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Epidural blockade with local anesthetic may cause hypotension resulting from sympathetic block and/or systemic effect produced by absorbed local anesthetic through epidural blood vessels. In the present study, we compared the hemodynamic effects of saline 0.5 ml.h-1, lidocaine 0.5 ml.h-1, bupivacaine 0.5 ml.h-1, lidocaine 2 ml.h-1, and bupivacaine 2 ml.h-1, which were given epidurally combined with morphine. There was not significant difference in hemodynamics among 5 groups. Continuous epidural infusion with a small dose of local anesthetic agent combined with morphine is unlikely to induce apparent hemodynamic effects during postoperative period.
Whereas currently available local anesthetics may be suitable for intraoperative and in-hospital postoperative use, long-acting analgesia after outpatient procedures will require new techniques and drugs. Catheter delivery systems are rapidly gaining clinical acceptance and allow for great flexibility in dosing. Encapsulated local anesthetics can provide the slow release of drugs. Novel, long-acting local anesthetics are being investigated but are not yet ready for clinical use. In addition to the effects on the sodium channel, other actions of these novel compounds need to be explored, because both beneficial and detrimental effects may be induced with these compounds.
Recent experiments are reviewed to present a current view of the mechanisms of conduction block by local anesthetics. Local anesthetics block the sodium channels whose opening causes the rising phase of the action potential. Both charged and neutral forms of local anesthetics are able to block channels. Charged anesthetics interfere with a "gating" mechanism after gaining access to a "receptor" site in the aqueous pore of the channel from the axoplasmic surface of the membrane. This site is only available to charged compounds when the gate of the channel is open. In contrast, uncharged compounds (including the free base form of local anesthetics) appear to reach the site through the membrane's lipid interior, bypassing the channel "gates." Anesthetics blocking the gate of the channel can either enhance or inhibit the normal inactivation mechanism of the sodium channel, depending on the particular anesthetic.
Local anesthetics and anticonvulsant drugs were differentiated biochemically by quantitating their effects on aconitine- and ouabain-induced inhibition of L-[3H]glutamate uptake in synaptosomes. Amine local anesthetics reversed the inhibition by both compounds whereas the anticonvulsant drugs such as carbamazepine and diphenylhydantoin reversed the effects of aconitine but not ouabain. These results support the concept that carbamazepine and diphenylhydantoin interact with voltage-sensitive Na channels to block Na conductance whereas the amine local anesthetics are less specific in their actions.
High concentrations of local anesthetics are neurotoxic, but the mechanism for this neurotoxicity is obscure. Here, we report increased concentrations of glutamate in the cerebrospinal fluid after intrathecal injections of high concentrations of tetracaine (a local anesthetic). The peak concentrations of glutamate after administration of 1%, 2%, and 4% tetracaine were 4-fold, 6-fold, and 10-fold higher than baseline values, respectively. Animals in the 1% group were all neurologically normal one week after tetracaine injection. In the group receiving 4%, no animal was able to hop and vacuolation of the white matter and/or central chromatolysis of the motor neurons were observed. Because high concentrations of glutamate are known to be neurotoxic, our results may provide some insight into the mechanisms for neurotoxicity of intrathecal local anesthetics.
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The surface local anesthetic activity (LAA) in the homologous series of racemic (+/-)-cis- and (+/-)-trans-N,N-dimethyl-2- (2-alkoxyphenylcarbamoyloxy)cyclopentylmethylamonium chlorides was evaluated. The potency was expressed in rabbits as efficiency indices (EI) in comparison to the standard drug cocaine. All tested racemic mixtures of the phenylcarbamates were local anesthetically active and their potency increased with the size of alkoxysubstitution from the propyloxy- to the hexyloxyderivative and then decreased abruptly (cut-off effect). When different mixtures of both diastereoisomers were applied the synergistic effect--i.e. increase of the LAA of one diastereomer when adding the other--was observed. It seems that an optimal racemic ratio of the compounds could increase their local anesthetic efficiency.
The clinically useful local anesthetic agents can be divided chemically into the amino-esters, e.g., procaine, chloroprocaine and tetracaine, and the amino-amides, e.g., lidocaine, mepivacaine, prilocaine, bupivacaine and etidocaine. Pharmacologically, these agents can be categorized as agents of low potency and short duration of action, e.g., procaine and chloroprocaine; agents of intermediate potency and duration of action, e.g., lidocaine, mepivacaine and prilocaine; and agents of high potency and long duration, e.g., tetracaine, bupivacaine and etidocaine. The blood level of local anesthetics is determined by the rate of uptake, tissue redistribution, metabolism and excretion. The rate of vascular absorption is a function of the site of injection, dosage, inclusion of a vasoconstrictor in the local anesthetic solution and the specific drug employed. The amino esters are eliminated by means of enzymatic hydrolysis in blood while the amino amides are metabolized primarily in the liver. Among the ester agents chloroprocaine is cleared most rapidly due to its fast rate of hydrolysis. Within the amide series, prilocaine is cleared most rapidly due to its fast rate of tissue redistribution and its rapid hepatic metabolism. Bupivacaine is cleared most slowly due primarily to its decreased rate of hepatic degradation.
Local anesthetics are extremely useful for providing anesthesia and analgesia for infants and children of all ages. Despite the toxicity issues raised here, the overall safety record of local anesthetic use in pediatrics has been very good, and local anesthetic administration within safe guidelines should be encouraged. In the great majority of cases, toxic reactions have been associated with either inadvertent intravascular injection or unintentional overdosage by physicians who did not adequately consider issues related to systemic drug uptake, distribution, or clearance. Unlike opioids, which can be titrated according to clinical signs to a wide range of doses, local anesthetic administration must be strictly limited "by the numbers." Pediatricians, surgeons, emergency room physicians, and anesthesiologists need to be informed regarding limits for the administration of local anesthetics and management of toxic reactions.
UNLABELLED: Some local anesthetics (LA), in concentrations present in blood during IV or epidural infusion, inhibit thrombus formation in the postoperative period. Studies on thromboxane A2 (TXA2) signaling in a recombinant model suggest that interference with TXA2-induced platelet aggregation may explain, in part, the antithrombotic actions of epidural analgesia and IV LA infusion. In this study we investigated the effects of clinically used LAs (lidocaine, ropivacaine, and bupivacaine) on TXA2-induced early platelet aggregation (1-5 s) by using quenched-flow and optical aggregometry. Our findings demonstrate that the LAs tested seem to have only a limited ability to inhibit TXA2-induced platelet aggregation assessed at early times (1-5 s). Therefore, the clinical effects of LAs on thrombi formation are unlikely to be explained by this manner alone. At large LA concentrations, moderate effects were obtained. Prolonged incubation with LA did not significantly increase effectiveness, and the lack of an effect could not be explained by generation of secondary mediators. The results were independent of the anesthetic studied. Local anesthetic effects on TXA2-induced early platelet aggregation (1-5 s) are unlikely to play a major role in the clinically observed antithrombotic effects of local anesthetics. IMPLICATIONS: Local anesthetic effects on thromboxane A2-induced early platelet aggregation (1-5 s) are unlikely to play a major role in the clinically observed antithrombotic effects of local anesthetics. Thus, other potential targets need to be explored.
BACKGROUND: Local anesthetics that produce analgesia of long duration with minimal impairment of autonomic functions are highly desirable for pain management in the clinic. Prenylamine is a known calcium channel blocker, but its local anesthetic blocking effects on voltage-gated sodium channels have not been studied thus far. METHODS: The authors characterized the tonic and use-dependent prenylamine block of native Na(+) channels in cultured rat neuronal GH3 cells during whole cell voltage clamp conditions and the local anesthetic effect of prenylamine by neurologic evaluation of sensory and motor functions of sciatic nerve during neural block in rats. RESULTS: Prenylamine elicits both use-dependent block of Na(+) channels during repetitive pulses (3 microm prenylamine produced 50% block at 5 Hz) and tonic block for both resting and inactivated Na(+) channels. The 50% inhibitory concentration for prenylamine was 27.6 +/- 1.3 microm for resting channels and 0.75 +/- 0.02 microm for inactivated channels. Furthermore, in vivo data show that 10 mm prenylamine produced a complete sciatic nerve block of motor function, proprioceptive responses, and nociceptive responses that lasted approximately 27, 34, and 24 h, respectively. Rats injected with 15.4 mm bupivacaine, a known local anesthetic currently used for pain management, had a significantly shorter duration of blockade (< 2 h) compared with rats injected with prenylamine. CONCLUSIONS: The data presented here demonstrate that prenylamine possesses local anesthetic properties in vitro and elicits prolonged local anesthesia in vivo.
UNLABELLED: The neurotoxicity of local anesthetics can be demonstrated in vitro by the collapse of growth cones and neurites in cultured neurons. We compared the neurotoxicity of procaine, mepivacaine, ropivacaine, bupivacaine, lidocaine, tetracaine, and dibucaine by using cultured neurons from the freshwater snail Lymnaea stagnalis. A solution of local anesthetics was added to the culture dish to make final concentrations ranging from 1 x 10(-6) to 2 x 10(-2) M. Morphological changes in the growth cones and neurites were observed and graded 1 (moderate) or 2 (severe). The median concentrations yielding a score of 1 were 5 x 10(-4) M for procaine, 5 x 10(-4) M for mepivacaine, 2 x 10(-4) M for ropivacaine, 2 x 10(-4) M for bupivacaine, 1 x 10(-4) M for lidocaine, 5 x 10(-5) M for tetracaine, and 2 x 10(-5) M for dibucaine. Statistically significant differences (P < 0.05) were observed between mepivacaine and ropivacaine, bupivacaine and lidocaine, lidocaine and tetracaine, and tetracaine and dibucaine. The order of neurotoxicity was procaine = mepivacaine < ropivacaine = bupivacaine < lidocaine < tetracaine < dibucaine. Although lidocaine is more toxic than bupivacaine and ropivacaine, mepivacaine, which has a similar pharmacological effect to lidocaine, has the least-adverse effects on cone growth among clinically used local anesthetics. IMPLICATIONS: Systematic comparison was assessed morphologically in growth cones and neurites exposed to seven local anesthetics. The order of neurotoxicity was procaine = mepivacaine < ropivacaine = bupivacaine < lidocaine < tetracaine < dibucaine. Although lidocaine is more toxic than bupivacaine and ropivacaine, mepivacaine, which has a similar pharmacological effect to lidocaine, is the safest among clinically used local anesthetics.
Local anesthetics are among the most used drugs in clinical practice. Various types of reactions have been reported and many patients are told that they are allergic to caines or are at risk of allergic reactions. We report our experience with 386 patients using skin test and progressive subcutaneous challenge in order to select a local anesthetic that could be safely used. The patients underwent specific protocol including clinical history, prick and intradermal tests, and subcutaneous incremental challenge with a local anesthetic from the amide group which was free of preservatives and vasoconstrictors. Thirteen patients showed a positive skin test: 10 with positive prick test underwent the subsequent challenge with no reactions; the three who were also positive by the intradermal route were carefully evaluated with a different drug. Eight of the patients with negative skin tests complained of various clinical symptoms after the challenge. All the patients found the local anesthetic to be well tolerated and nobody reported reactions after the clinical use. These results show that skin tests and subcutaneous challenge are safe and sufficient to reliably identify a local anesthetic that patients with a prior history of adverse reaction or at higher risk could tolerate.
In relieving local pains, lidocaine, one of ester type local anesthetics, has been used. To develop the lidocaine gels of enhanced local anesthetic effects, hydroxypropyl methylcellulose (HPMC) based bioadhesive polymer gel containing an enhancer was formulated. As the drug concentration in the gels increased up to 3%, the permeation rate of drug linearly increased, thereafter reaching a plateau. As the temperature of surrounding solutions increased, the permeation of drug increased. The activation energy of drug permeation was 3.29 kcal/mol for lidocaine. The permeation rate of drug through skin was studied using various enhancers, such as glycols, non-ionic surfactants, and bile salts. Among the enhancers studied, diethylene glycol showed the greatest enhancing effects on drug permeation through skin. The analgesic activity was examined using a tail-flick analgesimeter. In the area under the efficacy curve (AUEC) of the rat-tail flick tests, lidocaine gel containing diethylene glycol showed about 3.89-fold increase in analgesic activity compared with the control. The addition of vasoconstrictor in the gels prolonged the analgesic effects. The result of this study supports that the bioadhesive gel with efficient anesthetic effect could be developed using HPMC with combination of enhancer and vasoconstrictor.
OBJECTIVE: To review the pharmacology and mechanisms by which local anesthetics cause allergic reactions. Recommendations concerning appropriate use of local anesthetics and alternative therapies in patients with documented local anesthetic allergies are given. DATA SOURCE: A MEDLINE search of English-language literature identified pertinent clinical studies, case reports, and reviews. The periods of review were Med1, 1990-present, and Med2, 1985-1989, using the MeSH terms drug hypersensitivity and anesthetics. References from the selected studies, case reports, and reviews were reviewed. STUDY SELECTION: Controlled and uncontrolled prospective studies and case reports pertaining to local anaesthetic allergies were reviewed. The selection focused on information pertaining to the etiology and diagnosis of allergic reactions to local anesthetics and alternative therapies for patients with local anesthetic allergies. DATA SYNTHESIS: Local anesthetics are classified as either ester or amide compounds. Esters are associated with a higher incidence of allergic reactions, due to a p-aminobenzoic acid (PABA) metabolite. Amide agents do not undergo such metabolism. However, preservative compounds (methylparaben) used in the preparation of amide-type agents are metabolized to PABA. Patients who are allergic to ester local anesthetics should be treated with a preservative-free amide local anesthetic. If the patient is not allergic to ester local anesthetics, these agents may be used in amide-sensitive patients. In the rare instance that hypersensitivity to both ester and amide local anesthetics occurs, or if skin testing cannot be performed, than alternative therapies including diphenhydramine, opioids, general analgesia, or hypnosis can be used. CONCLUSIONS: A true immunologic reaction to a local anesthetic is rare. Intradermal skin testing of local anesthetic compounds, methylparaben, and metabisulfite should be performed in patients when a thorough history does not rule out a possible allergic reaction to local anesthetics and future local anesthesia is necessary. Skin testing enables the clinician to identify autonomic responses to minor surgical procedures and toxic reactions to anesthetics so that patients are not incorrectly labeled as "caine" allergic. Diphenhydramine can be used as an alternative to ester and amide local anesthetics in minor procedures of short duration.
Local anesthetics have been shown to affect a variety of cellular activities, such as exocytosis, membrane transport, permeability of calcium, and platelet aggregation, among others. Despite the disparate nature of the above phenomena, the calcium ion is essential for all of these cellular processes. Recently, it has been shown that local anesthetics inhibit specific calmodulin-dependent enzymes and protein kinase C-dependent enzymes. Therefore, the mode of action of local anesthetics in the activation of guinea pig neutrophils was examined in this study in order to understand the effect of local anesthetics on the intracellular calcium messenger system. In the presence of calmodulin inhibitors, FMLP-induced chemotaxis and superoxide anion production were strongly suppressed, whereas 1-oleoyl-2-acetylglycerol(OAG)(a direct activator of protein kinase C)-induced superoxide anion production was not affected. In contrast, protein kinase C inhibitors suppressed OAG-induced superoxide anion production but no inhibiting effect on FMLP-induced chemotaxis and superoxide anion production. Local anesthetics suppressed both FMLP- and OAG-induced activation of guinea pig neutrophils. These findings suggest that the inhibiting effect of local anesthetics on the activation of the intracellular calcium messenger system may be part of the pharmacological mechanism of local anesthetics in cellular activities.
Understanding of the pharmacology of local anesthesia is important for selection of a local anesthetic for use in equine standing surgery. In general, the action potential is inhibited by local anesthetics by preventing the influx of sodium ions across the axonal membrane. The physicochemical properties of each local anesthetic determine the onset of action, potency, and duration of action. Procaine, chlorprocaine, lidocaine, and mepivacaine are the local anesthetics still used clinically in horses; lidocaine is the most widely used. The future of equine local anesthesia may see the introduction of longer acting, more potent drugs currently used clinically in humans and dogs as well as drugs not classified as local anesthetics--alpha-2 agonists and opioids--for use in epidural anesthesia.