Immunological modulation by lidocaine-epinephrine and prilocaine-felypressin on the functions related to natural immunity in neutrophils and macrophages

There is accumulating evidence that local anesthetics have immunological properties in addition to their direct anesthetic activity. Because local anesthetics are often used together with blood vessel contraction drugs, such as epinephrine and felypressin in the clinical setting, we have examined possible abilities of both local anesthetic alone including lidocaine, mepivacaine, procaine, prilocaine and tetracaine, and local anesthetics with blood vessel contraction drugs including lidocaine with epinephrine and prilocaine with felypressin on the functions related to natural immunity in neutrophils and macrophages. In contrast, lidocaine, mepivacaine, procaine, prilocaine and tetracaine all inhibited adhesion, chemotaxis, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils and macrophages. Lidocaine with epinephrine and prilocaine with felypressin were effective in significantly inhibiting adhesion, chemotaxis, phagocytosis, and the production of hydrogen peroxide by neutrophils and macrophages. Interestingly, lidocaine with epinephrine potentiated the production of superoxide anion, whereas prilocaine with felypressine inhibited the production, irrespective of cells. In addition, epinephrine potentiated the production of superoxide anion, whereas epinephrine inhibited the production of hydrogen peroxide as well as lidocaine with epinephrine. This potentiation by epinephrine was not prevented by adrenergic antagonists. Furthermore, superoxide dismutase potentiated the production of hydrogen peroxide, which was in part prevented by epinephrine. These results suggest that local anesthetics may inhibit the functions related to natural immunity in neutrophils and macrophages. In addition, lidocaine with epinephrine evidently differs from prilocaine with felypressine regarding the molecular mechanisms underlying the modulation of superoxide anion production by neutrophils and macrophages.     

Benefit and risks of local anesthetics in infants and children

Regional anesthesia has become a routine part of the practice of anesthesiology in infants and children. Local anesthetic toxicity is extremely rare in infants and children; however, seizures, dysrhythmias, cardiovascular collapse, and transient neuropathic symptoms have been reported. Infants and children may be at increased risk from local anesthetics compared with adults. Larger volumes of local anesthetics are used for epidural anesthesia in infants and children than in adults. Metabolism and elimination of local anesthetics can be delayed in neonates, who also have decreased plasma concentrations of alpha(1)-acid glycoprotein, leading to increased concentrations of unbound bupivacaine. Most regional anesthetic procedures in infants and children are performed with the patient heavily sedated or anesthetized; because of this, and because a test dose is not a particularly sensitive marker of intravenous injection in the anesthetized patient, detection of intravascular local anesthetic injection is extremely difficult. The same local anesthetics used in adult anesthetic practice are also used in infants and children. Because of its extremely short duration of action, chloroprocaine has been used primarily for continuous epidural techniques in infants and children. The use of tetracaine has generally been limited to spinal and topical anesthesia. Lidocaine (lignocaine) has been used extensively in infants and children for topical, regional, plexus, epidural and spinal anesthesia. The association between prilocaine and methemoglobinemia has generally restricted prilocaine use in infants and children to the eutectic mixture of local anesthetics (EMLA). Because of its greater degree of motor block compared with other long-acting local anesthetics, etidocaine has generally been limited to plexus blocks in infants and children. Mepivacaine has been used for both plexus and epidural anesthesia in infants and children. Because postoperative analgesia is often the primary justification for regional anesthesia in infants and children, bupivacaine, a long-acting local anesthetic, is the most commonly reported local anesthetic for pediatric regional anesthesia. Given the lower toxic threshold of bupivacaine compared with other local anesthetics, the risk-benefit ratio of bupivacaine may be greater than that of other local anesthetics. Two new enantiomerically pure local anesthetics, ropivacaine and levobupivacaine, offer clinical profiles comparable to that of bupivacaine but without its lower toxic threshold. The extreme rarity of major toxicity from local anesthetics suggests that widespread replacement of bupivacaine with ropivacaine or levobupivacaine is probably not necessary. However, there are clinical situations, including prolonged local anesthetic infusions, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring a large mass of local anesthetic, where replacement of bupivacaine with ropivacaine, levobupivacaine or (for continuous techniques) chloroprocaine appears prudent.     

Cocaine and local anesthetics: Stimulant activity in rats with nigral lesions

Cocaine and several other local anesthetics were tested for their ability to induce rotational behavior in rats with unilateral 6-hydroxydopamine lesions of substantia nigra. Acute administration of bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, procaine or tetracaine failed to induce active rotation in this sensitive assay of dopamine agonist activity. On the other hand, cocaine or dimethocaine treatment induced active rotation directed ipsilaterally to the lesioned side, indicating indirect dopamine agonist activity. Repeated administration of cocaine or dimethocaine at 1-week intervals resulted in increased rotational response (i.e., sensitization) while there was no suggestion of sensitization or induction of rotational behavior after weekly repeated administration of procaine or tetracaine. Daily administration of mepivacaine, procaine or tetracaine for 5 days also failed to induce rotation. Dimethocaine thus was found similar to cocaine and different from the other local anesthetics tested both in terms of frank stimulant activity and development of sensitization upon repeated administration.     

Locomotor effects of cocaine, cocaine congeners, and local anesthetics in mice

Spontaneous locomotor activity of mice was stimulated by IP administration of cocaine and its closely related phenyltropane analogs. In contrast, locomotion was inhibited by IP administration of cocaine congeners such as norcocaine, (+)-pseudococaine, and tropacocaine, and of isomers of phenyltropane analogs. Also inhibitory were the local anesthetics procaine, tetracaine, benzocaine, lidocaine, and prilocaine. The locomotor inhibition induced by IP norcocaine or tetracaine could be reversed by subsequent treatment with cocaine. Both cocaine and norcocaine were centrally stimulatory when injected intracerebroventricularly. The rank order of potencies of cocaine congeners and local anesthetics in depressing locomotion was similar to that of their potencies in interacting with sodium channels. From these results we infer that the locomotor depression induced by systemic administration of cocaine congeners results from a local anesthetic action involving inhibition of the ion conductance of sodium channels.     

Local anesthetis and adjuvants in pediatric regional anesthesia

The pediatric loco-regional techniques are considered very safe and effective, first of all because they target the therapy directly to the site of surgery, decreasing the risks of intravenous analgesia. The quality of local anesthesia is influenced by structural and biophysical characteristics of local anesthetics drug, dose, site of injection, mixture of local anesthetics and possible addition of a vasoconstrictor or an adjuvant to prolong the analgesic effect. In children, unlike adults, small nerve diameters and short distance between Ranvier nodes permit to use large volumes and low concentrations of local anesthetics. The clinical practice has shown that in pediatric population, effective analgesia is obtained by 1% mepivacaine, 1% lidocaine and 0.25% bupivacaine or better 0.2% ropivacaine, 0.2-0.25% levobupivacaine. In addition, levobupivacaine and ropivacaine have a better profile in terms of safety in comparison to bupivacaine and are the local anesthetics of choice for the daily clinical practice also in children as in adults. Among the adjuvant, clonidine and ketamine showed the best pharmacokinetic and pharmacodynamic profiles of effective and safety, improving and prolonging the action of associated local anesthetics. Therefore, the use of enantiomers, in association with adjuvants as clonidine or ketamine, using the multimodal approach of integrated anesthesia, makes the clinical practice effective and safe in the pediatric operating rooms. This review focuses on the overview of local anesthetics and adjuvants used today in locoregional pediatric anesthesia, with an emphasis on the advantages and disadvantages of each drug.     

利多卡因凝胶经皮吸收的动力学和药效学

目的研究利多卡因凝胶的经皮吸收动力学以及药效学。方法用经皮微渗析的方法测定大鼠真皮内药物浓度的变化,计算相关参数;用电刺激法考察药效,并与市售EMLA(eutectic mixture of local anesthetics)霜剂进行药效比较。结果持续用药1 h,利多卡因经皮吸收动力学曲线在1.25 h达到峰值;起效时间与EMLA霜剂相近,局麻作用维持时间和局麻强度优于EMLA。结论利多卡因凝胶具有良好的局麻作用;局部用药后,利多卡因产生局部麻醉作用的真皮中最低有效浓度为12 mg·L^-1。     

Effects of local anesthetics on rat leukocyte functions]

To determine whether local anesthetics affect functions in macrophages, I examined the effects of 5 local anesthetics, lidocaine HCl, mepivacaine HCl, propitocaine HCl, procaine HCl, and tetracaine HCl, on chemotaxis and production of superoxide anion in rat peripheral macrophages. Rats were intraperitoneally injected with 1% glycogen. Peritoneal exudate cells containing macrophages were obtained from the peritoneal cavity 4 days after the administration. Chemotaxis was evaluated using a 48-well microchemotaxis chamber with a polycarbonate membrane filter. Production of superoxide anion was measured spectrophotometrically by a superoxide dismutase-sensitive reduction of ferricytochrome c. All of the local anesthetics examined at a dose of 1 mg ml inhibited (P < 0.05) chemotaxis and production of superoxide anion in macrophages. Moreover, pretreatment of macrophage suspensions with mepivacaine HCl, propitocaine HCl, procaine HCl, or tetracaine HCl at a dose of 1 mg ml resulted in inhibition of the production of superoxide anion. In contrast, pretreatment with lidocaine HCl at this concentration did not significantly affect the production of superoxide anion. These results suggest that all of the local anesthetics examined at a therapeutic concentration inhibit chemotaxis and production of superoxide anion in rat macrophages.     

Phase distribution studies on an oil-water emulsion based on a eutectic mixture of lidocaine and prilocaine as the dispersed phase

The distribution conditions in oil-water emulsions prepared by emulsifying a 1:1 eutectic mixture of lidocaine and prilocaine with a nonionic surfactant in water were studied by membrane and gel filtration methods. In this system, the local anesthetics are considered to be freely dissolved, surfactant solubilized, and emulsified in three separate phases. The dispersity of the oil phase was investigated by light microscopy and light-scatter spectroscopy. The majority of drops in the lidocaine-prilocaine emulsions were less than 1 micron in size. The concentration of freely dissolved drug in the aqueous phase of the emulsions was equal to the aqueous solubility of lidocaine-prilocaine in a 1:1 ratio. At constant lidocaine/prilocaine/surfactant ratio, increasing the total drug concentration in the emulsion resulted in an increase of the emulsified fraction of lidocaine-prilocaine, whereas the surfactant-solubilized fraction remained constant.     

Inhibition of human serum and rabbit muscle cholinesterase by local anesthetics

The effects of tertiary amine local anesthetics (procaine, mepivacaine, lidocaine, tetracaine, dibucaine, and bupivacaine) and chlorpromazine were investigated for rabbit muscle acetylcholinesterase and human serum cholinesterase. The muscle enzyme was poorly inhibited by local anesthetics containing an amide linkage. The serum cholinesterase was inhibited by all those compounds, their relative potencies being proportional to their octanol/water partition coefficients. The dissociation constants of tetracaine and procaine, ester anesthetics, were 1000-fold and 100-fold, respectively, that which would be expected from their partition coefficient basis respective to the other amide anesthetics. Procaine showed competitive inhibition of serum cholinesterase, whereas for most anesthetics a mixed type of inhibition was observed. Procaine probably binds at the main anionic site, while the other positively charged anesthetics bind to either the catalytic centre or to the peripheral or modulator anionic site, modifying the kinetic behaviour of cholinesterase as has been demonstrated by the appearance of negative cooperativity for binding to the substrate.     

Effects of local anesthetics on phospholipase D activity in differentiated human promyelocytic leukemic HL60 cells

Local anesthetics impair certain functions of neutrophils, and phospholipase D (PLD) is considered to play an important role in the regulation of these functions. To understand the mechanisms by which local anesthetics suppress the functions of neutrophils, we examined the effects of local anesthetics on PLD in neutrophil-like differentiated human promyelocytic leukemic HL60 cells. Tetracaine, a local anesthetic, inhibited formyl-methionyl-leucyl-phenylalanine (fMLP)- and 4beta-phorbol 12-myristate 13-acetate (PMA)-induced PLD activation, but potentiated fMLP-stimulated phospholipase C activity. All four local anesthetics tested suppressed PMA-induced PLD activation to different extents, and the order of their potency was tetracaine > bupivacaine > lidocaine > procaine. In a cell-free system, tetracaine suppressed guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)-induced PLD activation as well as PMA-induced PLD activation. Western blot analysis revealed that tetracaine prevented the membrane translocation of PLD-activating factors, ADP-ribosylation factor, RhoA, and protein kinase Calpha. Tetracaine also inhibited the activity of recombinant hPLD1a in vitro. These results suggest that local anesthetics suppress PLD activation in differentiated HL60 cells by preventing the membrane translocation of PLD-activating factors, and/or by directly inhibiting the enzyme per se. Therefore, it could be assumed that local anesthetics would suppress the functions of neutrophils by inhibition of PLD activation.     

Drug release studies on an oil-water emulsion based on a eutectic mixture of lidocaine and prilocaine as the dispersed phase

The in vitro drug release properties of a topical anesthetic formulation known to be effective on intact skin, based on a 1:1 eutectic mixture of lidocaine and prilocaine emulsified in water, were investigated with a poly(dimethylsiloxane) membrane partition model. Aqueous solutions and solubilized systems of lidocaine and prilocaine in a 1:1 ratio by weight were also included in the study as well as the eutectic mixture itself. Two identical sets of samples were used, one of which was gelled with carbomer 934 P. Drug solubilities in the membrane, partition coefficients between membrane and water, and diffusion coefficients in the membrane and the formulations were determined. As in the case of an aqueous medium, lidocaine and prilocaine in combination had lower solubilities in the membrane than they did separately. However, in the aqueous phase or in the membrane, the diffusion coefficients were mutually independent. Carbomer 934P, when neutralized totally with sodium hydroxide, did not decrease the aqueous diffusivities of the local anesthetic bases. The major advantages of using the emulsion formulation based on a eutectic mixture rather than more conventional formulations are: (a) the local anesthetic bases are present in their permeable uncharged forms; (b) the use of a poor solvent, water, as the vehicle provides a saturated system at low concentrations; (c) lipophilic solvent is absent in the dispersed phase, the presence of which would decrease the effective distribution coefficients of the active substances between the skin and the formulation; (d) the droplets consist of dissolvable drug and act as reservoirs to obtain steady-state release; and (e) the fluid state of the excess drug provides a higher dissolution rate than from a solid state.     

Inhibition of the Na,K-ATPase of canine renal medulla by several local anesthetics.

The ATPase activity of Na,K-ATPase-enriched membranes from canine renal medulla was determined in the absence of local anesthetic and in the presence of procaine, chloroprocaine, bupivacaine, mepivacaine, lidocaine, and two quaternary derivatives of lidocaine (QX-222 and QX-314) at 37( composite function)C. Chloroprocaine (IC(50)= 13 mM) had slightly greater potency than procaine (IC(50)= 17.7 mM). Bupivacaine (IC(50)= 6.7 mM) was more potent than its congener mepivacaine (IC(50)> 10 mM, the solubility limit). QX-222 (IC(50)> 600 mM) and QX-314 (IC(50)= 132 mM) had less potency than lidocaine (IC(50)= 30.4 mM). This study supports the interpretation that the uncharged forms of local anesthetics are much more potent inhibitors of Na,K-ATPase activity than the cationic forms.     

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.     

Palladium catalysts in the synthesis of local anesthetics (review)

Catalytic processes involving Pd-containing catalysts for the synthesis of local anesthetics such as anesthesin (benzocaine), novocaine (procaine), lidocaine, mepivacaine, bupivacaine, trimecaine, and pyromecaine (bumecaine) are reviewed.     

Effects of Four Local Anaesthetics on the Membrane Stability of Isolated Rat Liver Lysosomes

Abstract The effects of the local anaesthetics bupivacaine, lidocaine, mepivacaine and prilocaine on lysosomal membrane stability have been studied on isolated rat liver lysosomes. The lysosomal membranes were stabilized by the local anaesthetics only within a very narrow range of concentration (around 0.001 M). In lower concentrations there was no effect of the substances while in higher concentrations there was a marked labilizing effect on the lysosomal membranes. The phlogistic effect of an injected suspension of lysosomes in the rat paw was increased by mepivacaine in concentrations of 1 % (0.04 M) and higher. The labilizing effects of local anaesthetics on lysosomes were probably due to precipitation of lysosomal membrane proteins by the local anaesthetics.     

Effects of local anesthetics on pregnant uterine muscles

Obstetric analgesia and anesthesia should provide optimal pain relief for the parturient with minimal risks. The local anesthetic agents are most commonly used for obstetric analgesia and anesthesia. We investigated the effect of local anesthetic agents: prilocaine, bupivacaine, ultracaine on myometrium in pregnant rats. In our study, we evaluated the effects of three local anesthetics at cumulative concentrations on contractions of myometrium isolated from pregnant rats. The following characteristics of the contractions were analyzed after the addition of drugs: frequency, mean duration, amplitude of each contractions and integrated area under the contraction curve. We observed that the exposure to prilocaine, bupivacaine and ultracaine decreased amplitude, duration and integrated area under the contraction curve. In conclusion, the study drugs at higher concentrations decreased contractions of myometrium, but all drugs at higher concentrations elevated the frequency.     

Study of anaesthetic agents for their ability to elicit porphyrin biosynthesis in chick embryo liver

Effects of some anaesthetic drugs on the activity of delta-aminolevulinate synthetase and on the formation of porphyrins and cytochrome P-450 were studied in 18-day-old chick embryo livers in ovo. The drugs were either tested alone or with a small dose of 1,4-dihydro-3,5-dicarbethoxycollidine, which reproduces in the embryo liver a partial block in the heme biosynthesis pathway similar to that found in cells of human patients with porphyrias. Two series of local anaesthetics were tested: procaine and its derivatives (proxymetacaine, oxybuprocaine, butacaine and tetracaine) had no (or very slight) porphyrogenic effects. In contrast, lidocaine and its derivatives (bupivacaine, mepivacaine, etidocaine, pyrrocaine and prilocaine) were found to induce delta-aminolevulinate synthetase and to cause accumulation of porphyrins and cytochrome P-450. Some other drugs used in anaesthesiology were tested: fentanyl, morphine, sodium oxybate, pancuronium, pethidine and phenoperidine were found to be non-porphyrogenic; alcuronium was a slight inducer. It is suggested that the inducing drugs should be avoided in patients with hepatic porphyrias.     

Batrachotoxin-induced depolarization and [3H]batrachotoxinin-a 20 alpha-benzoate binding in a vesicular preparation from guinea pig cerebral cortex

The sodium channel-specific agent batrachotoxin (BTX) has been shown to induce a time- and concentration-dependent depolarization of a vesicular preparation from guinea pig cerebral cortex. The K0.5 for depolarization by BTX was 0.011 microM at 30 min. Membrane potential was determined by the equilibrium distribution of [3H]triphenylmethylphosphonium ion. A series of seven local anesthetics was shown to inhibit BTX-induced depolarization competitively with Ki values ranging from 0.9 microM for dibucaine to 780 microM for lidocaine ethiodide. The specific binding of labeled batrachotoxinin-A 20 alpha-benzoate ([3H]BTX-B) to voltage-sensitive channels in vesicular preparations from mouse cerebral cortex in the presence of scorpion venom was measured and found to yield a range of Kd values from 25 to 30 nM and Bmax values of 0.5 and 1.0 pmole/mg of protein; the same preparation from guinea pig cerebral cortex was found to yield Kd values from 13 to 56 nM and Bmax values of 0.8-2.2 pmoles/mg of protein. A series of 14 local anesthetics was shown to inhibit the specific binding of [3H]BTX-B with Ki values ranging from 0.6 microM for dibucaine to 400 microM for benzocaine. The rank order of potency of the local anesthetics as antagonists of [3H]BTX-B binding was as follows: dibucaine greater than tetracaine greater than bupivacaine greater than diphenhydramine greater than piperocaine greater than cocaine greater than procaine greater than lidocaine greater than benzocaine. The quaternary local anesthetic dimethyl-di(phenylcarbamoylmethyl)ammonium chloride was comparable in potency to tetracaine. The rank order and relative potency of the local anesthetics tested in both paradigms were similar with the exception of lidocaine ethiodide, which was 18 times more potent as an inhibitor of binding of [3H]BTX-B than it was as an inhibitor of BTX-elicited depolarization.     

Local anesthetic cream prepared from lidocaine-tetracaine eutectic mixture

Local anesthetic creams for the clinical treatment of conditions such as postherpetic neuralgia were prepared as an in-house formulation from the eutectic mixture of lidocaine-tetracaine (LT cream) using two eutectic mixtures of local anesthetic (EMLA) type bases. The LT formulation was compared with a lidocaine-prilocaine (LP cream) eutectic mixture formulated using the same base as EMLA. The chemical stability of lidocaine was examined in advance and was found to be stable for more than 3 months either in LT cream or in LP cream. The release rate of lidocaine from the formulated creams was examined using a cellulose ester membrane. The release rate of lidocaine from LT cream was similar to that from LP cream. The release rate of tetracaine was slightly slower than that of lidocaine in LT cream reflecting the larger molecular size of tetracaine. The penetration rate was examined in vitro using a Yucatan micropig skin. The penetration rate of lidocaine was similar between LT and LP creams. Infiltration anesthesia action examined in guinea pigs indicated that the difference between the two creams was statistically insignificant. The present study suggests the equivalence of the LT and LP creams as a local anesthetic and the potential of LT cream for clinical use either in the easy formulation or in the low-cost formulation.