal arterial co n-
centration ratio of ab o ut 0 .3 2 co mpared with a rati o of
0.73 for lid oca ine (ap proxim ately 70% protein b o und)
Lung Extraction
and a ratio of 0 .85 fo r prilocaine (approxi mately 55% pro-
Th e lungs are capable of extracting local anesthetics such as tein bound) (Thomas et aI. , 19 76 ) . Ester local anestheti cs,
lidocaine, bupivacaine, and prilocaine fro m the circulatio n because of their rapid hydrolysis, are n ot available to cross
 Cha pter 7: Local An esthetics 185

Fetus Fetus NaHC03

Normal Fetus Acidemia Correction
pH 7.30-7.35 pH 6.90-7 .18 pH 7.22-7.40
__ Continuous Maternal Lidocaine Infusion -+- Lidocaine Monoethylglycinexylidide
c.i 1.2
c

~
0
0
Q)
c 1.0
'n;
0

~N8cH2N ~~
0
'0
~
0.8

~
<t

0.6 p < 0.02 V CH 3

u. Xylidide
t Mean ± S.E .
n = 10
Figure 7-8. Met a bo lism of lid ocaine.

Figure 7-7. Fetal-m at e rn al arte ri al (FA/MA) lidocaine ratios are

greater duri ng acide mia compare d with a norm al pH . (From Bie hl
D, Shnider SM, Le vinson G, et al. Place nt a l tra nsfe r of lidocaine:
effe cts of feta l acido sis . Anesthesiology 1978;48: 409- 412; with lowed by hyd ro lysis of this metabolite to xylidide (Fig. 7-8 ).
pe rmi ssion. )
Mo noethylglycinexylidide has approxim ately 80% of the
activity of lid oca ine fo r protecting aga in st cardiac dys-
the pl acenta in signifi cant amo unts. Acid osis in the fetus, rhythmi as in an animal model. This m etabolite has a pro-
whi ch may occur durin g p ro lo nged labo r, ca n result in lo nged el iminatio n half-tim e, accounting fo r its efficacy in
accumul ation of loca l anes th etic molecul es in th e fetu s co ntro lling ca rdi ac dysrhyth mi as after the infusion of lido-
(io n trap ping) (Fig. 7-7 ) (Biehl et al., 1978 ). ca in e is disco ntinued . Xylidide has o nly approximately
10% of the card iac antidysrhythmic activity of lidocaine. In
hum ans, approxim ately 75% of xylidide is excreted in th e
Clearance
urin e as 4-hyd roxy-2, 6-dimethylaniline.
Clearance values and elimin atio n half-times fo r amid e Hepatic d isease or decreases in hepatic bl ood flow, whi cl1
local anesthetics pro bably rep resent mainly hepatic metab- may occur during anesthesia, can decrease the rate of metab-
olism, because renal excretion of unchanged drug is mini- olism of lidocaine. For exa mp le, the elimin ation half-time
mal (see Table 7-1 ). Ph arm acoki netic studies of ester loca l of lidoca ine is increased more th an fivefold in patients with
anesthetics are lim ited because of a sho rt elimination half- liver dysfunction co mpared with normal patients. Decreased
time due to their rapid hyd rolys is in the plas ma and liver. hepatic metabo lism of lid oca ine should be anticipated
when patients are anesthetized with vo latile anesth etics
(Fig. 7-9) (Adejepo n-Yamoah et aI., 1973 ). Matem al clear-
Metabolism of Amide Local Anesthetics
ance of lidoca in e is prolonged in the presence of pregna ncy-
Am ide local anes th etics undergo varying rates of metabo- induced hypertensio n, and re peated administrati o n of
lism by microso mal enzym es located prim arily in the liver. lidoca ine can result in higher plasma concentrations than in
Pril oca ine und ergoes th e m os t rapid m eta bo li sm ; lid o- no rmotensive palturients (Ramanathan et aI. , 1986).
ca ine and mepivaca ine are intermedi ate; and etidoca in e,
bupivacaine, and rop ivacaine undergo the slowest metabo- Etidocaine
lism among the amide local anesthetics. The initial step is A small amoun t ( < 1%) of etidocaine is excreted unchanged
co nvers ion of th e amide base to aminocarboxylic acid and in the urine. Despite its structural similarity to lidocaine, the
a cycl ic aniline derivative. Co mp lete metabo lism usually metabolites of etidocaine differ fro m those of lidocaine.
invo lves additional steps, such as hyd roxylation of the ani-
line moiety and N-dea lkylatio n of the amin ocarboxylic acid. Prilocaine
Co mpared with th at of es ter loca l anesth eti cs, th e Pril oca ine is an amide local anesthetic that is metabolized to
metabo lism of amid e local anesthetics is mo re co mpl ex o rthoto luidine. Orthotoluidin e is an oxidizing compound
and slower. Th is slower metabo lism m eans that sustained capab le of co nverting hemoglo bin to its oxidized form,
increases of the plas ma co ncentratio ns of amide loca l meth emoglobin, resulting in a po tentially li fe- threatening
anesthetics, and thus systemic toxicity, are mo re likely than co mpli ca tio n, methem oglo binemia (see the sectio n,
wi th ester local anesthetics. Furthermore, cumulative drug Me th emoglo bin emi a ). Wh en th e dose of priloca in e is
effects of amide local anestheti cs are more li kely than with > 600 mg, there may be sufficient m ethemoglobin present
ester local anesthetics. (3 to 5 gjdL) to cause the pati ent to appea r cyanotic, and
oxygen-carrying capacity is decreased. Methemoglobinemia
Lidocaine is readi ly reversed by th e administrati o n of m ethylene
Th e principal metabo lic pathway of lidoca ine is oxi dative blue, 1 to 2 mgj kg intraveno usly (IV), over 5 minu tes
dealkylation in the liver to mo noethylglycin exylidide fo l- (to tal dose should not exceed 7 to 8 mgjkg) . The ability of
186 Section I: Pharmacology

o. Ropivacaine
x
/ \ Ro pivaca ine is m eta bo li zed to 2,6 -pipeco loxylidid e a nd
I 'x-x
:€ o.
Ol
r
I
\
\
3-hyd roxyropivacaine by hepatic cytochrome P-450 enzymes.
Bo th met abo lites h ave signifi ca ntly less loca l an esth etic
2:
c I \ potency th an ro pivaca in e. Becuse o nly a very sm a ll fracti o n
o
I \ of ro pivaca in e is excreted unch a nged in the urin e (abo ut
.~ o. I x Laparoscopy
cQ)
\
Patients
1%) when th e liver is fun ctio ning normally, dosage adj ust-
I \
;
()
c I \
men ts b ased o n ren al fu nctio n do n ot seem necessary.
o
oQ) O.
I However, in uremi c pati ents, 2,6- pi peco loxy lidide m ay
c accumul a te and produce toxic effects (Pere et a I. , 2003).
.~ I
"' ,
g I
Overall , cl ea rance of ropivacaine is higher th a n that deter-
:3'0 .2
co
E
,
I
'x
'-
Healthy
Volunteers
mined fo r bupivaca in e, and its elim in ati o n ha lf-tim e is
sh o rter (McClure, 1996). The higher clearance of ro piva-
(/)
co
0::: 0 .1
,
I
'-'-,- j
x_
ca in e may offer an adva ntage over bupivacaine in term s of
systemic toxicity. Th e lipid solubility ofropivaca ine is inter-
medi ate between lidoca in e and bupivacaine. Ro pivacaine is
'\ highly bo und to alph a]-acid glyco protein .

Time after Ingestion (hours) Dibucaine

Dibucaine is a quino lin e derivative with an amid e bo nd in
Figure 7-9. Plasma lidocaine (lignocaine) concentration s are th e conn ecting hydrocarb o n chain. This loca l an esth eti c is
higher during general anesthesia (laparoscopy patients) th an in the
absence of general anesthesia (he althy volunteers). (From metabolized in the liver and is the most slowly elimin ated
Adejepon-Yamoah KK, Scott DB, Prescott LF. Impaired abso rption of all th e amide deri vatives.
and metabolism of oral lignocaine in p ati ents underg o ing
laparoscopy. Br J Anaesth 1973;45: 143-147; with permissio n.)
Metabolism of Ester Local Anesthetics
Ester local anesthetics undergo hydrol ys is by ch olinesterase
prilocaine to cause dose-related m ethemoglo binemi a lim- enzyme, principally in the plasma and to a lesser exten t in
its its clinica l usefuln ess, with the excepti o n of N regio nal th e liver. The rate of hyd rolysis varies, with chlorop roca ine
an esth esi a. Prilocaine causes less vasodil ati o n tha n o th er being m ost rapid, p roca in e being intermedi ate, and tetra-
local anesthetics and thus can be utilized without ep in eph - ca ine being the slowest. The resulting m etabo lites are ph ar-
rine added to the loca l anesth etic solutio n . maco logicall y in active, although p araaminobenzo ic acid
may be an an tigen respo nsible for subsequent allergic reac-
Mepivacaine tio ns. The exceptio n to hyd rolysis of ester local anestheti cs
Mepivacaine h as pharm acologic properti es similar to those in th e pl as m a is coca in e, whi ch undergoes signifi ca nt
of lidocaine, although the duration of action of m epiva- metabo lism in th e liver.
cain e is so m ewh at lo nger. Clearan ce o f mepivacain e is Systemi c toxicity is inversely pro po rtio nal to the rate of
decreased in n eon ates, leading to a prol o nged elimi nati o n hyd rolys is; thus, tetraca in e is m o re likely than chl o ropro-
h alf-tim e. In contrast to lid ocaine, m epivacain e lacks ca ine to result in excess ive plasm a concentrations. Because
vasodil ato r activity. As such, m epivaca in e is an altern ate cerebrospina l fluid co ntains littl e t o n o ch olin esterase
selection when addition of epinephrin e to the loca l anes- enzyme, anesthesia p roduced by suba rachn oid placem ent
thetic solutio n is not recomm ended. o f tetraca in e will persist until the drug h as b een absorbed
into the sys temic circul ation . Pl asm a cho linesterase activity
Bupivacaine and the hydrolysis rate o f ester loca l a nestheti cs are slowed
Possibl e pathways for metabolism of bupivacaine include in th e presence of liver disease o r an increased bl ood urea
arom ati c hydroxyl ati o n, N-d ealkylation, amide hydroly- nitrogen co ncentrati o n . Plasma ch o lin esterase activity m ay
sis, and co njugation (Pihl ajam aki et aI. , 1990). O nly th e be decreased in parturi ents and in patients being trea ted
N-dealkylated metabolite N-desbutylbupivacaine, has been with certain chem o therapeutic drugs. Patients with atyp i-
m easured in blood o r urine after epidural or spinal anes- ca l plas m a ch o linesterase m ay be at increased risk fo r
thesia. The mean to tal urinary excretio n ofbupivacaine and developing excess systemic concentratio ns of an ester local
its dealkylation and hydroxylation m etabo lites account for anesthetic du e to absent o r limited plasma hydrolysis.
> 40% of the total a nestheti c dose (Pihl ajamaki et a I. ,
1990) . Alpha]-acid glyco p ro tein is th e most im po rta nt Procaine
plasma pro tein binding site ofbupivacaine, and its concen- Procaine is hydrolyzed to paraam ino benzoic acid, wh ich is
tration is in creased in many clini cal situations, including excreted unchanged in urine, and to diethylaminoethan o l,
postoperative trauma (Dauphin et al., 1997 ). which is furth er metabolized because o nly 30% is recovered
 Chapter 7: Lo ca l Anest h etics 187

in urine. Overall, <50% of procaine is excreted unchanged in Mather, 1979). The exception is cocaine, of which 10% to
urine. Increased plasma concentrations of paraaminoben- 12% of unchanged drug can be recovered in urine. Water-
zoic acid do not produce symptoms of systemic toxicity. soluble metabolites of local anesthetics, such as paraami-
nobenzoic acid resulting from metabolism of ester local
Chloroprocaine anesthetics, are readily excreted in urine.
Addition of a chlorine atom to the benzene ring of procaine
to form chloroprocaine increases by 3.5 times the rate of Use of Vasoconstrictors
hydrolysis of the local anesthetic by plasma cholinesterase,
as compared with procaine. Resulting pharmacologically The duration of action of a local anesthetic is proportional
inactive metabolites of chloroprocaine are 2-chloro- to the time the drug is in contact with nerve fibers . For this
aminobenzoic acid and 2-diethylaminoethanol. Maternal reaso n, epinephrine (1:200,000 or 5 [Lg/mL) may be added
and neonatal plasma cholinesterase activity may be to local anesthetic solutions to produce vasoconstriction,
decreased up to 40% at term, but minimal placental pas- which limits systemic absorption and maintains the drug
sage of chloroprocaine confirms that even this decreased concentration in the vicinity of the nerve fib ers to be anes-
activity is adequate to hydrolyze most of the chloropro- thetized. Indeed, addition of epinephrine to a lidocaine
caine that is absorbed from the m aternal epidural space solution prolongs the duration of conduction blockade and
(Kuhnel1 et at., 1986a) . decreases systemic absorption of local anesthetics by
approximately one-third (Table 7-2) (Fig. 7-10) (Liu 1997;
Tetracaine Scott et at., 1972). Most loca l anesthetics, with the excep-
Tetracaine undergoes hydrolysis by plasma cl10linesterase, tion of ropivacaine, possess intrinsic vasodilator propelties,
but the rate is slower than for procaine. and it is possible that epinephrine-induced vasoconstric-
tion will slow clearance from the injection site, thus pro-
Benzocaine longing the time the drug is in contact with nerve fibers.
Benzocaine (ethyl amino benzoate ) is unique among clini- The impact of adding epinephrine to th e local anes-
cally useful local anesthetics because it is a weak acid th etic solution is influenced by the specific local anes-
(pKa 3.5), so that it exists only in the nonionized form at thetic selected and the level of sensory blockade required
physiologic pH. As such, benzocaine is ideally suited for if a spinal or epidural anesthetic is chosen. For example,
topical anesthesia of mucous membranes prior to tracheal the impact of epinephrine in prolonging the duration of
intubation, endoscopy, transesophageal echo cardiography,
and bronchoscopy. Onset of topical anesthesia is rapid and
lasts 30 to 60 minutes. A brief spray of 20% benzocaine
delivers the recommended dose of 200 to 300 mg. Systemic
absorption of topical benzocaine is enhanced by defects in TABLE 7-2.
the skin and mucosa as well as from the gastrointestinal EFFECTS OF ADDITION OF EPINEPHRINE
tract should any of the local anesthetic be swallowed. (1:200,000) TO LOCAL ANESTHETIC
Cetacaine is a combination of 14% benzocaine, 2% tetra- SOLUTIONS
caine, and 2% butamben. Methemoglobinemia is a rare but
Increase Decrease Blood
potentially life-threatening complication following topical Duration Levels (%)
application of benzocaine, especially when the dose exceeds
200 to 300 mg (see the section, Methemoglobinemia). Peripheral nerve block
Lidocaine ++ 20-30
Mepivacaine ++ 20-30
Cocaine Bupivacaine ++ 10-20
Cocaine is metabolized by plasma and liver cho linesterases Rop ivaca ine 0
to water-soluble m etabo lites that are excreted in urine. Epidural
Plasma cholinesterase activity is decreased in parturients, Chloroproca ine ++
neonates, the elderly, and patients with severe underlying Lidocaine ++ 20-30
Mepivacaine ++ 20-30
hepatic disease. Cocaine may be present in urine for 24 to Bupivacaine ++ 10- 20
36 hours, depending on the route of administration and Levobupivacaine 0
cholinesterase activity. Assays for the metabolites of Rop ivaca ine 0
cocaine in urine are useful markers of cocaine use or absorp- Spinal*
tion (see the section, Cocaine Toxicity) . Lidocaine ++
Tetracaine ++
Bupivacaine ++
Renal Elimination
*Epinephrine dose, 0.2 mg
Adapted from Liu 55. Local anesthetics and ana lgesia . In: Ashburn MA,
The poor water solubility of local anesthetics usu ally limits Rice U (eds). The management of pain. New York. Churchill
renal excretion of unchanged drug to < 5% (Tu cker and Livingstone, 1997;141-170.
188 Section I: Pharmacology

J.!g/ml Mean Maximum Values

8 Lignocaine 20 ml 2% (400 mg)

6
D Plain

4 II Adrenaline
1 :200,000
Figure 7-10. Addition of epineph-
rine (adrenaline) to the solution con-
taining lidocaine (lignocaine) or prilo-
2 caine decreases systemic absorption
of the local anesthetic by about one-
third. (From Scott DB, Jebson PJR,
Braid B, et al. Factors affecti ng
plasm a levels of lignocaine and
Intercostal Subcutaneous Epidural Subcutaneous prilocaine . Br J Anaesth 1972;44:
Vaqinal Abdominal 1040-1049; with permission .)

conduction blod<ade and decreasing systemic absorption Combinations of Local Anesthetics

of bupivacaine and etidocaine is less than that observed
with lidoca ine, presumably because the greater lipid solu- Local anes thetics may be combined in an effort to produce
bility of bupivacaine and etidocain e causes them to bind a rapid onset (chloroprocaine) and prolonged duration
avidly to tissues. The duration of sensOlY anesthesia in the (bupivacaine) of acti on. Nevertheless, placement of
lower extremities, but not the abdominal region, is chloroprocaine in the epidural space may decrease the effi-
extended when epinephrine (0 .2 mg) or phenylephrine (2 cacy of subsequent epidural bupivacaine-induced analgesia
mg) is added to local anesthetic solutions of bupivacaine during labor. It is specul ated that the low pH of the chloro-
or lidocaine placed into the subarachno id space. procaine solution could decrease the nonionized pharma-
Vasoconstrictors prolong the effect of tetracaine for spina l cologically active fraction of bupivacaine. Tachyphylaxis to
anesthesia. Epinephrine added to a low dose of tetracaine the local anesthetic mixture could also reflect local acidosis
(6 mg) increases the success rate of sp inal anesthes ia, due to the low pH of the bathing solution. For these rea-
whereas the success rate is not altered by ep in ephrine sons, ad justment of the pH of the chloroprocaine so lution
when the subarachnoid dose of tetracaine is 10 mg with the add iti on of 1 mL of 8.4% sodium bicarbonate
(Carpenter et a!., 1989). In addition to decreasing systemic added to 30 mL of ch loroprocaine so lution just before
absorption to prolong conduction blockade, ep in ephrine placement into the epid ural space m ay improve the effi-
may also enhance conduction blockade by increasing neu- cacy of the chloroproca in e-bupivacaine combination
ronal uptake of the local anesthetic. The alpha-adrenergic (Chestnut et aI., 1989). Local anesthetic toxicity of combi-
effects of epinephrine may be associated with some degree nati ons of drugs are additive rath er than synergistic
of ana lgesia that could contribute to the effects of the con- (Munson et al., 1977).
duction blockade. The addition of ep in ephrine to loca l
anesthetic solutio ns has little, if any, effect on the o nset
rate of local anesthesia. SIDE EFFECTS
Decreased system ic absorp tion of local anesthetic due
to vasoco nstriction produced by epinephrine increases the The principal side effects related to the use of loca l anes-
likeli hood that the rate of metabolism wi ll match that of thetics are allergic reactions and systemic toxicity due to
absorption, thus decreasing the possibility of system ic tox- excessive plasma and tissue concentrations of the local
icity. Whenever loca l anesthetic solutions containing epi- anesthetic. Systemic toxicity in association with regional
nephrine are adm inistered in the presence of inh aled anes- anesthesia is esti mated to result in seizures in 1 to 4 per
thetics, the possibility of en han ced card iac irritability 1,000 patient exposures to loca l anesthetics, with bupiva-
should be considered. System ic absorption of epinephrine caine being the drug most likely to be associated with this
may accentuate systemic hypertension in vu ln erable adverse response (Brown et aI., 1995).
patients.
Low-molecular-weight dextran added to local anesthetic
Allergic Reactions
solutions, as used for peripheral nerve block anesthesia,
prolongs the duration of action of the anesthetic. Allergic reactions to local anesthetics are rare despite the
Presumably, dextran decreases the sys tem ic absorption rate frequent use of these drugs. It is estim ated that less than
of loca l anesthetic (Kaplan et aI. , 1975) . 1% of all adverse reactions to local anesthetics are due to
 Chapter 7: Local Anesthetics 189

an all ergic mecha ni sm (Brow n e t aI. , 1981 ). lnstead, th e fro m abso rpti o n of the loca l anesth eti c fro m the inj ection
overwhelming majority of adverse respo nses th at are o ften site. The magnitude of thi s systemi c absorpti on depends
attributed to an all ergic reactio n a re in stead m ani fes tati o ns on th e (a) dose administered in to th e tissues, (b) vascular-
of excess pl as ma co ncentratio ns o f the local anestheti c. ity of th e inj ecti o n site, (c) presence of epinephri ne in the
Esters of loca l a nesth eti cs th a t p ro du ce m etab o lites so lutio n, a nd (d) physicoch emical properti es of th e drug
rela ted to pa raa mino b e nzoi c acid a re m o re li ke ly th a n (see Ta bl e 7-1 ). Fo r exampl e, sys temic abso rpti o n of local
a mid e loca l a nesth eti cs, whi ch a re no t m etab o lized to a nesth e ti cs is greatest afte r inj ecti o n fo r a n intercostal
paraa min obenzo ic acid, to evo ke an allergic reacti o n. An nerve bock, intermediate fo r epidural anesth esia, and least
all ergic reactio n after the use o f a loca l a nesth etic may be fo r a brachi al pl exus bl ock (see Fig. 7-4 ) (Cov ino a nd
du e to m eth ylparabe n o r s imil a r substan ces used as Vassa ll o, 1976 ). Addition of 5 f-Lg of epineph rine to every
preservatives in co mm ercial pre pa ratio ns o f este r and mill iliter o f loca l anesthetic solutio n (1: 200,000 diluti on)
amid e loca l a nes th eti cs. These prese rva ti ves a re struc- decreases sys te mic a bso rp ti o n of loca l a nesth eti cs by
turally simil a r to pa raa mino benzo ic acid. As a resul t, an approxim a tely o ne-third (Scott et aI. , 1972 ) (see th e sec-
allergic reactio n may refl ect pri o r stimul ati o n o f a ntibody ti o n, Use of Vasoconstri cto rs). Sys te mi c toxicity of local
pro ducti o n by th e preservative and not a reactio n to th e anesth eti cs in vo lves the centra l nervo us system (CNS) and
loca l anesth eti c. ca rdi ovascul ar system .

Cross-Sensitivity Central Nervous System

Cross-sens iti vity be tween loca l a nes th e ti cs refl ects the Low pl as ma co ncen trati o ns of loca l anestheti cs a re likely
co mm o n m eta b o lite p araamin o ben zo ic acid . A s imil a r to produ ce numbn ess of th e to ngue and circumoral tis-
cross-sensitivity, however, d oes no t ex ist betwee n cl asses sues, presum ably refl ecting delivery of drug to th ese highly
of local a nesth eti cs. Th erefo re, a patien t w it h a kn ow n vascul ar ti ss ues. As the p las m a co ncentrati o ns continue to
all ergy to a n ester local an es th eti c ca n rece ive a n a m id e increase, loca l an esth etics readil y cross th e bl ood-brain
loca l an estheti c w ith o ut an increased risk of an all ergic barri er and produce a predi ctabl e pattern of CNS changes.
reacti on. Likew ise, a n ester local anesth etic ca n be admin - Restless ness, vertigo , tinnitus, a nd diffi culty in focusing
istered to a pati ent with a known all ergy to an a mid e loca l occur ini tially. Further in creases in the CNS con centration
anestheti c. It is imp o rtant th at th e "sa fe" loca l anesth eti c o f loca l a nestheti c res ult in s lurred speech and skeletal
be preservative-free. muscl e twitching. Skeleta l muscl e tw itching is often first
Documentation of Allergy evident in the face and extremities a nd signals th e immi-
Docum entati o n of all ergy to a loca l a nesth etic is based o n nence of to ni c-cl onic seizures. Lidocaine a nd o th er amide
th e clinical history and p erhaps th e use of int radermal tes t- local anestheti cs may cause drows iness before th e o nset of
ing. The occurrence of rash, urti ca ri a, a nd laly ngea l edema, seizures. Se izures are cl ass ica lly fo ll owed by CNS depres-
with o r without hypotensio n and bro nchospasm, is hi ghly sio n, whi ch may be acco mpa ni ed by hyp o te nsion and
suggestive of a loca l a nesth eti c- indu ced all ergic reacti o n. apn ea. The o nset of seizures may refl ect selective depression
Conversely, hypo tensi on associated with synco pe o r tachy- of inhibi to ry co rti ca l neu ro ns by loca l anestheti cs, leaving
ca rdia wh en a n epinephrin e-co n ta inin g loca l a nes th eti c excitatoIY pa th ways unopposed. An alternative expl anation
soluti on is admini stered sugges ts an accid ental intravascu- fo r se izures is local an esth eti c- indu ced inhibiti o n of the
lar inj ecti o n of drug. Use of an intrade rm al test requires release o f neuro transmitters, pa rti cul arly gamma-aminobu-
inj ecti on o f p rese rvati ve-free p re pa ra ti o ns o f loca l a nes- tyri c ac id. The precise s ite of loca l an esth eti c-induced
th etic so lutio ns to eliminate th e poss ibili ty t hat th e all ergic seizures is not kn own, alth o ugh it appears to be in the tem-
reacti o n was ca used by a substa nce ot he r th a n th e loca l po rall obe o r th e amygdala.
anesthetic. Plas ma co ncentra ti o ns of loca l a nestheti cs producing
signs of ce ntral nervous system (CNS ) toxicity depend on
Systemic Toxicity th e spec ifi c drug invo lved . Lid oca in e, m epi vaca in e, an d
pril oca in e de mo nstrate effects o n th e CNS at pl asm a con-
Systemic toxicity o f a local anesth etic is due to a n excess centra ti o ns of 5 to 10 f-Lg/ mL. The typ ica l pl asma concen-
pl as ma conce ntrati on of th e drug. Pl as ma co nce ntrati ons t rati o n of bu p ivaca ine associated with seizures is 4.5 to 5.5
of local an es th eti cs are d etermin ed by th e ra te of d ru g f-Lg/ mL (Cov in o and Vassa ll o, 1976 ). Ro pi vaca ine and
entran ce into th e sys te mi c ci rcul a ti o n relati ve to th eir bupi vaca in e produce co nvuls ions in awake anim als at sim-
red istrib uti o n to in act ive tissu e s ites a nd clea ra nce by ilar doses (McClure, 1996 ). The thresh old p lasma concen-
metabo lis m . Acc ide ntal direct in travascul a r inj ectio n of trati o n at whi cll CNS toxicity occurs may be related more
local anes th eti c so lu tio ns durin g pe rfo rm a nce o f periph- to th e rate o f in crease o f th e se rum co ncentrati o n than to
eral nerve bl ock a nesth esi a o r epidural a nes th es ia is t he th e tota l a m o unt o f drug inj ected (Tucker a nd Math er,
most co mm o n m ech a nism fo r p ro du cti o n of excess 1979 ).
pl as ma co nce ntra ti o ns of loca l a nes th eti cs. Less ofte n, The active metabo lites o f lidoca ine, including monoethyl-
excess plas ma co nce ntrati o ns of loca l a nes th e ti cs res ult glyc in exy lidid e, m ay exert a n additi ve effec t in causing
190 Section I: Pharmacology

systemic toxicity after epidural administration of lidocaine. results from direct action on sensory neurons. Lidocaine-
For this reason, it has been recommended that the plasma induced increases in intracellular calcium ion concentrations
venous concentration of lidocaine be monitored when the may be the mechanism for this toxicity (Kuboyoma et al,
cumulative epidural dose of lidocaine is > 900 mg (Inoue 1997) . It is likely that other local anesthetics act similarly.
et aI., 1985). The seizure threshold for lidocaine may be
related to CNS levels of serotonin (S-hydroxytryptophan). Transient Neurologic Symptoms
For example, accumulation of serotonin decreases the Transient neurologic symptoms manifest as moderate to
seizure threshold of lidocaine and prolongs the duration severe pain in the lower back, buttocks, and posterior
of seizure activity. thighs that appears within 6 to 36 hours after complete
There is an inverse relationship between the Paco 2 and recovery from uneventful single-shot spina l anesthesia
seizure thresholds of local anesthetics, presumably reflect- (Schneider et al., 1993). Previous description of these
ing variations in cerebral blood flow and resultant delivery symptoms as transient radicular irritation is no longer
of drugs to the brain. Increases in the serum potassium con- used, as the etiology of transient neurologic symptoms is
centration can facilitate depolarization and thus markedly not known. For example, sensory and motor neurologic
increase local anesthetic toxicity. Conversely, hypokalemia, examination is not abnormal, and relief of pain with trig-
by creating hyperpolarization, can greatly decrease local ger point inj ections and nonsteroidal antiinflammatory
anesthetic toxicity. The threshold for neurotoxicity of lido- drugs suggests a musculoskeletal component. In some
caine may be decreased when patients being treated with patients, the pain is sufficiently intense to require treat-
the antidysrhythmic drug mexiletine receive lidocaine dur- ment with opioids. Full recovery from transient neurologic
ing the perioperative period (Christie et al., 1993). symptoms usually occurs within 1 to 7 days.
The incidence of transient neurologic symptoms is
Treatment greatest following the intrathecal injection of lidocaine (as
Treatment of lo cal anesthetic-induced seizures includes high as 30%) (Hodgson et aI., 1999). Initial reports of
ventilation of the patient's lungs with oxygen because arte- transient neurologic symptoms involved spinal anesthesia
rial hypoxemia and metabolic acidosis occur within sec- produced by hyperbaric 5% lidocaine, suggesting that the
onds (Moore et al., 1980). Equally important is the deliv- observed neurotoxicity might be, at least in part, concen-
ery of supplemental oxygen at the earliest sign of local tration dependent. Nevertheless, the incidence of transient
anesthetic toxicity. Hyperventilation of the patient's lungs neurologic symptoms is similar after intrathecal placement
seems logical in an attempt to decrease the delivery oflocal of 1 mgjkg of either 5% or 2% lidocaine in 7.5% glucose
anesthetic to the brain. Conversely, this maneuver cou ld (Hampl et aI. , 1996; Liu et al., 1996). For ambu latory
theoretically slow removal of local anesthetic from the patients undergoing arthroscopy, the incidence of transient
brain . IV administration of a benzodiazepine such as neurologic symptoms is not altered by decreasing spinal
midazolam or diazepam is effective in suppressing local lidocaine concentrations from 2% to 1% or 0.5% and are
anesthetic-induced seizures (see Chapter 5) . similar to the incidence of symptoms described with 5%
lidocaine (Pollock et al., 1999) . The risk of transient neu-
rologic symptoms associated with bupivacaine, tetracaine,
Neurotoxicity
mepivacaine, prilocaine, or procaine is significantly less
Neurotoxicity from placement of local anesthetic-containing than with lidocaine (Schneider and Birnbach, 2001) .
solutions into the epidural or subarachnoid space is an Mepivacaine 4%, placed in the subarachnoid space, has
increasingly recognized phenomenon. The spectrum of this also been associated with transient neurologic symptoms
neurotoxicity may range from patchy groin numbness and (Hiller and Rosenberg, 1997; Lynch et aI., 1997) . However,
persistent isolated myotomal weakness to cauda equina syn- the incidence of transient neurologic symptoms is lower
drome (Horlod<er et al., 1997). An intermediate manifesta- with 1.5% mepivacaine than 2% lidocaine in patients
tion of this continuous dose-dependent neurotoxic effect of undergoing unilateral knee arthroscopy (Liguori et aI.,
local anesthetics placed in the subarachnoid space are symp- 1998). Spinal anesthesia produced with 0.5% bupivacaine
toms characterized dinically as transient neurologic symp- or 0.5% tetracaine is associated with a lower incidence of
toms (see the section, Transient Neurologic Symptoms). In transient neurologic symptoms compared with lidocaine
the past, symptoms of neurotoxicity were likely to have been (Hiller and Rosenberg, 1997; Tarkkila et al., 1996; Sakura
erroneously attributed to myoskeletal discomfort secondary et al., 1997; Sumi et al., 1996).
to positioning. Likewise, myofascial pain may be erroneously Lumbosacral nerve root irritation by local anesthetics
diagnosed as transient neurologic symptoms after intrathecal may be exaggerated when the nerves are stretched by place-
placement oflocal anesthetics (Naveira et aI., 1998). Overall, ment of the patient in the lithotomy position (de long,
permanent neurologic injUly after regional anesthesia 1994; Douglas, 1995). Conversely, other data do not sup-
remains a very rare event (Eisenadl, 1997; Lee et aI., 2004). port the concept that patient positioning influences the
Clini cal studies and animal models suggests that lido- incidence of transient neurologic symptoms (Sakura et aI.,
caine is neurotoxic to sensory neurons, and this toxicity 1997). Early ambulation was not found to be a risk factor
 Chapter 7: Local Anesthetics 191

for transient neurologic symptoms after spinal anesthesia artery syndrome from those caused by spinal cord compres-
with 2% lidocaine (Silvanto et ai, 2004). Likewise, the glu- sion produced by an epidural abscess or hematoma.
cose concentration and osmolarity of the anesthetic solu-
tion do not influence the incidence of transient neurologic
Cardiovascular System
symptoms (Sakura et aI., 1997).
Epinephrine and phenylephrine are commonly added The cardiovascular system is more resistant to the toxic
to local anesthetic solutions to prolong the duration of effects of high plasma concentrations of local anesthetics
spinal anesthesia. Prolongation is thought to result, at least than is the eNS. For example, lidocaine in plasma concen-
in part, from a decrease in nerve blood flow resulting in trations of < 5 fLg/mL is devoid of adverse cardiac effects,
decreased systemic uptake of the local anesthetic. producing only a decrease in the rate of spontaneous
Therefore, it is theoretically possible that these vasocon- phase 4 depolarization (automaticity). Nevertheless, plasma
strictor drugs could contribute to the development of tran- lidocaine concentrations of 5 to 10 fLg/mL, and equivalent
sient neurologic symptoms directly, or indirectly by induc- plasma concentrations of other local anesthetics, may pro-
ing ischemia or by increasing exposure to the local duce profound hypotension due to relaxation of arteriolar
anesthetic. There is evidence that adding phenylephrine to vascular smooth muscle and direct myocardial depression
the local anesthetic solution increases the incidence of (Table 7-3). As a result, hypotension reflects both decreased
transient neurologic symptoms after spinal anesthesia with systemic vascular resistance and cardiac output.
tetracaine (Sakura et aI., 1997). There are some clinical Part of the cardiac toxicity that results from high plasma
data suggesting that addition of epinephrine to local anes- concentrations of local anesthetics occurs because these
thetic solutions does not alter the incidence of transient drugs also block cardiac sodium channels. At low concen-
neurologic symptoms (Pollack et aI., 1996). trations of local anesthetics, this effect on sodium channels
probably contributes to cardiac antidysrhythmic properties
Cauda Equina Syndrome of these drugs. However, when the plasma concentrations
Cauda equina syndrome occurs when diffuse injury across of local anesthetics are excessive, sufficient cardiac sodium
the lumbosacral plexus produces varying degrees of (a) channels become blocked so that conduction and auto-
sensory anesthesia, (b) bowel and bladder sphincter dys- maticity become adversely depressed . For example, exces-
function, and (c) paraplegia. Initial reports of cauda sive plasma concentrations of lidocaine may slow conduc-
equina syndrome were associated with the use of hyper- tion of cardiac impulses through the heart, manifesting as
baric 5% lidocaine for continuous spinal anesthesia prolongation of the P-R interval and QRS complex on the
(Lambert and Hurley, 1991; Rigler et aI., 1991). In these electrocardiogram. Effects of local anesthetics on calcium
cases, it was postulated that microcatheters used during ion and potassium ion channels and local anesthetic-
continuous spinal anesthesia (28 gauge or smaller) con- induced inhibition of cyclic adenosine monophosphate
tributed to nonhomogeneous distribution of the local (cAMP) production may also contribute to cardiac toxicity
anesthetic solution, with pooling of high concentrations of (Butterworth et at., 1997).
the local anesthetic solution on certain dependent or
stretched (lithotomy position) nerves. Nevertheless, this Selective Cardiac Toxicity
same complication has also been reported after intrathecal Accidental IV injection of bupivacaine may result in precipi-
injection of 100 mg of 5% lidocaine through a 25-gauge tous hypotension, cardiac dysrhythmias, and atrioventricular
needle (Gerancher, 1997). Intended epidural anesthesia
has also been implicated as a cause of cauda equina syn-
drome (Cheng, 1994).
TABLE 7-3.
Anterior Spinal Artery Syndrome DOSE-DEPENDENT EFFECTS OF LIDOCAINE
Anterior spinal arteIY syndrome consists of lower-extremity
paresis with a variable sensory deficit that is usually diag- Plasma Lidocaine
nosed as the neural blocl<ade resolves. The etiology of this Concentration (fLg/ml) Effect
syndrome is uncertain, although thrombosis or spasm of 1-5 Analgesia
the anterior spinal artelY is possible, as well as effects of 5-10 Circumoral numbness
hypotension or vasoconstrictor drugs. Although the addi- Tinnitus
tion of epinephrine to local anesthetic solutions has been Skeletal muscle twitching
Systemic hypotension
implicated as a theoretical cause, spinal cord perfusion stud-
Myocardial depression
ies do not show a deleterious effect of the catecholamine 10-15 Seizures
(Kozody et aI., 1984). Advanced age and the presence of Unconsciousness
peripheral vascular disease may predispose patients to 15-25 Apnea
development of anterior spinal artery syndrome. [t may be Coma
> 25 Cardiovascular depression
difficult to distinguish symptoms due to anterior spinal
192 Section I: Pharmacology

ous cardiac dysrhythmias only in animals receiving bupi-

TABLE 7·4. vacaine (Table 7-4) (Kotelko et al., 1984). Cardiotoxic
ANIMALS MANIFESTING ADVERSE CARDIAC plasma concentrations of bupivacaine are 8 to 10 fLg/mL
CHANGES AFTER ADMINISTRATION OF (Timour et al., 1990).
BUPIVACAINE OR LIDOCAINE Physiologic changes and concomitant drug therapy may
make patients more vulnerable to bupivacaine cardiac
Bupivacaine Lidocaine toxicity. For example, pregnancy may increase sensitivity to
Cardiac Change (% of Animals) (% of Animals)
cardiotoxic effects of bupivacaine, but not ropivacaine, as
Sinus tachycard ia 0 100 emphasized by occurrence of cardiopulmonary collapse
Supraventricular 60 9 with a smaller dose of bupivacaine in pregnant compared
tachycardia with nonpregnant anima ls (Fig. 7-11) (McClure, 1996;
Atrioventricular heart block 60 0 Morishima et aI., 1985). The threshold for cardiac toxicity
Ventricu lar tachycard ia 80 0
Premature ventricu lar 100
produced by bupivacaine may be decreased in patients
0
contractions being treated with drugs that inhibit myocardial impu lse
Wide QRS complexes 100 0 propagation (beta-adrenergic blockers, digitalis prepara-
ST-T wave changes 60 40 tions, calcium channel blockers) (Roitman et aI., 1993).
Indeed, in the presence of propranolol, atrioventricular
Source: Kotelko OM, Shnider SM, Dailey PA, et al. Bupivacaine-induced
cardiac arrhythmias in sheep. Anesthesiology 1984;60:10-18; with heart block and cardiac dysrhythmias occurred at plasma
perm ission. bupivacaine concentrations of 2 to 3 fLg/ml (Timour et al.,
1990). This suggests that caution must be taken in the use
heart b lock (Albright, 1979). After accidental rv injection, of bupivacaine in patients who are on antidysrhythmic
the protein-binding sites (alphaJ-acid glycoprotein and drugs or other cardiac medications known to depress
albumin) for bupivacaine are quickly saturated, leaving a impulse propagation. Epinephrine and phenylephrine may
significant mass of unbound drug available for diffusion increase bupivacaine cardiotoxicity, reflecting bupivacaine-
into the conducting tissue of the heart. IV injection of induced inhibition of catecholamine-stimulated produc-
bupivacaine or lidocaine to awake animals produces seri- tion of cAMP (Butterworth et aI., 1993). The cardiac toxicity

o Nonpregnant

~ Pregnant
Dosage
(mg/kg)
10

Ql
6
c
.<ij
()

~
.0.
:::>
co
4

Figure 7-11. The dose of bupivacaine

requi red to evoke toxic effects is less in preg-
nant than in nonpregnant ewes. (Mean :!:: Sf;
o *P < .05.) (F rom Morishima HO, Pedersen H,
Finster M, et al. Bupivacaine toxicity in preg-
Convu lsions Hypotension Respiratory Circulatory nant and nonpregnant ewes. Anesthesiology
Arrest Collapse 1985;63:134-139; with permission.)
 Chapter 7: Local Anesthetics 193

1.0

0.8

x
ell
~ 0.6
'"Cl
Q)
.~
cti
E
~ 0.4
o - Control (n =8)
Figure 7 -12. In an isolated papillary muscle • -10.0 l1g/ml Lidocaine (n = 4)
preparation, Vm ax is depressed more by bupiva- 0.2 ~ - 0.2 l1.g/ml Bupivacaine (n = 5)
caine than by lidocai ne. (* P < .05; ** P < .01.)
(From Clarkson CW, Hondeghem LM. Mechanism • - 1.0 l1g/ml Bupivacaine (n = 6)
for bupivacaine depression of cardiac conduction:
fast block of sodium channels during the action
potential with slow recovery from block during
diastole. Anesthesiology 1985;62:396-405; with o 50 100 150 20
permission.) Stimulation Rate (beast/minute)

of bupivacaine in animals is enhanced by arterial hypox- more likely in the presence of levobupivacaine (Groban
emia, acidosis, or hypercarbia. et al.. 2001 ; Huang et ai. , 1998) . Ropivacaine is a pure S
All local anesthetics depress the maximal depolariza- enantiomer that is less lipid so luble and less cardiotoxic
tion rate of the cardiac action potential (VIn"x) by virtue of than bupivacaine but more cardiotoxic than lidocain e
their ability to inhibit sodium ion influx via sodium chan- (Moller and Covino, 1990; Scott et ai. , 1989). Although,
nels. In isolated papillary muscle preparations, bupiva- ropivacaine-induced cardiac arrest has been described fol-
caine depresses Vlnax considerab ly more than lidocaine, lowing peripheral nerve block anesthesia, in contrast to
whereas ropivacaine is intermediate in its depressant effect bupivacaine, cardiac resuscitation is more likely to be suc-
on Vlnax (Fig. 7-12) (Clarkson and Hondeghem, 1985; cessful (Chaza lon et al.. 2003; Klein et al.. 2003; Polley and
McClure, 1996). The resulting slowed conduction of the Santos, 2003 a).
cardiac action potential manifests on the electrocardio- Tachycardia can enhance frequency-dependent block-
gram as prolongation of the P-R and QRS intervals and ade of cardiac sodium channels by bupivacaine, further
reentry ventricular cardiac dysrhythmias. Both bupivacaine contributing to the selective cardiac toxicity of this local
and lidocaine block cardiac sodium ion channels during anesthetic (Kendig, 1985) . Conversely, a low degree of
systo le, whereas during diastole, highly lipid so luble bupi- frequency-dependent blockade may contribute to the
vacaine dissociates off these channels at a slow rate com- antidysrhythmic properties of lidocaine. In anesthetized
pared with lidocaine, thus accounting for th e drug's persis- dogs, bretylium, 20 mg/kg IV, reverses bupivacaine-
tent depressant effect on Vmax and subsequent cardiac induced cardiac depression and increases th e threshold
toxicity (Atl ee and Bosnjak, 1990) . At normal heart rates, for ventricular tachycardia (Kasten and Martin, 1985). In
diastolic time is sufficiently long for lidocaine dissociation an effort to decrease th e potential for cardiotoxicity
but bupivacaine block intensifies and depresses electrical should accidental intravascular injection occur, it may be
conduction, causing reentrant-type ventricular dysrhyth- prudent to limit the concentration of bupivacaine to be
mias, Less lipid-soluble lidocaine dissociates rapidly from used for epidural anesthesia to 0.5%. In addition, slow
cardiac sodium channels and cardiac toxicity is low. or fractionated administration of all lo ca l anesthetics,
Furthermore, high plasma concentrations of bupivacaine but particularly bupivacaine, so as to detect systemic tox-
may cause ventricular cardiac dysrhythmias through a icity from accidental intravascular injection, should help
direct brainstem effect. The R enantiomer ofbupivacaine is decrease tile risk of cardiotoxicity (Xuecheng et ai., 1997).
more toxic than the S enantiomer. For example, seizure
activity following an interscalent block with levobupiva-
Methemoglobinemia
caine was not associated with cardiac dysrhythmias or
other signs of cardiovascular toxicity (Crews and Rothman, Metl1emoglobinemia is a rare but potentially life-threatening
2003). In anima ls, levobupivacaine compared with bupi- complication (decreased oxygen-carrying ca pacity) that
vacaine was associated with a lower incidence of ventricu- may follow the administration of certain drugs or chemicals
lar cardiac dysrhythmias, and successful resuscitation was that cause oxidation of hemoglobin to methemoglobin
194 Section I: Pharmacology

more rapidly than methemoglobin is reduced to hemoglo- Dysphoria

bin. Known oxidant substances include topical local anes-
thetics (prilocaine, benzocaine, Cetacaine, lidocaine), nitro- Vivid fea r of imminent death and a delusional be1ief of
glycerin, phenytoin, and sulfo namides (Nguyen et aI., having died have been described in patients experiencing
2000). Neonates may be at greater risk because of more toxic reactions to lo ca l anesthetics administered for
readily oxidized fetal hemoglobin. regional anesthesia and pain relief (Marsch et al., 1998).
Methemoglobin cannot bind oxygen or carbon dioxide,
resulting in loss of the h emoglobin molecule's transport
function. Methemoglobin norm ally constitutes < 1% of
USES OF LOCAL ANESTHETICS
the total hemoglobin. Central cyanos is usually occurs
Local anesthetics are most often used to produce topical,
when methemoglobin concentrations exceed 15%. The
infiltration, and regional anesthesia (Table 7-5) (Covino et
presence of methemoglobin emia is suggested by a differ-
at., 1998; Foster and Markham, 2000). Less common rea-
ence between the calculated and measured arterial oxygen
sons to select local anesthetics are to prevent or treat cardiac
saturation. The diagnosis is confirmed by qualitative mea-
dysrhythmias (see Chapter 17), prevent or treat increases in
surements of methemoglob in by cooximetry.
intracran ial pressure, provide analges ia, and treat grand mal
Methemoglobinemia is readily reversed by the admin-
seizures.
istration of methylene blue, 1 to 2 mg/kg TV, over 5 min-
AntiinfiammatOlY effects of local anesthetics may be
utes (total dose shou ld not exceed 7 to 8 mg/kg).
responsible for benefical effects in the perioperative period
Methylene blue is reduced to leukomethylene blue, whi ch
that are attributed to sp inal or ep idural anesth esia
then acts as an electron dono r and nonenzymatically
(Hollmann and Durieux, 2000).
reduces methemoglobin to hemoglobin. Normal levels of
methemoglobin should be achieved within 20 to 60 min-
utes after the administration of methylene blue. This ther- Regional Anesthesia
apeutic effect, however, is short-lived because methylene
blue may be cleared before conversion of all the methe- Regional anesthesia is classified according to the following
moglobin to hemoglobin. Furthermore, continued absorp- six sites of placement of the local anesthetic solution: (a)
tion of highly lipophilic loca l anesthetics such as benzo- topical or surface anesthesia, (b) local infiltration, (c)
caine from adipose tissue stores may co ntinu e to occur peripheral nelve block, (d) IV regional anesthesia (Bier
after methylene blue plasma concentrations are no longer block), (e) epidura l anesthesia, and (f) spinal (subarach-
therapeutic. noid) anesthes ia (see Tab le 7-3). Spinal anesthesia rather
than "subarachnoid anesthesia" or "spinal block" is the
preferred terminology because it is understood by
Ventilatory Response to Hypoxia nonanesthesiologists. Furthermore, th e term bloch implies
Lidocaine at clinically usefu l plasma concentrations an obstruction. Maxjmum doses of local anesthetics
depresses the ventilatory responses to arteria l hypoxemia (based on body weight) as recommended for topical or
(Gross et al., 1984). In this regard, patients with carbon peripheral nerve block anesth es ia must be viewed as
dioxide retention whose resti ng ventilation depends on imprecise guidelines that often do not consider the phar-
hypoxic drive may be at risk of ventilatory failure when macokinetics of th e drugs (Scott, 1989).
lid ocaine is administered for treatment of card iac dys-
rhythmias. Conversely, systemic absorption of bupiva-
Topical Anesthesia
caine, such as follows a brachia l plexus block, stimulates
the ventilatory response to carbon dioxide. Local anesthetics are used to produce topical anesthesia by
placement on the mucous membranes of the nose, mouth,
tracheobronchia l tree, esophagus, or genitourinary tract.
Hepatotoxicity Cocain e (4% to 10%), tetracaine (1% to 2%), and lido-
Continous or intermittent epidural administration ofbupi- caine (2% to 4%) are most often used. It is estimated that
vacain e to treat postherpetic neuralgia has been associated topical cocaine anesthesia is used in >50% of rhinolaryn-
with increased plasma concentrations of liver transami- go logic procedures performed annually in the United
nase enzymes that normalized when bupivacaine infusion States (Lange et al., 1989) (see the section on Cocaine
was discontinued or lidocaine was substitued for bupiva- Toxicity). Coca ine's popularity for topical anesthesia
ca in e (Yokoyama et at., 2001). The preselvative present in refl ects its unique ab ility to produce localized vasoconstric-
both local anesthetics was the same. Drug-induced liver tion, thus decreasing blood loss and improving surgical
injury can be a direct toxic injury, an all ergic reaction, or visualization. There is no difference between the intranasal
idosyncratic metabolic abnormality. The hepatic dysfunc- anesthetic or vasoconstrictive effects of cocaine and those
tion described seems most likely to represent an all ergic of a lidocaine-oxymetazoline or tetracaine-oxymetazoline
reaction (Craft and Good, 1994). mixture, emphasizing the usefulness of these combinations
 Chapter 7: Local Anesthetics 195

TA.BLE 7-5.
CLINICAL USES OF LOCAL ANESTHETICS
Recommended Maximum
Clinical Use Concentration (% ) Onset Duration (min) Single Dose (mg)

Lidocaine Topical 4 Fast 30-60 300

Infiltration 0.5- 1 Fast 60-240 300 or 500 with epinephrine
IVRA 0.25-0.5 Fast 30-60' 300
PNB 1-1.5 Fast 60-180 300 or 500 with epinephrine
Epidural 1.5- 2 Fast 60-120 300 or 500 w ith epinephrine
Spinal 1.5-5 Fast 30-60 100
Mepivacaine Infiltration 0.5-1 Fast 60-240 400 or 500 with epinephrine
PNB 1-1 .5 Fast 120-240 400 or 500 with epinephrine
Epidural 1.5-2 Fast 60-180 400 or 500 with epinephrine
Spinal 2-4 Fast 60-120 100
Etidocaine Infiltration 0.5 Fast 120-480 300 or 400 with epinephrine
PNB 0.5- 1 Fast 180-720 300 or 400 with epinephrine
Epidural 1-1 .5 Fast 120-480 300 or 400 with epinephrine
Prilocaine Infiltration 0.5-1 Fast 60-120 600
IVRA 0.25-0.5 Fast 30-60 600
PNB 1.5-2 Fast 90-180 600
Epidura l 2-3 Fast 60-180 600
Bupivacaine Infiltration 0.25 Fast 120-480 175 or 225 w ith epinephrine
PNB 0.25-0.5 Slow 240- 960 175 or 225 with epinephrine
Epidural 0.5-0.75 Moderate 120-300 175 or 225 with epinephrine
Spinal 0.5-0.75 Fast 60-240 20
Levobupivacaine Infi ltration 0.25 Fast 120-480 150
PNB 0.25- 0.5 Slow 840-1,020 150
Epidural 0.5-0.75 Moderate 300- 540 150
Spina l 0.5-0.75 Fast 60-360 20
Rop ivacaine Infi ltration 0.2-0.5 Fast 120- 360 200
PNB 0.5-1 Slow 300-480 250
Epidural 0.5-1 Moderate 120-360 200
SPINAL?
Ch loroprocaine Infiltration Fast 30- 60 800 or 1,000 with epinephrine
PNB 2 Fast 30-60 800 or 1,000 with epinephrine
Epidural 2-3 Fast 30-60 800 or 1,000 with epinephrine
Spinal 2-3 Fast 30-60 Preservative free*
Procaine Spinal 10 Fast 30- 60 1,000
Tetracaine Topical 2 Fast 30-60 20
Spina l 0.5 Fast 120-360 20
Benzocaine Topical Up to 20% Fast 30-60 200
Cocaine Topical 4-10 Fast 30-60 150

*Off label use

Adapted from Covino BG, Wildsmith JAW. Clinica l pharmacology of local anesthetic agents . In: Cousins
MJ, Bridenbaugh PO (eds). Neural blockade in clinical anesthesia and management of pain. Phi ladelphia.
Lippincott-Raven, 1998:97-128; and Foster RH, Markham A. Levobupivacaine: A review of its
pharmacology and use as a local anesthetic. Drugs 2000;59:551-559.

as substitutes for cocaine (Noorily et aI., 1995) . Procaine can cause bronchoconstriction in some patients with
and chloroprocaine penetrate mucous membranes poorly asthma, which may becom e an important consideration
and are ineffective for topical anesthesia. when bronchoscopy is planned in these patients (McAlpine
Nebulized lidocaine is used to produce surface anesthe- and Thomson, 1989) . Local anesthetics are absorbed into
sia of the upper and lower respiratory tract before fiberop- the systemic circulation after topical application to mucous
tic laryngoscopy and/or bronchoscopy and as a treatment membranes. Systemic absorption of tetracaine, and to a
for patients experi encing intractable coughing (McAlpin e lesser extent lidocaine, after placement on the tracheo-
and Thomson, 1989). The inhalation of local anesthetics bronchial mucosa produces plasma concentrations similar
by normal subj ects does not alter airway resistance and to those present after IV injection of the local anesthetic.
may even produce mild bronchodilation (Kirkpatrick et For examp le, plasma lidocaine concentrations 15 minutes
aI., 1987). In contrast, inhalation of nebulized lidocain e after laryngotracheal spray of the local anesthetic are similar