Ropivacaine

The new long-acting amino-amide local anesthetic, ropivacaine, combines the anesthetic potency and long duration of action of bupivacaine with a toxicity profile intermediate between bupivacaine and lidocaine.

The stereospecificity of s-ropivacaine decreases cardiotoxicity.
The bupivacaine and ropivacaine molecules both have chiral centers (Figure). Commercial bupivacaine is a 50:50 racemic mixture of the S- and R-enantiomers. Because of its greater affinity for and dwell time at voltage-gated sodium channels, the R configuration confers greater cardiotoxicity to racemic bupivacaine.¹ Compared to the S-enantiomer, R-bupivacaine binds three times more firmly to the sodium channel, and unbinds 4.4 times as slowly. R-bupivacaine is also more arrhythmogenic, and slows ventricular conduction 4.6 times as much as S-bupivacaine. Ropivacaine is manufactured as the pure S-enantiomer in order to take advantage of the decreased cardiotoxicity of the S-configuration. The decrease in cardiotoxicity due to S-ropivacaine's steroselectivity is the subject of a recent review.²

Pharmacokinetic parameters
Ropivacaine is 2-3 times less lipid soluble and has a smaller volume of distribution, greater clearance, and shorter elimination half-life than bupivacaine in humans.³ The two drugs have a similar pKa and plasma protein binding (Table).

Ropivacaine undergoes hepatic biotransformation and renal clearance of the intact drug accounts for a minor proportion of total clearance. Peak plasma levels of ropivacaine following epidural of peripheral nerve block may rise twice as high as levels of bupivacaine, likely due to ropivacaine's decreased lipid solubility and volume of distribution.⁴

Ropivacaine is slightly less potent than bupivacaine.
When used for spinal anesthesia, 0.75% ropivacaine produces less intense sensory and motor block than 0.5% bupivacaine.⁵ However, multiple clinical trials comparing the two local anesthetics in epidural and axillary block demonstrate similar potency of bupivacaine and ropivacaine with respect to the intensity of sensory anesthesia.^6,7,8,9,10 Randomized double-blind clinical trials show that ropivacaine is equipotent to bupivacaine when used for lumbar epidural labor analgesia and C-section.^{4,11,12 ,13,14} Motor block with ropivacaine, however, may be delayed in onset, less intense, and shorter in duration compared with bupivacaine.^6,15,16 Determination of the true anesthetic potency of ropivacaine relative to bupivacaine is important when interpreting studies on ropivacaine's toxicity, since toxicity usually parallels anesthetic potency.

Epinephrine does not prolong the duration of ropivacaine block.
The addition of epinephrine does not prolong the duration of ropivacaine in subclavian brachial plexus^17,18 or epidural¹⁹ block. Low concentrations of ropivaciane may produce clinically significant vasoconstriction, which is not increased further by the addition of epinephrine.

Ropivacaine is indistinguishable from bupivacaine when used in obstetric anesthesia.
When continuous infusions of 0.25% ropivacaine were compared with 0.25% bupivacaine in lumbar epidural labor analgesia in two randomized double-blind clinical trials, no difference was detected in between the two drugs in intensity, duration or incidence of motor block, onset and quality of sensory analgesia, number of instrumented deliveries, number of C-sections, or neonatal neurobehavioral scores at 24 hours.^11,12 Neonates in the ropivacaine group had higher neurobehavioral scores before 24 hours.¹¹

Three randomized double-blinded clinical trials that compared 0.5% ropivacaine and 0.5% bupivacaine for C-section found no difference in sensory anesthesia, hemodynamic effects, Apgar scores, umbilical cord gases, or neonatal neurobehavioral scores.⁴,¹³,¹⁴ Maternal and neonatal free plasma concentrations of ropivacaine were higher than bupivacaine at time of delivery (0.09 mg/L vs 0.06 mg/L). The elimination half-life of ropivacaine was shorter than bupivacaine (5.2 vs 10.9 hours).

Pregnancy decreases the protein binding of bupivacaine and increases its toxicity. Pregnancy also decreases the volume of distribution of ropivacaine, but is not associated with an increase its toxicity in animals.^19,20 This finding suggests that ropivacaine may offer an even greater advantage over bupivacaine regarding its toxicity in the setting of pregnancy.

Ropivacaine has a smaller direct negative inotropic and arrhythmogenic effect compared with bupivacaine.
A study which measured the effect of bupivacaine and ropivacaine on multiple electrophysiologic parameters in isolated Purkinje fiber-ventricular muscle preparations found that bupivacaine produced greater depression of cardiac excitability and conduction.²¹ Equivalent myocardial depression with ropivacaine was produced at concentrations twice that of bupivacaine. In addition, bupivacaine induced electrophysiological alterations which could make re-entrant type ventricular arrhythmias more likely. These findings were consistent with another study that examined the effect of ropivacaine and bupivacaine on isolated rabbit hearts.²² Similar myocardial depression with ropivacaine was produced at concentrations twice as great as bupivacine. Bupivacaine produced more severe arrhythmias (AV block and ventricular arrhythmias), and more rapid onset of myocardial depression. In a live pig model in which local anesthetics were directly infused into the left anterior descending coronary artery, the electrophysiologic toxicity ratio of bupivacaine to ropivacaine (determined by the dose of drug required to produce prolongation of the QRS interval) was 6.7: 15.²³ These studies suggest that the direct myocardial toxicity of ropivacaine is about half that of bupivacaine.

Animals tolerate higher doses of intravenous ropivacaine than bupivacaine.
Ropivacaine and bupivacaine have been compared in animal studies which simulate accidental intravascular injections of local anesthetics during attempted regional block. Studies in sheep demonstrate that the dose required to produce seizures and cardiovascular collapse, and the mortality after administration of such doses, is less with ropivacaine.²⁴ The plasma concentrations measurred during seizures or cardiac arrest are also greater with ropivacaine. The pattern of death in sheep (which with lidocaine is characterized by respiratory arrest followed by hypotension without cardiac arrhythmias, and with bupivacaine is characterized by the sudden onset of ventricular arrhythmias), shares characteristics of both lidocaine and bupivacaine, although cardiac arrhythmias are not necessarily the final mechanism of death.

The incidence of arrhythmias and death is lower in animals given toxic doses of intravenous ropivacaine than bupivacaine.
Unanesthetized dogs were subjected in a blinded fashion to rapid intravenous bolus administration of twice the previously determined convulsive dose of either ropivacaine or bupivacaine.²⁵ All of the six animals receiving bupivacaine developed ventricular arrhythmias and five of these animals died. Ventricular arrhythmias developed in two of six animals given ropivacaine and one of these animals died. The incidence of ventricular arrhyhmias and death was significantly greater in the bupivacaine group. The study was then repeated in 12 more dogs, but this time resuscitation was attempted by the intravenous adminstration of thiamylal, endotracheal intubation, and ventilation with oxygen when seizures occurred.²⁶ Two dogs in the bupivacaine group died despite attempted resuscitation with epinephrine, closed chest cardiac massage, electrical cardioversion and adminstration of bretylium. Only one dog in the ropivacaine group required treatment of ventricular arrhythmias, and all dogs in the ropivacaine group survived. The difference between the ropivacaine and bupivacaine groups in survival was not significant.

The central nervous system toxicity of ropivacaine in humans is proportional to its anesthetic potency.
In studies which subjected volunteers to continuous intravenous infusions of ropivacine and bupivacaine until the onset of CNS symptoms, volunteers tolerated a 25% greater total dose of ropivacaine than bupivacine, and plasma levels of ropivacaine were greater at onset of symptoms.²⁷ This difference in dose tolerated by subjects is consistent with the reported anesthetic potency ratio of ropivacaine to bupivacaine.

Conclusions
Ropivacaine is slightly less potent than bupivacaine, but multiple studies show that it can provide adequate surgical anesthesia when used in similar concentrations. Ropivacaine is half as potent as bupivacaine in its direct negative inotropic effect and slowing of ventricular conduction. A potential for sudden ventricular arrhythmias still exists with systemic ropivacaine toxicity. Any slight advantage ropivacaine has over bupivacaine may be eliminated if higher concentrations of ropivacaine are used. Since it may provide greater differentiation of sensory and motor block at low concentrations and pregnancy does not increase its toxicity, ropivacaine may be a drug well-suited for use in epidural labor analgesia .

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