• Leslie C Th omas, MD
• Alan C Santos, MD

        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

Historical Perspective

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 Pearls

        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 intermediateacting 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 (V_max) and creating the potential for reentrant-type ventricular arrhythmias⁷

        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 V_max 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.

Chirality

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 levoisomers 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, singleisomer preparations of local anesthetics are now available. The first to be approved for clinical use was ropivacaine, followed shortly by levobupivacaine.

Figure 7-1. Levo- and dextro-stereoisomer configuration of amide local anesthetics.

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 monohydratesalt (molecular weight [MW] 329) of the base (MW 275).¹⁵ The pK_B 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.

Pharmacokinetics

Ropivacaine

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

Figure 7-2. Chemical structure of mepivacaine, ropivacaine, and bupivacaine.

        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

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 halflife 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

Systemic Toxicity

Ropivacaine

In vitro studies using isolated rabbit Purkinje fibers have shown that ropivacaine depresses electrophysiologic parameters such as V_max, 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

Clinical Pearls

Levobupivacaine

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

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).

Clinical Pearls

Figure 7-3. Dose (mean) required to produce convulsions and circulatory collapse with bupivacaine, levobupivacaine, and ropivacine. (Adapted from Santos AC, DeArmas P: Systemic toxicity of levobupivacaine, bupivacaine and ropivacaine during continuous intravenous infusion to nonpregnant and pregnant ewes. Anesthesiology 2001;95:1256-1264.)

        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.³⁸The 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.³⁹The 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

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

Clinical Pearls

Related posts:

Regional Anesthesia in the Patient with Preexisting Neurologic Disease. The History of Local Anesthesia. Stimulating Catheters. Diagnosis & Management of Intraspinal, Epidural, & Peripheral Nerve Hematoma. Histology of Peripheral Nerves. Supraclavicular Brachial Plexus Block.