Molecular determinants of state-dependent block of Na+ channels by local anesthetics.

Sodium ion (Na+) channels, which initiate the action potential in electrically excitable cells, are the molecular targets of local anesthetic drugs. Site-directed mutations in transmembrane segment S6 of domain IV of the Na+ channel alpha subunit from rat brain selectively modified drug binding to resting or to open and inactivated channels when expressed in Xenopus oocytes. Mutation F1764A, near the middle of this segment, decreased the affinity of open and inactivated channels to 1 percent of the wild-type value, resulting in almost complete abolition of both the use-dependence and voltage-dependence of drug block, whereas mutation N1769A increased the affinity of the resting channel 15-fold. Mutation I1760A created an access pathway for drug molecules to reach the receptor site from the extracellular side. The results define the location of the local anesthetic receptor site in the pore of the Na+ channel and identify molecular determinants of the state-dependent binding of local anesthetics.

Inhibition of sodium currents by local anesthetics in chloramine-T-treated squid axons. The role of channel activation.

In order to test the requirement of Na channel inactivation for the action of local anesthetics, we investigated the inhibitory effects of quaternary and tertiary amine anesthetics on normally inactivating and noninactivating Na currents in squid axons under voltage clamp. Either the enzymatic mixture pronase, or chloramine-T (CT), a noncleaving, oxidizing reagent, was used to abolish Na channel inactivation. We found that both the local anesthetics QX-314 and etidocaine, when perfused internally at 1 mM, elicited a "tonic" (resting) block of Na currents, a "time-dependent" block that increased during single depolarizations, and a "use-dependent" (phasic) block that accumulated as a result of repetitive depolarizations. All three effects occurred in both control and CT-treated axons. As in previous reports, little time-dependent or phasic block by QX-314 appeared in pronase-treated axons, although tonic block remained. Time-dependent block was greatest and fastest at large depolarizations (Em greater than +60 mV) for both the control and CT-treated axons. The recovery kinetics from phasic block were the same in control and CT-modified axons. The voltage dependence of the steady state phasic block in CT-treated axons differed from that in the controls; an 8-10% reduction of the maximum phasic block and a steepening and shift of the voltage dependence in the hyperpolarizing direction resulted from CT treatment. The results show that these anesthetics can bind rapidly to open Na channels in a voltage-dependent manner, with no requirement for fast inactivation. We propose that the rapid phasic blocking reactions in nerve are consequences primarily of channel activation, mediated by binding of anesthetics to open channels, and that the voltage dependence of phasic block arises directly from that of channel activation.

Topical etidocaine during laparoscopic tubal occlusion for postoperative pain relief.

Narcotic requirements in 51 day-surgery patients following laparoscopic tubal occlusion were significantly reduced (P less than .01) by the use of 1% etidocaine 5 mL, dropped on each fallopian tube from uterus to fimbrias before tubal banding when compared with a control group of 51 day-surgery patients who had no topical anesthetic agent. All patients received general anesthesia. Although there was no significant difference in nausea rate, the incidence of vomiting was decreased. Eight of 51 patients (16%) having topical etidocaine and 19 of 51 (37%) who had no etidocaine vomited during the postoperative period. The frequency of overnight stay was significantly reduced in the topical etidocaine group of patients (P less than or equal to .01).

Deamination of released 3H-noradrenaline in the canine saphenous vein.

Experiments were designed to determine the effect of monoamine oxidase (MAO) inhibitors on the release and the metabolism of noradrenaline in the canine saphenous vein. Helical strips were incubated with 3H-noradrenaline and mounted for superfusion and measurement of the efflux of labelled transmitter and its metabolites; in certain experiments the tissue content of 3H-noradrenaline and its metabolites was also determined. The MAO-A inhibitor clorgyline, and the non-specific inhibitor pargyline, but not the MAO-B inhibitor deprenyl decreased the appearance of deaminated and O-methylated deaminated metabolites under basal conditions and during electrical stimulation. The MAO-A and the non-specific MAO inhibitor did not decrease the efflux of VMA to the same extent as that of the other deaminated metabolites. During superfusion with etidocaine, an agent causing increased leakage of stored transmitter, clorgyline abolished the appearance of DOPEG. Addition of semicarbazide in preparations treated with pargyline did not affect the efflux of deaminated and O-methylated deaminated metabolites. From the measurement of tissue VMA, it appeared that the efflux of VMA poorly reflects quick changes in the rate of its formation but that formation is abolished by pretreatment with pargyline. These experiments indicate that in the canine saphenous vein: (1) DOPEG is formed mainly in intraneuronal sites, while DOMA, MOPEG and VMA are formed extraneuronally; (2) VMA is retained in the tissue after its formation; and (3) the only subtype of MAO involved in the metabolism of 3H-noradrenaline released from adrenergic nerve endings can be classified as MAO-A.

Hydrophobic membrane interaction of etidocaine, bupivacaine and 2-chloroprocaine. A spin and fluorescent probe study.

It has been suggested that local anesthetics may block sodium conductance through nervous membranes also by hydrophobic interaction, e.g., by expanding the membrane. Decreased anisotropy (fluidization) and depressed phase transition temperatures have been shown by relatively high local anesthetic concentrations. We studied the dose dependence of the effect of three clinically used local anesthetics, with different lipid solubility, on lipid fluidity parameters of four different model membranes. With stearic acid spin labels in dipalmitoyl lecithin vesicles etidocaine (1-5 mM) had the clearest fluidizing effect followed by bupivacaine (5 mM); 2-chloroprocaine was without effect on lipid fluidity. In synaptic plasma membranes a fluidizing effect near the hydrophilic part of the lipid bilayer was similar with etidocaine and bupivacaine (5-10 mM); 2-chloroprocaine had no effect. Bupivacaine at 125 and 250 muM had a small ordering effect, which was not seen at a more hydrophobic site of the membrane. Etidocaine had the strongest fluidizing effect at the latter site of the synaptic plasma membranes. In erythrocyte ghost membranes, probed by stearic acid spin labels near the hydrophilic end, none of local anesthetics affected fluidity at 24 degrees C, while at 37 degrees C etidocaine (1-5 mM) and bupivacaine (5 mM) had a fluidizing effect. Dimyristoyl lecithin vesicles were probed by cis- and trans-parinaric acid. Etidocaine and bupivacaine (5-10 mM) clearly depressed the phase transition temperature evaluated from fluorescence intensity scans. The effect was most marked with bupivacaine (1-10 mM) when cis-parinaric acid was used. While isolated mammalian nerves are blocked by local anesthetic concentrations below 100 muM, this study shows that the clinically used local anesthetics increase fluidity and depress phase transition temperature only at 10-100 times higher concentrations at physiological pH. This kind of hydrophobic membrane interaction may not be important for the nerve blocking effect.

Visual evoked potentials after retrobulbar or periocular anaesthesia.

The effect of the local anaesthetic agent, etidocaine, on the optic nerve function was examined at regional ophthalmic anaesthesia. Visual evoked potential (VEP) was recorded before and 15 minutes after injection of the anaesthetic agent in 19 patients scheduled for elective cataract surgery (seven retrobulbar and 12 periocular). Both the anaesthetised--that is, the eye to be operated on--and the fellow eye were examined. In the retrobulbar group, two patients displayed non-recordable VEPs while one had virtually non-detectable waves following the anaesthesia. In two retrobulbarly anaesthetised eyes, later peaks were unidentifiable while two other eyes had decreased amplitudes. In the periocular group, in nine patients, there was no clearcut effect on VEP resulting from the anaesthetic. In three patients of this group mild changes in the anaesthetised eyes were found. The differences in the effect of retrobulbarly or periocularly injected anaesthetics on VEP are probably due to the different concentration of the anaesthetic agent around the optic nerve.

Etidocaine HCl local anesthetic for periodontal flap surgery.

Long acting local anesthetics have been used successfully during third molar extractions and endodontic procedures. They were shown to provide longer duration of anesthesia and contribute to less postoperative pain. This study evaluated the effectiveness of one long acting local anesthetic agent (etidocaine) for periodontal flap procedures. A double-blind, split mouth design treated 17 matched contralateral pairs of posterior sextants. One region was treated following administration of 1.5% etidocaine HCl with 1:200,000 epinephrine. The matched control region was treated following administration of 2% lidocaine with 1:100,000 epinephrine. The results indicate that, while etidocaine provided a longer duration of anesthesia (P less than 0.005), no difference was noted in the number of pain pills patients took or the period of time over which they took them. Inadequate hemostasis was a recurrent problem with etidocaine anesthesia. The use of 1.5% etidocaine HCl with 1:200,000, epinephrine offers no significant advantages over traditional anesthetic solutions.

Do local anesthetics have an influence on the percutaneous penetration of a model corticosteroid? An in vivo study using the vasoconstrictor assay.

Local anesthetics may exert nonspecific interactions with membrane components which can affect drug permeability. To investigate pharmacodynamically whether these membrane interactions lead to penetration enhancement of the coadministered model drug betamethasone-17-benzoate through human skin, the vasoconstrictor assay was used. Information on the penetration-enhancing properties of local anesthetic-containing vehicles compared to a plain standard were obtained from activity-response curves, where the enhancement factor was determined from the horizontal distance between the standard and a test in the linear range of the curves. The local anesthetics are able to enhance drug penetration through human skin to a different extent with lidocaine being the most efficient enhancer. An increase in the drug solubility and the diffusion coefficient in the stratum corneum due to membrane fluidization are possible mechanisms of action.

Effect of local anaesthetics on the stimulus-secretion coupling in bovine adrenal chromaffin cells.

This study was carried out to determine the relative potencies of local anesthetics to inhibit the cholinergic synaptic transmission using cultured bovine adrenal chromaffin cells, and to clarify if the inhibitory action would correlate with biophysical and pharmacological properties. Local anaesthetics (bupivacaine, etidocaine, tetracaine, lignocaine and procaine; 0.02-2 mM) inhibited carbachol-induced catecholamine release from the cells in a concentration-dependent manner. This inhibition was completely reversible. IC50 (concentration of 50% inhibition) of each anaesthetic showed no correlation with the lipid solubility. The local anaesthetics showed greater inhibitory potency at a higher extracellular pH. The results suggest that clinically relevant concentrations of local anaesthetics inhibit the stimulus-secretion coupling in the chromaffin cells. The un-ionized based form plays a major role, and the inhibitory potency does not depend on the lipid solubility of the anaesthetics.

Vasospasm and platelet deposition in human arteries: effects of topical methylene blue.

Vasodilation of small blood vessels is controlled in part by the endothelium-derived relaxing factor (EDRF), which also inhibits platelet adhesion. Methylene blue (MB), which is occasionally applied directly to blood vessels during microsurgery to provide orientation and prevent torsion, is an irreversible inhibitor of the effects of endothelium-derived relaxing factor and may thereby augment both vasospasm and platelet responses. We have investigated the effects of the extravascular adventitial application of methylene blue on platelet deposition to human placental arteries (HPA) in the presence and absence of surgically induced vasospasm. A trend toward increased platelet deposition to human placental arteries was seen in each group but did not reach significance. The degree of platelet deposition to control human placental arteries suggests that the effects of methylene blue on platelet deposition may be dwarfed by the effects of surgical trauma and ischemia.

Conduction anesthesia in obstetrics and its effects upon fetus and newborn.

The use of conduction anesthesia has made childbearing a vastly more pleasant experience for the mother and certainly made the practice of obstetrics safer and easier. However, its safety to the fetus and newborn, once unquestioned, has become the subject of much study and concern in recent years. It is the purpose of this article to examine the fetal effects of local anesthetic agents and review some of these agents as well as the regional techniques most commonly employed in the perinatal period with respect to their fetal and maternal safety.

Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5% etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block.

OBJECTIVE: The purpose of this study was to determine the anesthetic efficacy and heart rate effects of an intraosseous (IO) injection of 1.5% etidocaine with 1:200,000 epinephrine after an inferior alveolar nerve block. STUDY DESIGN: In a repeated-measures designed study, 48 subjects randomly received 2 combinations of injections at 2 separate appointments. The combinations were an inferior alveolar nerve (IAN) block (with 3% mepivacaine) + IO injection with 1.8 mL of 1.5% etidocaine hydrochloride containing 1:200,000 epinephrine, and an IAN + mock IO injection. The first molar was blindly tested with a pulp tester at 2-minute cycles for 60 minutes after the injection. Anesthesia was considered successful when 2 consecutive 80 readings (no subject response) were obtained. Heart rate (pulse rate) was measured with a pulse oximeter. RESULTS: Lip numbness occurred in 100% of the subjects with both the techniques. For the first molar, anesthetic success for the IAN + mock IO and the IAN + IO etidocaine hydrochloride groups, respectively, were 81% and 100%. The differences were significant (P <.05) when the IAN + IO etidocaine hydrochloride technique was compared with the IAN + mock IO. A mean increase in heart rate of 32 beats/min occurred in 90% of the subjects with the IO injection of the etidocaine hydrochloride solution. In 89% of these subjects, the heart rate returned to within 5 beats of baseline values 4 minutes or less after solution deposition. CONCLUSIONS: The IO injection of 1.8 mL of 1.5% etidocaine hydrochloride with 1:200,000 epinephrine, when used to augment an inferior alveolar nerve block, significantly increased anesthetic success in the first molar. The majority of subjects receiving the IO injection of the etidocaine hydrochloride solution had a transient increase in heart rate.

Epidural anesthesia for surgery: a comparative double-blind study of etidocaine and bupivacaine.

The author reports the comparative effects of 2 local anesthetic agents injected into the epidural space: 1% etidocaine and 0.5% bupivacaine, both containing epinephrine (5 microgram/ml). Twenty ml of one of these solutions were administered under double-blind conditions to 40 patients undergoing orthopedic, urological, gynecological or general surgery. The onset of analgesia, as determined by the "pin-prick test" was more rapid after 1% etidocaine than after 0.5% bupivacaine. The duration of analgesia, the return of sensation and the extent and intensity of the sensory blockade were identical for both drugs. After etidocaine, motor block occurred more often, was more complete and developed more rapidly than after bupivacaine. The incidence of peroperative and postoperative complications was comparable in both groups.

Long-acting local anesthetics in oral surgery: an experimental evaluation of bupivacaine and etidocaine for oral infiltration anesthesia.

The effect of bupivacaine 7.5 mg/ml with epinephrine 5µg/ml, etidocaine 15 mg/ml with epinephrine 5 µg/ml, and lidocaine 20 mg/ml with epinephrine 12.5 µg/ml was studied when used for oral infiltration anesthesia. Twenty healthy volunteers took part in the experimental and double-blind study. One ml of the respective anesthetic solution was deposited supraperiosteally in the apical area of the maxillary right lateral incisor. Onset time, frequency of analgesia, gingival spread, and duration of tooth analgesia were studied and duration of soft-tissue numbness registered. The present investigation showed that lidocaine had a shorter onset time compared with bupivacaine. No difference with regard to frequency was found. Bupivacaine and etidocaine had a longer period of soft-tissue numbness, but a significantly shorter duration of tooth analgesia than lidocaine.

Long-acting local anesthetics in dentistry.

Long-acting local anesthetics have proved to be effective for the suppression of both intraoperative and postoperative pain. They are useful for lengthy dental treatments and for prevention of severe pain following many types of surgical procedures. Although the currently available long-acting local anesthetics for dentistry have minimal side effects in the doses usually employed, there are potential problems. Bupivacaine, for example, can cause significant cardiac depressant and dysrhythmogenic responses. Etidocaine has less pronounced effects on the cardiovascular system, but its use may be associated with inadequate control of intraoperative bleeding. A new long-acting local anesthetic, ropivacaine, appears to offer advantages over either of the currently used long-acting agents.

Comparison of the effectiveness of etidocaine and lidocaine as local anesthetic agents during oral surgery.

In a double-blind study conducted in 112 patients undergoing removal of four impacted third molar teeth, etidocaine hydrochloride 1.5% solution with epinephrine 1:200,000 and lidocaine hydrochloride 2.0% solution with epinephrine 1:100,000 were used, one on each side of the face, to produce inferior alveolar nerve block, infiltration anesthesia of the maxillary tooth and hemostasis of the mucoperiosteum around each tooth.Surgically adequate anesthesia was rapidly produced by both agents but the duration of action of etidocaine was longer than that of lidocaine as reflected in more prolonged numbness of the lip and delayed onset of pain. Moreover, after etidocaine treatment fewer patients reported severe pain as the local anesthesia receded. No adverse local or systemic effects were observed in, or reported by, any of the patients.

[Alkalinization of local anesthetics: theoretically justified but clinically useless]. / Alcalinisation des anesthésiques locaux: théoriquement justifiée mais inutile cliniquement.

PURPOSE: In vitro studies have demonstrated the potential advantages of alkalinization on anaesthetic activity, by decreasing the ratio of ionized to nonionized molecules, there by permitting more rapid penetration of local anaesthetic through biological membranes, thus decreasing the onset time. The proportion of each form depends on the pKa of the agent and the ultimate pH of the solution. When NaHCO3 is mixed with local anaesthetics, CO2 is produced. Carbon dioxide has been reported to enhance local anaesthetic action by diffusion trapping of the cationic form in pH gradient combined with a direct depressant action of CO2. The purpose of this study was to examine if clinical studies confirmed the in vitro action of alkalinisation. SOURCE: The literature pertinent to alkalinization of local anaesthetics published in the major anaesthesia and pharmacology journals of North America and Europe. PRINCIPAL FINDINGS: While in vitro studies have demonstrated potential advantages for alkalinization on anaesthetic activity, clinical studies have shown that alkalinization of local anaesthetics produces inconsistent results. For bupivacaine and etidocaine, alkalinization of local anaesthetic solution can produce precipitation, thus limiting the feasibility of increasing the pH. CONCLUSIONS: On the basis of this review, routine alkalinization of local anaesthetics is not recommended.

Effects of etidocaine administered epidurally on changes in somatosensory evoked potentials after dermatomal stimulation.

The effect of lumbar epidural anesthesia with similar volumes (approximately 20 ml) of 1% and 1.5% etidocaine on early (less than 0.5 seconds) somatosensory evoked potentials (SEPs) to electrical stimulation of the S1, L1, and T10 dermatomes was examined in two groups of ten patients in a randomized, double-blind study. Level of analgesia to pinprick was T7.7 +/- 0.9 in the 1% group and T6.6 +/- 0.6 in the 1.5% group and all patients had total motor block. Despite similar analgesia to pinprick, SEP amplitude was more reduced in the 1.5% group, in which SEPs were abolished in all patients at the L1 level.