Comparative pharmacokinetics of bupivacaine and ropivacaine, a new amide local anesthetic

The pharmacokinetics of ropivacaine, a new amide local anesthetic, and bupivacaine were determined in dogs after IV and epidural administration. After 15-minute IV infusions of 3.0 mg/kg ropivacaine (n = 6) and 3.4 mg/kg bupivacaine (n = 4), the maximum arterial concentrations (Cmax) of ropivacaine averaged 2.41 +/- 0.52 micrograms/ml compared with 3.35 +/- 0.16 micrograms/ml of bupivacaine. The elimination half life (t 1/2 beta) of ropivacaine (25.9 +/- 1.7 min) was significantly shorter than for bupivacaine (39.1 +/- 13.3 min) after IV infusion. This was reflected by mean clearance values (Cl) for ropivacaine of 41.1 +/- 8.2 ml.min-1.kg-1 compared with 32.3 +/- 4.8 ml.min-1.kg-1 for bupivacaine, although the difference was not statistically significant. After epidural injections (ropivacaine n = 6; bupivacaine n = 5), a dose-related increase in Cmax was observed with both drugs. Although Cmax tended to be higher for ropivacaine, a significant difference was only attained when comparing Cmax after administration of 0.25% plain solutions of both agents. The addition of epinephrine did not consistently decrease the Cmax of either agent. The apparent t 1/2 beta of both agents was significantly longer after epidural administration than after IV infusion. No differences existed between t 1/2 beta values for ropivacaine and bupivacaine after epidural administration. Total body clearance of both agents tended to be lower after epidural administration, particularly when epinephrine-containing solutions were employed. Little difference existed between the two drugs when equivalent solutions were administered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic

Ropivacaine is a new amino-amide local anesthetic whose anesthetic profile appears similar to that of bupivacaine. Moreover, in intact animals ropivacaine was reportedly less arrhythmogenic than bupivacaine. These experiments evaluated the cardiac transmembrane electrophysiologic effects of ropivacaine compared with those of lidocaine and bupivacaine in an isolated rabbit Purkinje fiberventricular muscle preparation. Only bupivacaine (3-5 micrograms/ml, 0.92-1.5 x 10(-5) m) significantly decreased Purkinje fiber maximum diastolic potential. Action potential amplitude and maximal rate of depolarization (Vmax) were significantly decreased by all agents in the following order: bupivacaine, ropivacaine, lidocaine. High concentrations of bupivacaine and ropivacaine caused premature depolarizations during phase 3 in some preparations. In addition, bupivacaine altered the action potential configuration by producing "notching" not seen with either ropivacaine or lidocaine. This may reflect effects caused by changes in Ca2+, K+, or electrotonic effects. Ropivacaine and bupivacaine (30 micrograms/ml, 9.2 x 10(-5) m) and lidocaine (100 micrograms/ml, 3.74 x 10(-4) m) caused Purkinje fiber inexcitability and Purkinje fiber-ventricular muscle conduction block. However, the duration of PF inexcitability following exposure to ropivacaine and lidocaine was significantly shorter than in bupivacaine-treated preparation. Duration of PF-VM conduction block also tended to be shorter for ropivacaine than bupivacaine, but significantly longer than lidocaine. In general, ropivacaine is less potent than bupivacaine but more potent than lidocaine in terms of its depressant effect on cardiac excitation and conduction.     

Electrophysiologic cardiac effects of the new local anesthetic IQB-9302 and of bupivacaine in the anesthetised dog

BACKGROUND: Local anesthetics are not free from potentially fatal complications. Therefore every new local anesthetic should be tested to demonstrate a lower, or at least similar, degree of toxicity over clinically used analogs. Most toxic effects from local anesthetics affect the cardiac electrophysiologic function, so the aim of this study was to characterize the electrophysiologic effects of a new long-acting local anesthetic (IQB-9302, Ciprocaine), and compare them with those of bupivacaine in the anesthetized dog. METHODS: Eight Beagle dogs received three increasing infusion doses of either IQB-9302 or bupivacaine. Under isoflurane anesthesia, dogs were instrumented to monitor cardiovascular (cardiac output, arterial and venous blood pressures) and cardiac electrophysiologic data (sinus and atrioventricular (AV) node function, atrial, nodal and ventricular conduction times, and refractoriness). RESULTS: Only the highest dose of both drugs induced hemodynamic or electrophysiologic alterations: cardiac output and heart rate were reduced while blood pressures remained unchanged. Atrial and intranodal conduction times and atrial refractoriness increased similarly with both anesthetics, but to a slightly lesser extent with IQB-9302. Significant increases in His-Purkinje and intraventricular conduction times were the most severe noxious effects and occurred only with large doses of either drug. IQB-9302 was slightly less toxic than bupivacaine and, unlike this latter drug, potentially fatal arrhythmias were not induced. CONCLUSION: IQB-9302 has hemodynamic and cardiac electrophysiologic effects similar to those caused by bupivacaine. Nevertheless, slightly less toxic effects were derived from IQB-9302 administration than with bupivacaine, and, unlike the latter, the former might be less proarrhytmogenic. The new long-acting local anesthetic IQB-9302 may offer clinical advantages compared with bupivacaine.     

A new local anesthetic, ropivacaine. Its epidural effects in humans

The current study was initiated to evaluate the epidural anesthetic properties of 0.5%, 0.75%, and 1.0% ropivacaine, a new local anesthetic agent structurally similar to bupivacaine. Fifteen patients scheduled for lower limb orthopedic surgery were enrolled in the study. As the concentration of ropivacaine increased from 0.5% to 1.0%, the time to onset of sensory anesthesia decreased from 6.4 +/- 1.7 (SD) min to 2.4 +/- 0.6 min and the maximum level of sensory anesthesia increased from T6 to T1. These changes were not statistically significant. Time to regression of anesthesia to T12 increased from 255 +/- 73 min with the 0.5% solution to 356 +/- 75 min with 1.0% ropivacaine (P less than 0.05). The degree of motor blockade using the Bromage scale varied with the concentration. When the 0.5% concentration was used, only one patient (20%) had greater than 1+ motor blockade. However, all of the patients receiving the 0.75% or 1.0% solution had at least 2+ motor blockade. Sensory anesthesia was adequate for surgery in 14 of the 15 patients. The mean peak plasma concentration of ropivacaine (Cmax) increased from 0.65 +/- 0.15 micrograms/mL with the 100-mg dose to 1.30 +/- 0.43 microgram/mL with the 200-mg dose. No adverse effects were noted in any patient in the study. These initial studies in humans suggest that ropivacaine provides satisfactory sensory anesthesia with minimal motor blockade at a concentration of 0.5%. An increase in concentration resulted in a more profound motor blockade. The Cmax of ropivacaine in this study was below levels associated with toxicity in animal studies.     

Motor blocking minimum local anesthetic concentrations of bupivacaine, levobupivacaine, and ropivacaine in labor

BACKGROUND AND OBJECTIVES: Adequate comparison of blocking capabilities of local anesthetics should be done with some knowledge of their relative potencies. The objective of this clinical trial was to simultaneously determine the motor blocking minimum local anesthetic concentrations (MMLAC) and the relative potency ratios for racemic bupivacaine, levobupivacaine, and ropivacaine during labor. METHODS: We studied parturients with singleton term pregnancies in vertex presentation. Each patient received a 20 mL epidural bolus of bupivacaine, levobupivacaine, or ropivacaine determined by the MMLAC model. Baseline and 30 min after injection, measurements of pain and muscle strength were performed, with assessment of motor strength in the legs at 30 min being the primary outcome measure. RESULTS: There were no differences in demographic, hemodynamic, or obstetric characteristics between the patients receiving the three local anesthetics. The estimated MMLAC with the 95% confidence intervals (CI) were: Bupivacaine: 0.26% wt/vol (0.22-0.30); Levobupivacaine: 0.30% wt/vol (0.25-0.36); Ropivacaine: 0.34% wt/vol (0.29-0.38). ANOVA of MMLAC estimates was significant (F = 3.32, P = .046), and when ranked by analgesic potencies, a significant linear trend (P = .014) to increasing motor blocking potencies from ropivacaine to levobupivacaine to bupivacaine was also found. CONCLUSIONS: This study confirms a motor blocking hierarchy for the three pipecoloxylidines.     

Cardiotoxicity of ropivacaine – a new amide local anaesthetic agent

Anaesthetically equipotent doses of lidocaine, bupivacaine and a new bupivacaine-like local anaesthetic agent, ropivacaine, were injected into the left anterior descending coronary artery of pentobarbital-anaesthetized pigs. The aim was to study the cardiotoxicity of ropivacaine in relation to the two other drugs. A random, crossover, dose response study design was used. The following doses of the drugs were administered: lidocaine (L): 1,2,4,8 and 16 mg, bupivacaine (B): 0.25, 0.5, 1,2 and 4 mg and ropivacaine (R): 0.33, 0.66 1.33, 2.66 and 5.33 mg. Systemic haemodynamics, left ventricular dP/dT and a 12-lead electrocardiogram were recorded continuously during the study period. The drugs depressed cardiac contractility in relation to their local anaesthetic potency on the isolated nerve-4:3:1 (B:R:L). The prolongation of the ECG QRS-interval was regarded as a measure of electrophysiologic toxicity. Comparable prolongation of the QRS-interval was recorded after 2 mg of bupivacaine, 4.5 mg of ropivacaine and 30 mg of lidocaine. Thus, the electrophysiological toxicity ratio was 15:6.7:1 (B:R:L). Provided local anaesthetic potency data can be extrapolated from the isolated nerve preparation to regional anaesthesia in humans, ropivacaine appears to provide a greater margin of safety than bupivacaine, if inadvertently injected into the venous circulation.     

Antinociceptive and motor-blocking action of epidurally administered IQB-9302 and bupivacaine in the dog

BACKGROUND AND OBJECTIVES: The aim of this study was to compare the antinociceptive and motor-blocking effects of epidurally administered IQB-9302 (C18H26N2O.HCl) and bupivacaine in the dog. METHODS: Twelve adult female Beagle dogs were used. Each animal received 3 concentrations (0.25%, 0.50%, and 0.75%) of either IQB-9302 (n = 6) or bupivacaine (n = 6) by means of a chronic epidural catheter. The nocifensive and motor-blocking status were determined at regular intervals before (baseline) and after drug administration. RESULTS: Epidurally administered IQB-9302 caused a more potent nocifensive and motor-blocking action than bupivacaine. The duration of complete nocifensive block was the longest with IQB-9302, whereas the duration of dermatome nocifensive block was similar for both drugs. The nocifensive to motor block ratio was significantly higher with IQB-9302. CONCLUSIONS: IQB-9302 produced an anesthetic action similar to that of bupivacaine, although the former drug induced a slightly more potent nocifensive block. Nocifensive and motor block duration are very similar with IQB-9302, whereas bupivacaine induces a more prolonged motor block without nocifensive block.     

The effects of bupivacaine, ropivacaine and mepivacaine on the contractility of rat myometrium

Local anesthetic agents are commonly used for obstetric anesthesia and analgesia. We determined the effects of bupivacaine, ropivacaine and mepivacaine on the contractility of isolated pregnant rat uterine muscle strips. Uterine specimens were obtained from 18- to 21-day pregnant Wistar rats (n = 28). Myometrial strips were obtained from the uterine horns after removing the fetuses and non-uterine tissue, incubated in organ baths and contractions stimulated with oxytocin. When contractions became regular, strips were exposed to increasing concentrations of the study drugs. Mepivacaine (n = 8), ropivacaine (n = 10) and bupivacaine (n = 10) were used at cumulative doses from 10(-8) to 10(-4) mol/L. Two of the local anesthetics, bupivacaine most, ropivacaine least, caused a dose-dependent inhibition of uterine contractility. In contrast, mepivacaine significantly increased uterine contractility. Bupivacaine, ropivacaine and mepivacaine were found to have no effect on frequency of uterine contractions. These results demonstrate that bupivacaine and ropivacaine may inhibit myometrium contractility.     

Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog

This study evaluated the systemic toxicity, arrhythmogenicity, and mode of death of convulsant and supraconvulsant doses of lidocaine, bupivacaine, and ropivacaine. Experiments in awake dogs were designed to mimic the clinical situation of an accidental intravenous (IV) injection of local anesthetics. On the first experimental day, lidocaine (8 mg.kg-1.min-1), bupivacaine (2 mg.kg-1.min-1), and ropivacaine (2 mg.kg-1.min-1) were infused intravenously until seizures occurred (n = 6 for each group). The average dose and arterial plasma concentration at seizure onset was 20.8 +/- 4.0 mg/kg and 47.2 +/- 5.4 micrograms/mL for lidocaine, 4.31 +/- 0.36 mg/kg and 18.0 +/- 2.7 micrograms/mL for bupivacaine, and 4.88 +/- 0.47 mg/kg and 11.4 +/- 0.9 micrograms/mL for ropivacaine. The margin of safety between the convulsive and lethal doses was determined by administering two times the convulsive dose 24 h later. Two dogs given lidocaine died because of progressive hypotension, respiratory arrest, and finally cardiovascular collapse with an average peak plasma concentration (Cmax) of 469 micrograms/mL. No ventricular arrhythmias were observed in this group. Ventricular arrhythmias occurred in five of six dogs receiving bupivacaine. Four animals died because of hypotension, respiratory arrest, and cardiovascular collapse. One additional animal died because of ventricular fibrillation. The Cmax for bupivacaine was 70.1 +/- 14.6 micrograms/mL in nonsurvivors. In the ropivacaine group one animal died because of hypotension, respiratory arrest, and cardiovascular collapse (Cmax = 72.4 micrograms/mL). A surviving dog had transient premature ventricular contractions. Twenty-four hours later three times the convulsive dose was administered to the survivors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine

We tested the hypothesis that local anesthetics instilled at the end of laparoscopic gynecologic procedures are able to prevent postoperative pain at wake-up and during the first 24 h. A total of 180 patients were randomly assigned into three groups to receive an intraperitoneal instillation of 20 mL of either bupivacaine 0.5% (Group B), ropivacaine 0.75% (Group R) or saline (Group S) at the end of surgery. All patients received analgesia with acetaminophen and ketoprofen IV infusions. Pain was assessed by using a 0-10 graded numerical scale (NS) every 5 min in the postanesthesia care unit and IV morphine was administered if NS was >4. Assessment of pain was continued every 4 h on the ward, and subcutaneous morphine was injected if needed to keep the NS score < 4. Postoperative nausea and vomiting (PONV) was rated on a 4-point scale. The morphine consumption at wake-up and over the first 24 h was significantly lower (P < 0.05) in Group B (mean, 0.92 mg at wake-up; 3.08 mg over 24 h) and in Group R (mean, 0.25 mg at wake-up; 0.69 mg over 24 h), than in Group S (mean, 4.18 mg at wake-up; 12.93 mg over 24 h). The morphine-sparing effect of ropivacaine was significantly greater than that of bupivacaine. Both local anesthetics were effective in the prevention of PONV. We concluded that local anesthetics should be instilled in all gynecologic patients at the end of all laparoscopic procedures. Implications: Local anesthetic instillation (ropivacaine rather than bupivacaine) at the end of laparoscopy prevents postoperative pain and dramatically decreases the need for morphine. This technique, compared with placebo, is safe, improves patient comfort, shortens the stay in the postoperative care unit and decreases nursing care in the ward.     

Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103)

The local anaesthestic properties of 1-propyl-2',6'-pipecoloxylidide, a congener of mepivacaine and bupivacaine, and its enantiomers were compared in animals. The (S)-enantiomer (ropivacaine, LEA 103) produced a longer duration of sciatic nerve block and infiltration anaesthesia than the racemate and the (R)-form. Ropivacaine and bupivacaine were equally potent in terms of block of evoked action potential in vitro and minimum effective concentration in vivo. Ropivacaine 0.25-1.0% was distinctly longer acting than bupivacaine on infiltration, equally effective in sciatic and brachial plexus block and somewhat shorter lasting in epidural and spinal blockade. There were tendencies towards a greater benefit from the addition of adrenaline with ropivacaine in epidural anaesthesia and a shorter latency to block in some of the tests. Ropivacaine seems less vasodilative than bupivacaine and capable of producing some vasoconstriction over a wider range of low concentrations, which may explain its longer duration of intradermal anaesthesia. The somewhat shorter duration of central blockade of ropivacaine is probably a result of lesser lipid solubility. Ropivacaine was less toxic (i.v. and s.c. LD50-values) than bupivacaine but more toxic than lidocaine, and produced only weak local irritation. Due to a combination of interesting local anaesthetic properties and relative safety including cardiotoxic potential, we consider ropivacaine a candidate for further studies.     

Comparative efficacy of ropivacaine and bupivacaine infiltrative analgesia in otoplasty

A prospective double-blind study was conducted to compare the anesthetic efficacy of ropivacaine and bupivacaine in a bilaterally symmetrical otoplasty model. Because ropivacaine has a significantly lower toxic potential than bupivacaine, it may be established as the anesthetic agent of choice for low-dose infiltration anesthesia in routine aesthetic facial operations. Each of the 24 adult patients undergoing bilateral otoplasty received infiltration with ropivacaine in 1 auricle and an equal volume of bupivacaine in the other. Patients were requested to assess their pain separately in each side at the times of infiltration, during cartilage scoring, and 2, 6, and 10 hours postoperatively on a visual analog scale. Intraoperative success rates were similar, and overall analgesia achieved at 2 hours, 6 hours, and 10 hours postoperatively was not found to be statistically different between ropivacaine and bupivacaine. The authors conclude that ropivacaine can be used as an effective alternative to bupivacaine in otoplasty.     

Comparative effects of bupivacaine and ropivacaine on intracellular calcium transients and tension in ferret ventricular muscle

BACKGROUND: Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. METHODS: Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. RESULTS: Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. CONCLUSION: The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.     

Median effective local anesthetic doses of plain bupivacaine and ropivacaine for spinal anesthesia administered via a spinal catheter for brachytherapy of the lower abdomen

BACKGROUND AND OBJECTIVES: Continuous spinal anesthesia via a spinal catheter allows adjusting the duration and extent of anesthesia to surgical needs, maintenance of hemodynamic stability, and good postoperative analgesia. This study was designed to determine the median effective local anesthetic dose of plain ropivacaine and bupivacaine administered intrathecally for interstitial brachytherapy of the lower abdomen using the Dixon up-and-down method. METHODS: Forty patients were randomly allocated to receive either intrathecal bupivacaine 5 mg per mL or ropivacaine 10 mg per mL via a 24-gauge spinal catheter at the L3-4 interspace. The initial dose was 10 mg of bupivacaine or 20 mg of ropivacaine; the dosing intervals were 1 mg and 2 mg, respectively. Doses for subsequent patients were determined by the response of the previous patient in that group. Successful anesthesia was defined as a loss of sensation to a cold stimulus at the T6 level and full motor blockade within 20 minutes after administration of the local anesthetic. RESULTS: The median effective local anesthetic dose for intrathecal bupivacaine was 11.2 mg (95% confidence interval [CI], 10.3-12.1) and 22.6 mg for ropivacaine (95% CI, 20.5-24.6). A relative analgesic potency ratio of 0.50 (95% CI, 0.44-0.56) was calculated between the median effective local anesthetic dose of intrathecal bupivacaine and ropivacaine. CONCLUSIONS: Bupivacaine and ropivacaine are appropriate for continuous spinal anesthesia for interstitial radiation therapy procedures of the lower abdomen. In the dose-ranges investigated, intrathecal ropivacaine is approximately half as potent as bupivacaine.