+++
Newer Amide Local Anesthetics: Introduction
++
The use of regional anesthesia has been increasing not only in
obstetrics, where it is the predominant anesthetic technique used, but also
during surgery and for acute postoperative pain management. This has been
partly due to the safety of regional anesthesia because of better injection
techniques and equipment, increased attention to detecting (preventing)
misplaced injection, greater vigilance/monitoring, and the introduction of
newer long-acting amide local anesthetics. The increasing demand for
regional anesthesia is nowhere more true than in obstetric anesthesia, where
local anesthetics have become the most frequently administered drugs for
obstetric pain relief or cesarean delivery. When injected epidurally or
intrathecally, local anesthetics provide effective labor analgesia that is
superior to that of systemic opioids and without the attendant risks of
maternal sedation and neonatal depression. Regional anesthesia is now the
most frequently used technique for cesarean section delivery in the
U.S.1
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Historical Perspective
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Why the need for new amide local anesthetics? The answer is partly
related to the history of bupivacaine use, particularly in North America and
Europe. After its introduction into clinical practice, bupivacaine quickly
became very popular for several reasons, particularly for use in obstetrics.
It has a longer duration of action than 2-chloroprocaine and lidocaine and
thus requires less frequent supplemental doses, a feature that is less
important now with the widespread use of continuous epidural infusion
techniques. More important and in contrast to other local anesthetics,
bupivacaine has a motor-sparing effect; it produces less motor block for a
comparable degree of sensory analgesia. This is particularly true at the low
concentrations used for labor epidural analgesia and acute postoperative
pain management. Furthermore, bupivacaine has excellent compatibility with
neuraxial opioids, and this allows for concentrations as low as 0.03% and
0.04% bupivacaine to be used successfully so that many patients are
pain-free and even able to ambulate during labor or with regional analgesia
after surgery. Less motor block also improves expulsive efforts during the
second stage of labor and may reduce the need for an instrumental vaginal or
abdominal delivery.2 The ability of bupivacaine to provide
good sensory analgesia with little motor block is essential for management
of postoperative, during which early mobilization may decrease the risk of
deep venous thrombosis and result in better respiratory mechanics.
Nonetheless, despite its many advantages, there have been some concerns
regarding bupivacaine, particularly in obstetric anesthesia.
++
++
Clinical experience has been that cardiac arrest after unexpected
intravascular injection of clinical doses of local anesthetics could be
prevented by prompt oxygenation, ventilation, and, if necessary,
cardiovascular support. However, in 1979, George Albright3
alerted anesthesia practitioners to a cluster of six anecdotal cases of
sudden cardiac arrest after unexpected intravascular injection of what then
were the newer amide local anesthetics, bupivacaine and etidocaine. In his
editorial, Albright3 suggested that intoxication with
bupivacaine (and etidocaine), in contrast to lidocaine and mepivacaine,
could result in almost simultaneous onset of convulsions and circulatory
collapse without antecedent hypoxia and acidosis.
++
Since then, bupivacaine has been shown to have a narrower margin of safety
than lidocaine and mepivacaine.4–6 The ratio of the
doses or plasma concentrations required to produce cardiovascular collapse
compared with those associated with convulsions is lower for bupivacaine
than for the other two drugs.5,6 Also, in contrast to the
intermediate-acting local anesthetics, bupivacaine intoxication is
associated with malignant ventricular arrhythmias, which may be difficult to
treat.5,6 This is because unlike other amide local
anesthetics, bupivacaine dissociates from blocked sodium channels at a much
slower rate, resulting in a prolongation of the maximal rate of
depolarization (Vmax) and creating the potential for
reentrant-type ventricular arrhythmias.7
++
The epidemic of bupivacaine-related cardiac arrests, particularly among
parturients in the U.S., directed interest toward discovering whether
pregnancy itself enhances the arrhythmogenicity of
bupivacaine.8 Indeed, in vitro studies conducted on rabbit
heart preparations have demonstrated that myocardial muscle treated with
progesterone and exposed to bupivacaine showed greater depression of
Vmax than those exposed to lidocaine, thus increasing
susceptibility to malignant reentrant-type ventricular
arrhythmias.9
++
In vivo experiments have been less conclusive. In an early study using a
small number of animals given a continuous intravenous infusion of
bupivacaine, circulatory collapse occurred at lower doses and lower plasma
drug concentrations in pregnant than in nonpregnant ewes.5
However, a subsequent study involving a larger group of animals and the use
of blinding and randomization failed to confirm these
findings.10 Cardiac arrest also occurred in surgical
patients after intoxication with bupivacaine, but less frequently.
++
Some suggested that the disproportionate number of cardiac arrests among
parturients compared with surgical patients was not related to increased
sensitivity to the drug during pregnancy but to the widespread use of
bupivacaine in obstetrics and, in some instances, to inadequate
cardiopulmonary resuscitation.11 In many of these cases
that were fatal, the fetus had not been delivered immediately, thus
hampering efforts to restore maternal circulation as a result of aortocaval
compression.11
++
Nonetheless, the U.S. and Drug Administration (FDA) proscribed the use
of the higher concentration of bupivacaine, that is,. 0.75%, in pregnant
women; by clinical practice, this was extended to surgical patients as well.
Since then, anesthesiologists have perceived a need for alternative amide
local anesthetics with the beneficial blocking properties of bupivacaine but
with a greater margin of safety.
++
Amide local anesthetics of the mepivacaine homologue type are known as
chiral drugs because they can exist in isomeric (enantiomeric) forms, which
are mirror images of each other (Figure 7–1). The isomers are
defined according to the direction that a molecule rotates polarized light:
dextrorotary (+ or rectus) and levorotary (– or sinister). Isomers
of the same compound may have different biologic activities. For instance,
it was suggested in early studies, that the levo-isomers of amide local
anesthetics tend to produce greater vasoconstriction but have lower systemic
toxicity than the dextro form of the drug.12–14
++
++
However, until the 1990s, the formulations of amide local anesthetics
used in clinical practice contained a racemic mixture (approximately 50:50)
of both the levo- and the dextro-isomers because single-isomer preparations
were costly to produce. Fortunately, with technologic advances and an
interest in a less toxic alternative to bupivacaine, single-isomer
preparations of local anesthetics are now available. The first to be
approved for clinical use was ropivacaine, followed shortly by
levobupivacaine.
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Physicochemical Properties
++
Ropivacaine (1-propyl-2′, 6′-pipecoloxylidide) is a
homologue of mepivacaine and bupivacaine (Figure 7–2). It differs
from bupivacaine in having a propyl rather than a butyl group attached to
the pipechol ring). Ropivacaine is formulated as the single levo-isomer
(99.5% purity) rather than as a racemic mixture. As would be expected,
ropivacaine's physicochemical properties are intermediate between those of
mepivacaine and bupivacaine15 (Table 7–1).
Ropivacaine, like other amide local anesthetics, is used in its
water-soluble form as the hydrochloride monohydrate salt (molecular weight
[MW] 329) of the base (MW 275).15 The
pKB value of ropivacaine is 8.07 and similar to that of
bupivacaine (8.1). Ropivacaine, like bupivacaine, is highly protein-bound at
94% and thus has a long duration of action. However, it is considerably
less lipid-soluble than bupivacaine.15 This may be
important for two reasons. It may explain why bupivacaine has greater
motor-blocking effects than ropivacaine because the greater lipid solubility
of the former may result in enhanced penetration into the heavily
myelinated, large motor neurons. Second, it raises the question as to
whether ropivacaine is truly equipotent to bupivacaine.
++
++
++
Levobupivacaine (Chirocaine, Chiroscience, Ltd) is the other single
levorotary isomer formulation of local anesthetic available for clinical
use. Its physicochemical characteristics are virtually indistinguishable
from those of bupivacaine15 (see Table 7–1).
Unfortunately, although a promising drug, financial and economic
considerations have resulted in levobupivacaine no longer being available
for use in North America, although it is available in other parts of the
world. The advantage of levobupivacaine is that it may be closer in its in
vitro potency and efficacy to the currently used clinical formulation of
racemic bupivacaine,12,16 whereas ropivacaine is
20–30% less potent.17,18 Thus, in contrast to
ropivacaine, any expected benefits to be gained from the lower
cardiotoxicity of levobupivacaine do not appear to be at the expense of
potency.
++
Generally speaking, ropivacaine has lower lipid solubility and slightly
lower protein binding than racemic bupivacaine15 (see
Table 7–1). Note that the elimination half–life (T{1/2}B) of ropivacaine is shorter than that of bupivacaine after
intravenous administration to animals and humans.19–21
The shorter elimination half-life of ropivacaine has been attributed to a
faster clearance and shorter mean residence time than
bupivacaine.21
++
In sheep, pregnancy is associated with smaller volumes of distribution
during the terminal phase of drug elimination and steady state and a slower
clearance for both drugs.21 In pregnant animals,
ropivacaine also had shorter elimination half-life and mean residence times
and a faster clearance than bupivacaine.21 Similarly,
ropivacaine has been shown to have a lower T{1/2}B
value than bupivacaine in women having epidural anesthesia for cesarean
section delivery.22
++
Levobupivacaine has similar protein binding and lipid solubility to
those of racemic bupivacaine15 (see Table 7–1). However,
there are differences between the two optically active isomers of
bupivacaine. Levobupivacaine exhibits a slightly greater degree of protein
binding, lower volume of distribution, higher plasma clearance, and shorter
elimination half-life than the dextrorotary form of the
drug.23 However, in pregnant women given levobupivacaine
or bupivacaine for epidural anesthesia during cesarean section delivery,
there was no significant difference between the two drugs in the maximum
concentration of drug in the plasma and the area under concentration versus
time curve.24
++
In vitro studies using isolated rabbit Purkinje fibers have shown that
ropivacaine depresses electrophysiologic parameters such as
Vmax, much less than does bupivacaine.25
A number of studies performed in laboratory animals have also demonstrated
that ropivacaine has a greater margin of safety than bupivacaine. In dogs,
the margin of safety, defined as the ratio between the dose required to
produce cardiovascular collapse and the dose associated with convulsions,
was greater for ropivacaine than for bupivacaine.26 In
another study, almost twice the dose of ropivacaine compared with
bupivacaine was necessary to prolong the QRS interval after intravenous
administration to pigs.27 In sheep, the mean fatal dose of
ropivacaine was greater than that of bupivacaine at 60 and 45 mg,
respectively.28
++
In human volunteers, the doses of ropivacaine required to produce
premonitory signs of central nervous system (CNS) toxicity during slow
intravenous infusion were approximately 25% greater than for
bupivacaine.29,30 Furthermore, bupivacaine depressed
cardiac conduction and contractility at lower dosages and plasma
concentrations than did ropivacaine.29
++
Pregnancy does not enhance the systemic toxicity of ropivacaine. In vitro
studies have shown that progesterone has little effect on myocardial
sensitivity to ropivacaine.31 In sheep, the doses and
plasma concentrations required to produce convulsions and circulatory
collapse were similar in pregnant and nonpregnant animals.10,32 However, in pregnant animals, the doses required to produce
circulatory collapse were approximately 40–50% greater for ropivacaine
than for bupivacaine, but the corresponding serum concentrations of the two
drugs were similar.10 This has been attributed to a
shorter elimination half-life and faster clearance of
ropivacaine.21
++
++
Levobupivacaine has less of an inhibitory effect on inactivated cardiac
sodium channels than dextro or racemic drug.33 Using
isolated perfused rabbit hearts, Mazoit et al.34
demonstrated that levobupivacaine caused less QRS widening and less severe
ventricular arrhythmias than dextro or racemic bupivacaine. Similarly,
levobupivacaine produced less atrial–ventricular conduction delay and
second-degree heart block in isolated perfused guinea pig hearts than the
other two forms of the drug.35
++
In vivo toxicity also appears to be less with levobupivacaine than with
bupivacaine. For instance, the convulsant dose range for levobupivacaine was
greater (75–100 mg) than for the racemate (50–75 mg) in sheep given graded
intravenous doses of the drug.36 Levobupivacaine was also
associated with a lower incidence of cardiac arrhythmias, whereas 43% of
sheep given racemic bupivacaine died as a result of irreversible malignant
ventricular arrhythmias.36
++
In healthy male volunteers, intravenous infusion of levobupivacaine until
premonitory symptoms of toxicity resulted in a smaller reduction in mean
stroke index, acceleration index, and ejection fraction than racemic
bupivacaine.37
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Comparative Systemic Toxicity
++
The most useful studies compare the systemic toxicity of bupivacaine,
levobupivacaine, and ropivacaine under a single methodology. For the most
part, the results of these studies indicate that bupivacaine has a narrower
margin of safety compared with that of ropivacaine, with levobupivacaine
being intermediate. In vitro studies performed on isolated and perfused
rabbit heart preparations suggest that bupivacaine, levobupivacaine, and
ropivacaine prolong the duration of the QRS interval in a potency ratio of
1.0:0.4:0.3.34.
++
++
Studies comparing the three drugs have also been performed using various
laboratory animals. In one study, chronically prepared sheep were randomized
to receive a constant intravenous infusion of bupivacaine, levobupivacaine,
or ropivacaine at an equal rate until circulatory collapse
occurred.38 The cumulative dose of local anesthetic
required to produce convulsions and circulatory collapse was lowest for
bupivacaine and highest for ropivacaine, with levobupivacaine being
intermediate38 (Figure 7–3). The incidence of
ventricular arrhythmias as the terminal event, was similar among the three
drugs. In another study, anesthetized swine were given an intracoronary
injection of one of the three local anesthetics.39 The
lowest lethal dose occurred with bupivacaine, with ropivacaine and
levobupivacaine being somewhat greater.39 Application of
high concentrations of local anesthetics to specific areas of the brainstem
can result in ventricular arrhythmias. In sheep, CNS-directed (carotid
artery) infusion of all three local anesthetics resulted in increased
arrhythmias, but the overall rank order of potency was ropivacaine
< levobupivacaine < bupivacaine.40
++
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The Controversy Regarding Systemic Toxicity
++
It is well accepted that lipid solubility usually goes hand in hand
with local anesthetic potency. All things being equal, greater lipid
solubility is related to increasing length of the aliphatic chain on the
amino ring. Structurally, ropivacaine has one less carbon on the aliphatic
chain (C3) than bupivacaine, which has four carbons (see Figure 7–2). This
difference in the length of the aliphatic chain between the two drugs
renders bupivacaine approximately 10 times more lipid-soluble than
ropivacaine15 (see Table 7–1). In vitro studies performed
on rat sciatic nerve indicate that bupivacaine is approximately 25% more
potent in blocking conduction than ropivacaine.12,13
However, the argument has been made that although bupivacaine is slightly
more potent than ropivacaine, the two drugs would be equieffective in
producing clinical regional anesthesia. Because of this, most of the studies
of systemic toxicity have compared equal doses of the two drugs. Thus, these
studies did not resolve the controversy as to whether ropivacaine is truly
less cardiotoxic than bupivacaine because it is also 20–30% less potent.
However, this would be of clinical significance only if greater doses of
ropivacaine than bupivacaine would be needed to produce a comparable level
of regional blockade. In fact, we now know that in some situations
bupivacaine and ropivacaine are not equieffective. For instance, the median
local analgesic concentration of local anesthetic for epidural analgesia in
laboring woman is approximately 40% greater for ropivacaine compared with
bupivacaine18 (Figure 7–4).
++
++
In a recent study, the median analgesic (effective) dose for intrathecal
labor analgesia was lowest for bupivacaine (2.37 mg) and highest for
ropivacaine (3.64 mg), with levobupivacaine being intermediate (2.94
mg).41 In other studies, greater doses of ropivacaine
compared with bupivacaine were required to produce comparable surgical
spinal anesthesia.42 This is important because if larger
doses of ropivacaine compared with bupivacaine are required to produce
comparable regional anesthesia, then the anticipated benefit of lower
cardiotoxicity with ropivacaine compared with bupivacaine may be reduced.
However, the results of a recently published study performed in rats
suggests that ropivacaine is still less cardiotoxic than bupivacaine, even
when given at equipotent doses.43
++
++
Regardless of the controversy, our belief is that these new
single-isomer preparations of long-acting local anesthetics, namely,
ropivacaine and levobupivacaine, are very potent, and, if injected
intravenously or with a relative overdose, can cause severe manifestations
of cardiotoxicity, though easier to treat than with racemic bupivacaine.
Indeed, there already have been three published reports of cardiac arrest
following intoxication with ropivacaine.44–46 In
contrast to the reported cases of bupivacaine cardiotoxicity in
humans,3 two patients44,45 had
progressive bradycardia and asystole rather than a lethal ventricular
arrhythmia, and all patients were able to be resuscitated easily.44–46 Nonetheless, there is no substitute for adhering to maximum
recommended dosage guidelines, using appropriate test doses to identify
misplaced needles/catheters, always fractionating the total dose of local
anesthetic, and carrying out heightened monitoring and vigilance in
preventing toxic reactions with local anesthetics.47
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Ease of Resuscitation
++
Two studies, performed in animals, suggest that cardiac resuscitation
after intoxication with the newer amide local anesthetics is easier than
with bupivacaine.48,49 In the first study, Groban et
al.48 administered incremental doses of bupivacaine,
ropivacaine, or levobupivacaine to anesthetized dogs until cardiac arrest.
At the point of cardiovascular collapse, the dogs were treated with
epinephrine, open chest cardiac massage, and an advanced life support
protocol. Mortality was greatest at 50% with bupivacaine, followed by
levobupivacaine at 30%, ropivacaine at 10%, and lidocaine at 0%.
Unfortunately, these differences did not achieve statistical significance
because of the small number of dogs studied. In another study, anesthetized
rats given an infusion of bupivacaine, ropivacaine, or levobupivacaine until
cardiovascular collapse were resuscitated with epinephrine and closed-chest
cardiac massage.49
++
Although the total number of successful resuscitations did not differ
among the groups, less epinephrine was required with ropivacaine compared
with the other two drugs. It is interesting that in the two aforementioned
case reports of cardiac arrest after ropivacaine intoxication, one patient
was resuscitated easily with atropine 1 mg and ephedrine 12 mg, and the
other with epinephrine 1 mg.44,45
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Effects on Uterine Blood Flow & Placental Transfer
++
All local anesthetics can reduce uterine blood flow at plasma levels
that greatly exceed those occurring during routine obstetric
anesthesia.50 However, because the levo-isomers of amide
local anesthetics tend to produce vasoconstriction at clinically relevant
plasma concentrations, there has been an added concern that their use could
result in a decrease in uteroplacental perfusion. It is reassuring that
neither bupivacaine, ropivacaine, nor levobupivacaine affected uterine tone
or blood flow during intravenous infusion to pregnant
sheep.51,52 Furthermore, even at relatively high drug
concentrations, fetal heart rate, blood pressure, and acid–base state were
not affected by the three drugs.52 In humans, Doppler
velocimetry studies have shown that ropivacaine has negligible effects on
the uteroplacental circulation during epidural anesthesia for cesarean
section delivery.53
++
The placental transfer of levobupivacaine and ropivacaine is similar to
that of bupivacaine.52 Intravenous infusions of
ropivacaine, levobupivacaine, or bupivacaine for 1 hour to pregnant sheep
resulted in steady-state maternal plasma concentration of 1.5–1.6 mcg/mL
and fetal concentrations of approximately 0.25 mcg/mL (Figure
7–5).52 More important, there was no significant
difference in brain and myocardium drug concentrations among the three
drugs52 (Figure 7–6).
++
++
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The clinical use of each drug is covered in chapters pertaining to
specific regional techniques. Generally speaking, there are two important
advantages of the newer amide local anesthetics. First, they tend to produce
less motor than sensory block compared with racemic bupivacaine,
particularly at the low concentrations used for pain management and
obstetrics.54,55 This is important in allowing patients
with continuous epidural/peripheral nerve block to ambulate, thus decreasing
the potential for deep venous thrombosis. It is also important in obstetric
patients, by allowing ambulation during labor and more effective expulsive
efforts during the second stage of labor. Indeed, the ratio of the median
local anesthetic concentration to achieve a Bromage score less than 4 was
0.66 for ropivacaine:bupivacaine and 0.87 for levobupivacaine:bupivacaine.
This indicates that bupivacaine produced greater motor block than either
ropivacaine or levobupivacaine.54,55 Second, as mentioned
earlier, the levorotary isomers of local anesthetics tend to produce
vasoconstriction rather than vasodilation56
(Figure 7–7) This could be useful in some clinical scenarios in
prolonging the duration of block.23
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The introduction of stereospecific levorotary isomers of the amide
local anesthetics, ropivacaine and levobupivacaine, is important because
these drugs, although more costly, appear to have a wider margin of safety
but blocking properties similar to the currently available formulation of
racemic bupivacaine. Because studies have compared the systemic toxicity of
these local anesthetics at equal doses with that of bupivacaine, this would
apply only if equal concentrations of drug are used clinically across the
board. Although this may hold true with levobupivacaine and bupivacaine, it
appears that in clinical use, anesthesiologists are using higher
concentrations of ropivacaine (0.75%). Regardless, it is noteworthy that,
even before the introduction of ropivacaine and levobupivacaine,
modifications in clinical practice, such as the use of appropriate test
doses and fractionation of the therapeutic dose, have made regional
anesthesia a very safe procedure.57 In no situation should
a greater margin of safety be a substitute for proper technique.