Amino-amide Local Anesthetics Research Articles

Comparison Between Dexamethasone Versus Clonidine as Adjuvants to 0.75% Ropivacaine in Ultrasound Guided Brachial Plexus Block for Upper Limb Orthopedic Surgeries: A Randomized Prospective Clinical Study

Background: Ropivacaine is an amino-amide local anesthetic, extensively used for peripheral nerve blocks, numerous adjuvants have been added to Ropivacaine to prolong the duration of analgesia. Aim: To compare the effectiveness of adding Dexamethasone to Ropivacaine versus adding Clonidine to Ropivacaine in ultrasound guided supraclavicular brachial plexus block in terms of analgesic duration, onset & duration of sensory and motor blockade.
 Methods: A prospective randomized single blinded study carried out in 70 patients of ASA grade I and II, aged 20 to 60 years scheduled for elective upper limb orthopedic surgeries. Patients were randomly allocated into two groups, Group RC - patients received 20ml of 0.75% ropivacaine along with 1mcg/kg of clonidine diluted to 2ml of normal saline, Group RD - patients received 20ml of 0.75% ropivacaine along with 8mg of dexamethasone (2ml). Statistical Analysis: Onset & duration of sensorimotor blockade, duration of analgesia was assessed by Unpaired t-test. If p-value <0.05, results were statistically significant & p-value <0.001 were highly significant.
 Results: Duration of analgesia is superior and statistically significant in Group RD (1,172.57± 18.37 vs 931.09± 16.3). Onset time for sensory (3.14 ± 1.00 vs 9.71± 1.23) and motor (7.60 ± 1.54 vs 13.66± 1.03) block is rapid in Group RD. Duration of sensory (1,106.57± 20.28 vs 786.26± 31.43) and motor (997.74 ± 24.9 vs 674.57 ± 2.18) block is enhanced in Group RD.
 Conclusion: Dexamethasone as an adjuvant to ropivacaine provided superior post-operative analgesia, faster onset and longer duration of sensory and motor blockade.

Crystallization of Ropivacaine and Bupivacaine When Mixed With Different Adjuvants: A Semiquantitative Light Microscopy Analysis

(Reg Anesth Pain Med. 2022:rapm-2022-103610) The use of adjuvants to local anesthetics may prolong their duration or speed the onset of action. Amino-amide local anesthetics have the potential to precipitate when mixed with commonly used adjuvants, which can result in crystal deposition in the perineural or vascular regions. This study aimed to assess the occurrence of crystallization with commonly employed local anesthetic-adjuvant combinations, determine if there is a correlation with the solution’s pH, and assess if there is a change over time in crystallization grade.

Fabrication and Evaluation of Lidocaine Hydrochloride loaded Cubosomes

Topical delivery of local anaesthetic drugs such as Lidocaine HCl using carriers and novel nanotechnology can enhance effective drug permeation through the skin into deeper layers and exhibit desirable duration of action. The present study was aimed to formulate and evaluate Lidocaine HCl loaded cubosomes (LHLCs) for sustained therapeutic topical action. Cubosomes emanated as favourable means for the delivery of the drug. LHLCs were prepared by top-down technique using lipid and polymer. Eight formulations of LHLCs were prepared using different concentrations of glyceryl monooleate (GMO) and Poloxamer 407 (P-407). Local anaesthetics create loss of sensation in particular region of the body by inhibiting impulse generation and propagation. Lidocaine HCl is most commonly used amino amide local anaesthetic. It is used as local, topical, intravenous, epidural, peripheral and spinal anaesthesia. The prepared cubosomal dispersions were evaluated to determine surface morphology, particle size, poly dispersibility index (PDI), zeta potential, entrapment ability, tissue distribution studies, and in vitro drug release studies. Scanning Electron Microscopic analysis confirmed that drug was encapsulated in bicontinuous structure. The maximum entrapment efficiency was found to be 89.85±1.1% with vesicle size as 228±2.1nm, charge as -5.68±2.7, PDI as 0.295 and 98.83%± 0.12 in vitro drug release at the end of 12 hr for F7 formulation, which was confirmed as optimized cubosomal dispersion.

A comparative study of plain and hyperbaric solutions of 0.75% ropivacaine in spinal anaesthesia in elective lower abdominal and lower limb surgeries

Background and objective: Spinal anaesthesia is the most common technique of regional anaesthesia used for lower abdominal and lower limb surgeries. Bupivacaine is the commonly administered drug. Ropivacaine, is an amino amide local anaesthetic, which has less cardiovascular and central nervous systems toxicity compared with bupivacaine. This study is undertaken to compare plain and hyperbaric solutions of ropivacaine in spinal anaesthesia. Methods: 80 patients of ASA I/II physical status undergoing elective lower abdominal and lower limb surgeries were randomised into 2 groups. Group C (n=40) patients received 3ml of 0.75% plain ropivacaine with 0.4 ml of normal saline and Group D (n=40) patients received 3 ml of 0.75% plain ropivacaine with 0.4 ml of 25% dextrose. Hemodynamic parameters, time of onset and duration of sensory and motor blockade, maximum height of block, total duration of sensory and motor blockade and time to mobilise were recorded. Results: Hemodynamic parameters were comparable between the two groups except at few intervals. Demographic data and duration of surgery were comparable. The onset of block to T10 in group C 10.1 ± 1.6 min, group D 4.6 ± 0.9 (p value <0.001), mean time to maximum block in group C 13.0 ± 2.7 min, group D 8.9 ± 0.9 (p value <0.001) were statistically significant. Mean duration of block at T10 in group C was 94.7± 24.7 min, group D 146.1 ± 31.9 (p value <0.001), duration of sensory regression in group C 291.6 ± 74.3 min, group D 239.9 ± 39.8 (p value <0.001), duration of motor regression in group C 225.4 ± 68.4 min, group D 186.0 ± 41.0 (p value 0.003) and time to mobilise in group C was 309.1 ± 76.3 min, group D 251.0 ± 41.1 min (p value <0.001) which were statistically significant. Conclusion: Hyperbaric ropivacaine has early and faster onset, spreads more to higher levels, has more denser block and is early to regress compared to plain ropivacaine.

A PLGA-PEG-PLGA Thermosensitive Gel Enabling Sustained Delivery of Ropivacaine Hydrochloride for Postoperative Pain Relief.

Postoperative pain is a complex physiological response to disease and tissue injury. Moderate-to-severe pain typically occurs within 48 h after surgery. Amino amide local anesthetics are widely applied to manage postoperative pain, and they have high efficacy, a low risk for addiction and limited side effects. However, these anesthetics also have short half-lives, often necessitating continuous injection to obtain satisfactory pain relief. In the current work, we used a poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA (PLGA-PEG-PLGA) temperature-sensitive gel to deliver a local anesthetic, ropivacaine hydrochloride (RP), to prolong its analgesic effect. We investigated the influence of polymer and drug concentration on gelation temperature and the in vitro drug release rate from the temperature-sensitive gel. RP-loaded PLGA-PEG-PLGA solution is a liquid at room temperature and forms a gel at temperatures slightly lower than body temperature. With regard to the gel's drug release rate, 37.5, 51.3 and 72.6% of RP was released at 12, 24 and 48 h, respectively. This in vitro drug release profile conformed to the Higuchi equation. To assess pain control efficacy when using the gel, we evaluated the mechanical paw withdrawal reflex threshold, thermal pain threshold and incision cumulative pain scores in a rat incisional model. The results showed that the anti-pain effect of a single injection of RP-loaded gel at the incision site lasted for 48 h, which is significantly longer than the effect produced by injection of RP solution alone. The use of RP-loaded thermosensitive gels could provide a promising method for managing postoperative pain.

A DFT study on the geometry, spectroscopic properties, and tautomerization of the local anaesthetic drug prilocaine

The prilocaine is a significant amino amide local anaesthetic. This drug can exist as three possible tautomers. Herein, by using density functional theory (DFT), and handling the solvent effects with the PCM model, the structure, energetic behavior, kinetics and mechanism of tautomerization, as well as the natural bond orbital analysis (NBO) of the prilocaine are reported. P1 is the most stable tautomer of the prilocaine, which can be tautomerized to two other tautomers via the intramolecular-proton transfer. Good agreement between the calculated NMR chemical shifts and IR vibrational frequencies with the experimental values approves the suitability of the optimized geometry for the prilocaine. A large HOMO-LUMO energy gap implies a high stability of the prilocaine.

Comparison of Intra-Operative ECG Variations (QRS and PR Interval Prolongation) Between 0.25% Ropivacaine and 0.25% Bupivacaine in Patients Undergoing Lower Limb Surgery under Epidural Blockade

Background: Ropivacaine, new aminoamide local anaesthetic (LA) drug, is chemically homologous to bupivacaine. The lower lipid solubility and higher clearance of ropivacaine compared with bupivacaine is presumed to retard penetration of myelin sheaths, leading to a decreased potential for neural and cardiac toxicity. This may offer an advantage in terms of systemic toxicity. Experimental studies and case reports confirm this hypothesis, showing that ropivacaine causes fewer cardiotoxic effects and is better alternative to bupivcaine. Material & Method: Thirty ASA grade I and II patients of either sex, aged between 20 -50 years undergoing elective lower limb surgeries were enrolled in each group using double-blind randomization. Each group received 0.25%, 25 ml of either bupivacaine or ropivacaine with 18 G needle as single shot epidural injection. A sensory level of T10 was achieved. Variations in heart rate, arterial blood pressure and ECG (PR interval & QRS prolongation, ectopics, arrhythmias) were recorded before epidural injection, 10 minutes after epidural injection and thereafter every 10 minutes interval till the end of surgery. Result: This study showed that epidural ropivacaine produced ECG changes which were substantially similar to those produced by equipotent concentrations and doses of bupivacaine. Conclusion: ECG changes in terms of ventricular arrhythmias, QRS and P-R interval were clinically simi

Dexmedetomidine Dose-Dependently Attenuates Ropivacaine-Induced Seizures and Negative Emotions Via Inhibiting Phosphorylation of Amygdala Extracellular Signal-Regulated Kinase in Mice.

Ropivacaine (Ropi), one of the newest and safest amino amide local anesthetics, is linked to toxicity, including the potential for seizures, changes in behavior, and even cardiovascular collapse. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has been widely used in anesthesia and critical care practice. To date, the underlying mechanisms of the effects of Dex premedication on Ropi-induced toxicity have not been clearly identified. In the current study, we investigated the effects of increasing doses of Dex premedication on 50% convulsive dose (CD50) of Ropi. With increasing doses of intraperitoneal (i.p.) Dex 10 min prior to each i.p. RopiCD50, the latency and duration of seizure activity were recorded. Open-field (OF) and elevated plus maze (EPM) test were used to measure negative behavioral emotions such as depression and anxiety. Immunohistochemistry and Western blot were utilized to investigate phosphorylation-extracellular regulated protein kinases (p-ERK) expression in the basolateral amygdala (BLA) on 2 h and in the central amygdala (CeA) on 24 h after convulsion in mice. The results of our investigation demonstrated that Dex dose-dependently increased RopiCD50, prolonged the latency and shortened the duration of each RopiCD50-induced seizure, improved the negative emotions revealed by both OF and EPM test, and inhibited p-ERK expression in the BLA and the CeA.

Genotoxic evaluation of bupivacaine and levobupivacaine in the Drosophila wing spot test.

Bupivacaine and levobupivacaine are amino amide local anesthetics commonly used in medical practice. Although bupivacaine consists of a racemic mixture of S (-)-bupivacaine and R (+)-bupivacaine enantiomers, levobupivacaine is comprised of pure S (-)-bupivacaine. It has been known that levobupivacaine is preferable to bupivacaine since it may cause cardiovascular and nervous system toxicity. For determining genotoxicity of these anesthetics, we used the wing somatic mutation and recombination test in Drosophila melanogaster. Three-day-old trans-heterozygous larvae were treated with bupivacaine and levobupivacaine. Analysis of the standard crosses indicated that bupivacaine and levobupivacaine did not exhibit mutagenic or recombinogenic activity until toxic doses have been reached at the larval stage. When we examined bupivacaine and levobupivacaine in the HB cross, bupivacaine did not exhibit any genotoxicity at high concentrations (500µg/mL), but levobupivacaine did exert genotoxicity at high concentrations (1000µg/mL)-depending on the substantial recombinogenic effect.

Cytotoxic Effects of Ropivacaine, Bupivacaine, and Lidocaine on Rotator Cuff Tenofibroblasts

Background: Concern has recently arisen over the safety of local anesthetics used on human tissues. Hypothesis: Aminoamide local anesthetics have cytotoxic effects on human rotator cuff tenofibroblasts. Study Design: Controlled laboratory study. Methods: Cultured human rotator cuff tenofibroblasts were divided into control, phosphate buffered saline (PBS), and local anesthetic study groups; the PBS study group was further subdivided by pH level (pH 7.4, 6.0, and 4.4). The 6 local anesthetic subgroups (0.2% and 0.75% ropivacaine, 0.25% and 0.5% bupivacaine, and 1% and 2% lidocaine) were also studied at 10% dilutions of their original concentrations. Exposure times were 5, 10, 20, 40, or 60 minutes for the higher concentrations and 2, 6, 12, 24, 48, or 72 hours for the lower concentrations. Cell viability was evaluated through live, apoptotic, and necrotic cell rates using the annexin V–propidium iodide double-staining method. Intracellular reactive oxygen species (ROS) and the activity of mitogen-activated protein kinases (MAPKs) and caspase-3/7 were investigated. Results: The control and PBS groups showed no significant differences in cell viability (P > .999). In the local anesthetic study groups, cell viability decreased significantly with increases in anesthetic concentrations (P < .001) and exposure times (P < .001), with the exception of the lidocaine subgroups, where this effect was masked by the very high cytotoxicity of even low concentrations. Among the studied local anesthetic subgroups, 0.2% ropivacaine was the least toxic. The levels of intracellular ROS of each local anesthetic subgroup also increased significantly (P < .05). The studied local anesthetics showed increases in the phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 as well as in levels of caspase-3/7 activity (P < .001). Conclusion: The cytotoxicity of the anesthetics studied to tenofibroblasts is dependent on exposure time and concentration. Of the evaluated anesthetics, ropivacaine is the least toxic in the clinically used concentration. The studied anesthetics induce tenofibroblast cell death, mediated by the increased production of ROS, by the increased activation of ERK1/2, JNK, and p38 and by the activation of caspase-3/7. Clinical Relevance: This study identified the cytotoxic mechanisms of aminoamide local anesthetics acting on rotator cuff tenofibroblasts. The greatest margin of safety was found in lower anesthetic concentrations in general and more specifically in the use of ropivacaine.

Development of hydrophilic nanocarriers for the charged form of the local anesthetic articaine

One of the current challenges in drug encapsulation concerns the development of carrier systems for hydrophilic compounds. Potential carriers include nanocapsules prepared with amphiphilic polymers, which consist of a polymeric coating surrounding an aqueous nucleus, or dense matrices such as nanospheres of alginate/chitosan, where the drug may be dispersed in the matrix or adsorbed on the surface. The development of new formulations of nanocarriers, for example the poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG–PCL) nanocapsules and alginate/chitosan (AG/CS) nanospheres described in this work, is needed in the case of ionized drugs such as articaine. This amino amide local anesthetic is the drug of choice in dentistry for regional anesthesia as well as the relief of acute and chronic pain. Here, the physico-chemical properties of suspensions of the nanoparticles (considering diameter, polydispersion, and zeta potential) were determined as a function of time, in order to establish the stability of the systems. The formulations did not show any substantial changes in these parameters, and were stable for up to 120 days of storage at ambient temperature. Satisfactory encapsulation efficiencies were obtained for the PEG–PCL nanocapsules (60%) and the AG/CS nanospheres (45%). Cytotoxicity assays confirmed that the encapsulation of articaine reduced its toxicity, relative to the free drug. The most promising results were obtained using the vesicular system (PEG–PCL nanocapsules), which not only altered the release profile of the drug, but also resulted in the lowest toxicity. This carrier system therefore holds promise for use in future practical applications.

Mepivacaine-induced contraction involves increased calcium sensitization mediated via Rho kinase and protein kinase C in endothelium-denuded rat aorta

Mepivacaine is an aminoamide local anesthetic that produces vasoconstriction in vivo and in vitro. The goals of this in vitro study were to determine whether mepivacaine-induced contraction involves calcium sensitization in isolated endothelium-denuded aortas, and to investigate the specific protein kinases involved. The effects of mepivacaine and potassium chloride on intracellular calcium concentrations ([Ca2+]i) and tension in the presence or absence of Y-27632 or GF 109203X were measured simultaneously using the acetoxymethyl ester of fura-2-loaded aortic strips. Cumulative mepivacaine concentration–response curves were generated in the presence or absence of the following inhibitors: Rho kinase inhibitor Y-27632, protein kinase C (PKC) inhibitor GF 109203X, extracellular signal-regulated kinase (ERK) inhibitor PD 98059, c-Jun NH2-terminal kinase (JNK) inhibitor SP600125, and p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580. Phosphorylation of PKC and MAPK, and membrane translocation of Rho kinase were detected in vascular smooth muscle cells by Western blotting. The slope of the mepivacaine-induced [Ca2+]i-tension curve was higher than that of the KCl-induced [Ca2+]i-tension curve. Pretreatment with Y-27632 or GF 109203X shifted the mepivacaine-induced [Ca2+]i-tension curve to the lower right. Pretreatment with Y-27632, GF 109203X, PD 98059, or SP600125 attenuated mepivacaine-induced contraction in a concentration-dependent manner. Y-27632 and GF 109203X attenuated mepivacaine-induced Rho kinase membrane translocation and PKC phosphorylation, respectively. PD 98059 and SP600125 attenuated mepivacaine-induced ERK and JNK phosphorylation, respectively. Taken together, these results indicate that mepivacaine-induced contraction involves increased calcium sensitization mediated by Rho kinase and PKC. Such contraction mainly involves activation of ERK- and JNK-mediated pathways.

Molecular Dynamics Study on the Encapsulation of Prilocaine in Liposomes at Physiological pH

In this work, we investigated the concentration effects on the encapsulation of prilocaine (PLC), an aminoamide local anesthetic, into a small unilamellar liposome, at physiological pH. On the line of our previous work, we have carried out Molecular Dynamics (MD) simulations using a coarse grain (CG) model that allow us to reach the microsecond time scale. At physiological pH there is a partition between protonated and neutral PLCs. In order to estimate the protonated/neutral PLC ratio at physiological pH (7.4), we have used the Henderson-Hasselbach equation. We have studied three PLC:lipid molar concentrations, ranging between 10:10 to 1:4. We essentially found that all neutral PLC molecules rapidly diffuse into the hydrophobic region of the vesicle adopting an asymmetric bimodal distribution. Moreover, protonated PLC molecules partition between the external monolayer of the vesicle and the water phase, having a high rate of exchange between this two phases, with no access to the inner part of the liposome in a concentration dependent way. In this way, we found that the behavior of PLCs at physiological pH is a combination of high and low pH, especially at low concentration of local anesthetics.

Vasoconstriction Potency Induced by Aminoamide Local Anesthetics Correlates with Lipid Solubility

Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED50) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED50) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED50 in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r2 = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa.

A comparison of the systemic toxicity of lidocaine versus its quaternary derivative QX-314 in mice

We recently showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia with a slow onset in animal models in vivo. As quaternary agents do not rapidly penetrate biological membranes or the blood-brain barrier, QX-314 may represent a local anesthetic with decreased systemic toxicity compared with conventional tertiary aminoamines. To test this hypothesis, we conducted an in vivo animal study in mice to compare QX-314 with lidocaine in terms of its relative central nervous system (CNS) and cardiac toxicity. With approval from the institutional Animal Care Committee, we used the "up-and-down" method to determine the relative potencies (ED(50)) of lidocaine and QX-314 for CNS and cardiac toxicity in adult CD-1 mice (weight, 20 to 35g). The animals were administered either intravenous lidocaine or QX-314 (dose range, 7.5 to 30mg·kg(-1)) and were observed for signs of CNS toxicity (convulsions, ataxia, loss of righting reflex, and/or death). We also observed animals for electrocardiographic evidence of toxic effects on cardiac automaticity, conductivity, and rhythmicity. The ED(50) of lidocaine for CNS toxicity as determined by the "up-and-down" method was 19.5mg·kg(-1) (95% confidence interval [CI], 17.7 to 21.3mg·kg(-1); n=6) compared with 10.7mg·kg(-1) for QX-314 (95% CI, 9.1 to 12.3mg·kg(-1); n=6) (potency ratio, 1.8). Similarly, the ED(50) of lidocaine for electrocardiographic evidence of cardiac toxicity was significantly higher than that of QX-314 (ED(50) of lidocaine, 21.2mg·kg(-1); 95% CI, 19.0 to 23.4mg·kg(-1); n=6 vs ED(50) of QX-314, 10.6mg·kg(-1); 95% CI, 8.4 to 12.8mg·kg(-1); n=6) (potency ratio, 2.0). In this in vivo animal study, the relative potencies of QX-314 for systemic CNS and cardiac toxicity were significantly higher than those of lidocaine. These data do not support the hypothesis that QX-314 is a safer local anesthetic compared with lidocaine in terms of systemic toxicity. Whereas our results do not exclude the possibility that QX-314 may represent a clinically useful agent to produce long-lasting local anesthesia and nociceptive blockade after a single shot in humans, its systemic toxicity relative to conventional tertiary aminoamide local anesthetics and the underlying mechanisms warrant further study.

Preferential location of prilocaine and etidocaine in phospholipid bilayers: A molecular dynamics study

In this work, we report a 20-ns constant pressure molecular dynamics simulation of the uncharged form of two amino–amide local anesthetics (LA), etidocaine and prilocaine, present at 1:3 LA:lipid, molar ratio inside the membrane, in the hydrated liquid crystal bilayer phase of 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphatidylcholine (POPC). Both LAs induced lateral expansion and a concomitant contraction in the bilayer thickness. A decrease in the acyl chain segment order parameter, − S CD, compared to neat bilayers, was also observed. Besides, both LA molecules got preferentially located in the hydrophobic acyl chains region, with a maximum probability at ∼12 and ∼10 Å from the center of the bilayer for prilocaine and etidocaine, respectively.

Lipid infusion resuscitation for aminoamide local anesthetic toxicity

Systemic local anesthetic toxicity is a rare, but potentially fatal complication. Experiments have shown that lipid emulsion therapy can rapidly restore circulation after aminoamide local anesthetic induced cardiovascular collapse in both intact ani-mals and isolated hearts. Several case reports have showed that lipid emulsion quickly resuscitated cardiac arrest following regional anesthesia and reversed central nervous system symptoms induced by local anesthetic intoxication. The mechanism of lipid rescue is probably a combination of reduced tissue binding local anesthetic and a beneficial cardiac cell energetic-metabolic effect. Key words: Lipid infusion; Local anesthetics toxicity; Asystlole; Resuscitation

Drug interactions: lipoxygenase inhibitors interfere with ropivacaine-induced vasoconstriction

Local anesthetics are used to facilitate analgesia through their inhibition of sensory nerve conduction. As sodium channel blockers, local anesthetics inhibit the propagation of action potentials along nerve axons participating in the transmission of pain signals through the peripheral and central nervous systems. Aside from sodium channel inhibition, it is now becoming clear that local anesthetics have actions on other important cellular components. In this issue of the Journal, Sung et al. explore the mechanisms of ropivacaine-induced vasoconstriction through the modulation of arachidonic acid metabolism and production of vasoactive leukotrienes. Their article raises the interesting possibility that existing drug therapies in patients can affect the pharmacokinetics of co-administered local anesthetics. Ropivacaine is a relatively new, long acting aminoamide local anesthetic that is structurally similar to bupivacaine. However, ropivacaine has relatively low central nervous system (CNS) toxicity and cardiotoxicity compared to bupivicaine. The pharmacokinetic properties of these two local anesthetics are similar with respect to their pKa values and protein binding properties. However, ropivacaine has a smaller volume of distribution, higher plasma clearance and is less lipid soluble than bupivacaine. Because of its lower lipid solubility and epidural/neural fat absorption, ropivacaine used for epidural and peripheral nerve blockade has a reduced duration of action compared to bupivacaine. The shorter duration of action is due to a greater plasma resorption resulting in a lower elimination half-life (t1/2) and higher maximal concentration in the plasma (Cmax). 6–9 In contrast, local wound infiltration of ropivacaine results in a longer duration of action compared to bupivacaine, which has been attributed to a direct vasoconstrictive effect of ropivacaine on surrounding vessels. In 2005, Yu et al. demonstrated the direct vasoconstrictive effect of ropivacaine on de-endothelialized rat aortic vasculature which Sung et al. reaffirm in this issue. Sung et al. demonstrated that clinically relevant concentrations of S-ropivacaine (Naropin) at between 10 lM to 1 mM caused vasoconstriction of de-endothelialized rat aorta. These concentrations, though much above central neurotoxic and cardiotoxic thresholds, would be found in proximity of nerves during peripheral, neuraxial, or local injections of ropivacaine. The direct vasomotor actions of ropivacaine have been studied in different vascular structures including capillaries, femoral veins, umbilical arteries, femoral arteries, and the aorta. Some of these studies showed no effect of ropivacaine on impairment of vasorelaxation while others observed its direct vasoconstrictive effects. The vasoconstrictive properties of ropivacaine are not unique, and are shared by several other amide local anesthetics such as lidocaine and bupivacaine. Unfortunately, the preparations used by both Sung et al. and Yu et al. were de-endothelialized, thereby, eliminating the effect of nitric oxideand some KATP channel-induced vasorelaxation mechanisms that D. T. Joo, MD, PhD (&) Department of Anesthesia, Program in Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, 555 University Ave., Rm. 5013D, Toronto, ON M5G 1X8, Canada e-mail: daisy_joo@yahoo.com

Un effet direct de la ropivacaïne implique l’activation des voies de la lipoxygénase dans le muscle lisse de l’aorte du rat

Ropivacaine is a long-acting amino-amide local anesthetic that induces vasoconstriction in vitro and in vivo. The aim of this study was to investigate the pathways involved in arachidonic acid metabolism associated with S-ropivacaine-induced contraction of rat aortic smooth muscle in vitro. Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dose-response curves were generated with concentrations of 10(-5) to 10(-3) M ropivacaine enantiomer in the presence or absence of quinacrine dihydrochloride, nordihydroguaiaretic acid, quinacrine dihydrochloride plus nordihydroguaiaretic acid, indomethacin, fluconazole, AA-861, and verapamil. The maximal S-ropivacaine-induced contractile response achieved at 3x10(-4) M was also assessed in aortic rings pretreated with normal or calcium-free Krebs solution. Ropivacaine enantiomers induced dose-dependent biphasic contractions in aortic rings. S-ropivacaine (10(-4), 3x10(-4) M) induced a stronger contraction than R-ropivacaine. Quinacrine dihydrochloride (2x10(-5), 4x10(-5) M) attenuated the S-ropivacaine-induced biphasic contraction in a dose-dependent manner. Indomethacin (3x10(-5), 6x10(-5) M), nordihydroguaiaretic acid (10(-5) M), and AA-861 (10(-5) M) also attenuated the S-ropivacaine-induced dose-dependent biphasic contraction, whereas fluconazole (3x10(-5)) had no effect. Combined pretreatment with quinacrine dihydrochloride and nordihydroguaiaretic acid almost completely abolished the S-ropivacaine-induced contraction. S-ropivacaine-induced contractile responses were attenuated by verapamil (10(-5) M) and calcium-free Krebs solution. S-ropivacaine induces dose-dependent biphasic contractions in rat aortic smooth muscle through a mechanism requiring extracellular calcium that is mediated by activation of the lipoxygenase pathway and, to a lesser extent, the cyclooxygenase pathway.

Lipophilic and Stereospecific Interactions of Amino-amide Local Anesthetics with Human Kv1.1 Channels

This study's aim was to investigate the interaction of amino-amide local anesthetics with human Kv1.1 potassium channels. These channels were chosen because of their proven physiologic role. By using a homolog series of local anesthetics with different lengths of the N-substituent, it was intended to elucidate the role of lipophilic interactions with Kv1.1. The use of stereoisomers allowed testing of the role of polar drug actions. Human Kv1.1 channels were measured with the patch clamp technique. Concentration-response data were described by Hill functions. Gating changes were described by Boltzmann functions. Inhibition of Kv1.1 channels by dextrobupivacaine, bupivacaine, levobupivacaine, dextroropivacaine, levoropivacaine, and mepivacaine was concentration dependent, reversible, stereoselective, voltage dependent, and frequency independent. The IC(50) values were (mean +/- SEM) 41 +/- 3 microm (n = 20), 56 +/- 3 microm (n = 26), 76 +/- 8 microm (n = 24), 135 +/- 29 microm (n = 23), 313 +/- 32 microm (n = 25), and 1,451 +/- 351 microm (n = 23), respectively. The midpoint of current activation was shifted into the hyperpolarizing direction. The inhibitory potency as well as the potency to induce gating changes correlated with the number of CH(2) groups in the side chain of the drugs (r > 0.9, P < 0.05). Kv1.1 channels constitute an important biophysical model for elucidating molecular mechanisms underlying local anesthetic drug effects. Inhibition likely results from an open state-dependent blocking mechanism. Interaction of local anesthetics with the ion channel protein is determined by lipophilic drug properties.