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PubMed2001

Evidence for a common binding cavity for three general anesthetics within the GABAA receptor.

The GABA(A) receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABA(A) receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABA(A) receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 A(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.

Anesthetics↗

PubMed2001

General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility.

A series of 27 analogs of the general anesthetic propofol (2,6-diisopropylphenol) were examined for general anesthetic activity in Xenopus laevis tadpoles and for the ability to produce enhancement of submaximal GABA responses and/or direct activation at recombinant GABA(A) receptors. Fourteen of the propofol analogs produced loss of righting reflex in the tadpoles, whereas 13 were inactive as anesthetics. The same pattern of activity was noted with the actions of the compounds at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The potencies of the analogs as general anesthetics in tadpoles correlated better with potentiation of GABA responses than direct activation at the GABA(A) alpha(1)beta(2)gamma(2s) receptor. The calculated octanol/water partition coefficients for the analogs did not explain the lack of activity exhibited by the 13 nonanesthetic analogs, although this physicochemical parameter did correlate modestly with in vivo anesthetic potency. The actions of one nonanesthetic analog, 2,6-di-tert-butylphenol, were examined in detail. 2,6-Di-tert-butylphenol was inactive at GABA(A) receptors, did not function as an anesthetic in the tadpoles, and did not antagonize any of the actions of propofol at GABA(A) receptors or in tadpoles. A key influence on the potency of propofol analogs appears to be the size and shape of the alkyl groups at positions 2 and 6 of the aromatic ring relative to the substituent at position 1. These data suggest steric constraints for the binding site for propofol on the GABA(A) receptor.

Allosteric Regulation↗

PubMed2002

[Diphenhydramine is useful in a parturient with hypersensitivity to local anesthetics to manage her delivery].

We did an obstetric management of a parturient, aged 32 years, with a history of local anesthetic hypersensitivity. The results of histamine release test, and cellular antigen stimulation test with lidocaine, mepivacaine, bupivacaine and preservative-free lidocaine during her pregnancy showed that all local anesthetics studied were positive. We used diphenhydramine as an alternative local anesthetic for episiotomy to the parturient during the delivery. Infiltration with diphenhydramine provided adequate analgesia without noticeable adverse reaction. One month after the delivery, we performed provocative challenge test with local anesthetics, and confirmed she had positive tests to lidocaine, mepivacaine and preservative-free lidocaine, and negative test to bupivacaine. Diphenhydramine is an adequate alternative of local anesthetics in patients with history of hypersensitivity to local anesthetics.

Adult↗

PubMed1992

[The anesthetic effects of steroids and their actions on the properties of model membrane].

The action of anesthetic steroid on the GABAA receptor in the postsynaptic membrane has been suggested as a mechanism of steroid anesthesia. Alphaxalone, the main component of althesin, is a strong anesthetic, whereas its analogue, delta 16-alphaxalone is not. The only structural difference between the two is a presence of the double bond in the D ring of delta 16-alphaxalone. The effects of these steroids on the model membrane structure and the hydrogen bonding between lipid membrane and water were examined by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) and compared with their anesthetic potencies in goldfish. Alphaxalone decreased the phase-transition temperature from the solid-gel to the liquid-crystal state of DPPC liposome. FTIR showed that alphaxalone molecules released the bound water molecules in the lipid-water interface of D2O-in-CCl4 reversed micelles. delta 16-alphaxalone in high concentration was also an anesthetic in goldfish. It also showed a weak effect on the phase-transition temperature and the hydrogen bond breaking activity. These changes in the membrane properties correlated to the anesthetic potency. These results suggest that anesthetic potency of steroids is related to their action in destabilizing the structures of the water molecules in the macromolecule-water interface and the macromolecules.

Anesthetics↗

PubMed1992

Topical ocular anesthetics in ocular irritancy testing: a review.

The routine use of topical anesthetics to alleviate discomfort associated with in vivo ocular irritancy testing has been advocated. This review provides information about the adverse effects of topical ocular anesthetics and answers the questions: are topical anesthetics practical and effective in ocular irritancy protocols, is long-term use contraindicated, will topical anesthetics alter the response of a test substance, and are there significant side-effects which might cause pain and suffering in test animals? There was no evidence to support the use of a specific topical anesthetic. Further, information about using systemic analgesics or combinations with local anesthetics that would effectively alleviate discomfort associated with ocular irritancy testing without affecting test results was not found. Comprehensive studies are needed to identify the most effective combination of drugs that would ameliorate discomfort associated with ocular irritation testing.

Administration, Topical↗

PubMed2004

Effect of cutaneously applied nonionic surfactants and local anesthetic bases on thermal sensations.

With cutaneously applied local anesthetic bases various effects may be observed, such as a decrease in pricking pain and a change in burning, itch, and thermal sensations. These effects occur after skin penetration and may be attributed to the action of the anesthetics on nociceptors and thermoreceptors, i.e., on C and A delta nerve fibers, respectively. As little is known about the pharmacodynamic response of nonionic surfactants with a potentially anesthetic action such as polidocanol, this study characterizes nonionic surfactants pharmacodynamically by measuring thermal thresholds with a thermal sensory analyzer after cutaneous application. The results obtained with the nonionic surfactants were compared with data resulting from the cutaneous application of local anesthetic bases such as mepivacaine, bupivacaine, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine contained in EMLA and a triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1). The results show that none of the investigated surfactants affect thermal thresholds probably due to their high molecular weight. The same was observed with the anesthetics mepivacaine and bupivacaine. In contrast, prilocaine, lidocaine, the 1:1 mixture of lidocaine and prilocaine and the triple mixture consisting of lidocaine, prilocaine and tetracaine (1:1:1) proved to be potent local anesthetics. However, their pharmacodynamic responses do not differ significantly from each other.

Administration, Topical↗

PubMed1992

Alteration of general anesthetic potency by agonists and antagonists of the polyamine binding site of the N-methyl-D-aspartate receptor.

Anesthetic potency was examined in mice after pretreatment with various putative agonists and antagonists of the polyamine site of the N-methyl-D-aspartate (NMDA) receptor. Anesthetic potency was determined for ethanol and pentobarbital by measurement of duration of loss of righting reflex, and for the volatile anesthetics, halothane and diethyl ether, by measurement of the minimum alveolar concentration (MAC). The polyamines, spermine and spermidine, increased the duration of ethanol and pentobarbital anesthesia and reduced halothane MAC, but had no effect on diethyl ether MAC. Putative antagonists of the polyamine site, ifenprodil and arcaine, also increased the anesthetic potency of ethanol, but diaminodecane, an inverse agonist, was inactive. Concurrent pretreatment with spermine or ifenprodil reduced the ability of MK-801 to increase ethanol anesthesia duration, but did not alter the ability of CGS 19755 to increase ethanol anesthesia duration. Although this study did not rule out effects of polyamines on other neurochemical systems, these results suggest that spermine and spermidines could increase anesthetic potency by acting at a site on the NMDA receptor which negatively modulates the binding of MK-801. Results of this study also suggest that the anesthetic potency of ethanol and halothane is more closely linked to the activity of brain NMDA receptors than is that of pentobarbital or diethyl ether.

Anesthesia↗

PubMed2004

Comparison of injection pain, heart rate increase, and postinjection pain of articaine and lidocaine in a primary intraligamentary injection administered with a computer-controlled local anesthetic delivery system.

The purpose of this prospective, randomized, double-blind study was to compare the pain of injection, heart rate increase, and postinjection pain of the intraligamentary injection of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine administered with a computer-controlled local anesthetic delivery system. Using a crossover design, intraligamentary injections of 1.4 mL of 4% articaine with 1:100,000 epinephrine and 1.4 mL of 2% lidocaine with 1:100,000 epinephrine were randomly administered on the mesial and distal aspects of the mandibular first molar with a computer-controlled local anesthetic delivery system in a double-blind manner at 2 separate appointments to 51 subjects. The results demonstrated the incidence of moderate pain was 14%-27% with needle insertion, with 0%-4% reporting severe pain. For solution deposition, moderate pain was reported 8%-18% of the time, with no reports of severe pain. There were no significant differences between the articaine and lidocaine solutions. Regarding heart rate changes, neither anesthetic solution resulted in a significant increase in heart rate over baseline readings. On day 1 postinjection, there was a 31% incidence of moderate/severe pain with the articaine solution and 20% incidence of moderate/severe pain with the lidocaine solution. The moderate/severe pain ratings decreased over the next 2 days. There were no significant differences between the articaine and lidocaine solutions. We concluded that the intraligamentary injection of 4% articaine with 1:100,000 epinephrine was similar to 2% lidocaine with 1:100,000 epinephrine for injection pain and postinjection pain in the mandibular first molar when administered with a computer-controlled local anesthetic delivery system. For both anesthetic solutions, heart rate did not significantly increase with the intraligamentary injection using the computer-controlled local anesthetic system.

Adult↗

PubMed1990

[The significance of the sampling site in the determination of plasma levels of local anesthetics using 0.75% bupivacaine as an example].

Knowledge of the actual concentrations of local anesthetic administered by various techniques is essential requisite when undesirable side effects and possible toxicity of a substance are to be evaluated. Therefore, numerous studies of plasma concentrations have been presented, which were carried out with the additional purpose of analyzing the kinetics of different local anesthetics with respect to limiting-value concentrations in the organism. Despite a sufficient degree of precision in the analysis of amide local anesthetics, it is uncertain whether the results of the different studies are comparable, because blood samples have been taken variously from peripheral veins, central veins or arteries. In the present study changes in bupivacaine concentrations were monitored by means of a standardized method consisting in simultaneous sampling of blood in peripheral veins, central veins and arteries. METHODS. Each of 12 patients undergoing orthopedic hip surgery received average 17 ml bupivacaine (0.75%) via peridural lumbar catheter. After the administration of bupivacaine, blood samples were taken simultaneously from peripheral veins, central veins and arteries at 1, 3, 5, 10, 15, 30, 45, 60, and 90 min after injection. Placement of an arterial cannula and central venous catheter was indicated in all patients (hip-joint revision arthroplasty). Quantitative analysis of bupivacaine concentration was carried out by means of high-pressure liquid chromatography (HPLC). All patients had given their informed consent. RESULTS. All patients showed a rapid increase in bupivacaine concentration in the central venous blood within the first few minutes after administration, the maximum being reached between 3 and 10 min after. A similar course was observed with arterial plasma concentrations; absolute values, however, were an average of 10-20% lower at 15 min following administration. Bupivacaine concentrations in peripheral veins rose more slowly and reached a maximum between 15 and 30 min. At 30 min after peridural application the concentration curves in blood from all three sites were similar. DISCUSSION. In earlier studies the influence of the site of blood sampling has often been underestimated. According to our results, central venous and arterial plasma concentrations correspond closely at all times following peridural application. The observed uniform differences in concentrations at the various sites of sampling can be explained by the fact that pulmonary uptake of local anesthetics causes the lower arterial levels. Especially in the early phase of resorption after administration of local anesthetics, the concentration in peripheral blood does not seem to be representative, because an equilibrium is not established between arterial and central venous blood until 30 min after administration at the earliest. In our opinion the peripheral venous concentrations are unreliable, particularly in the early phases, for the evaluation of unwanted effects or toxicity of local anesthetics, because the initial low values and the delayed increase in these could lead to a false sense of security.

Aged↗

PubMedDate not supplied

[Allergic reactions to local anesthetics].

We studied 35 patients which had been sent by various specialists to the Allergy department of a general hospital because they had an adverse reaction to some type of local anesthetic. The subjects underwent three types of tests: a prick test, an intradermoreaction test and a provocation test using three local anesthetics: procaine 2%, lidocaine 2%, mepivacaine 1% with no vasoconstrictors or parabens in order to rule out the possibility that the reaction was due to these substances rather than the local anaesthetic being tested. The results indicated that both the prick test and the provocation test of the local anesthetics included in the study were negative for all of the patients. One patient who had an adverse reaction to Hostacain was tested with that same anesthetic. The patient tested positive in the intradermoreaction test with a 1/10 solution but was not able to be tested with a solution free of parabens due to lack of availability. The results of our study coincide with the bibliographic research done in that real allergic reactions to local anesthetics are infrequent. The methodology used effectively distinguishes those patients with a risk of real allergic reactions there by indicating to the physician the safest local anesthetic for the patient.

Adolescent↗

PubMed1987

Neurochemical actions of anesthetic drugs on the gamma-aminobutyric acid receptor-chloride channel complex.

Interaction of intoxicant-anesthetic drugs with the gamma-aminobutyric acid (GABA) receptor-chloride channel complex of mouse brain was studied using the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to isolated membranes and the GABA-stimulated uptake of 36Cl- by membrane vesicles. Anesthetic drugs, including barbiturates, chloroform, diethylether and ethanol, inhibited the binding of TBPS and enhanced the GABA-dependent influx of chloride. In the presence of bicuculline, barbiturates increased the binding of TBPS, but this action was not shared by other anesthetic agents. Inhibition of TBPS binding was found with drug concentrations that produce anesthesia in vivo, whereas augmentation of GABA action occurred at subanesthetic concentrations. Effects of a series of n-alcohols (methanol to decanol) were studied on TBPS binding and membrane fluidity (using 1,6-diphenyl-1,3,5-hexatriene as a fluorescent probe). The potencies of the alcohols for inhibiting TBPS binding and fluidizing synaptic membranes were similar to their anesthetic potencies, but there were differences in the relative potencies of the drugs for inhibition of TBPS binding and membrane fluidization. These results, together with effects of assay temperature, suggest that effects of anesthetics on the GABA receptor-chloride channel complex were not due to changes in bulk membrane fluidity. Correlation of anesthetic potencies of chemically diverse agents with both inhibition of TBPS binding and augmentation of GABA-dependent chloride flux suggests a role for the GABA complex in anesthesia.

Alcohols↗

PubMed1989

Halogenation and anesthetic potency.

Previous studies have shown that the anesthetic potency of organic compounds increases as a given halogen is replaced with successively larger halogens. These studies often are limited in the accuracy of determination of potency, rarely correlate potency with physical properties, and usually fail to include ether compounds. Because establishing relationships between structure and activity may shed light on anesthetic action, we studied the new anesthetic, I-537 (CHF2-O-CHBr-CF3), relative to two other ether anesthetics, I-653 (CHF2-O-CHF-CF3) and isoflurane (CHF2-O-CHCl-CF3) for both of which MAC and oil/gas partition coefficients are accurately known. The oil/gas partition coefficient of I-537 at 37 degrees C was found to be 245 +/- 6 (mean +/- SD) and the MAC in Sprague-Dawley rats 0.52 +/- 0.07%. Increasing atomic weight of the 1-ethyl halogen (i.e., F in I-653, Cl in isoflurane, and Br in I-537) progressively decreases MAC (increases potency) and increases lipid solubility. Although potency and solubility change by more than 10-fold, the product of MAC and the oil/gas partition coefficient remains essentially constant (120 +/- 11). However, this product is significantly less than that for other inhaled anesthetics, a finding which either challenges the unitary theory of narcosis or suggests that the lipid solvent classically used to model the site of anesthetic action (olive oil) is inappropriate.

Anesthetics↗

PubMed1988

Local anesthetics: comparison of effects on batrachotoxin-elicited sodium flux and phosphoinositide breakdown in guinea pig cerebral cortical synaptoneurosomes.

Local anesthetics inhibited the sodium influx and the inositol phosphate accumulation elicited by the sodium channel activator batrachotoxin in guinea pig cortical synaptoneurosomes. Inhibitory effects of local anesthetics on sodium influx correlated with inhibitory effects on binding of a tritiated batrachotoxin analog to sodium channels in synaptoneurosomes. There was also a correlation between inhibitory effects on sodium influx and on inositol phosphate accumulation; most local anesthetics inhibited sodium influx at concentrations similar to those required for inhibition of inositol phosphate accumulation. Indeed, euprocin, bupivacaine, lidocaine, and certain analogs were nearly equipotent with respect to inhibition of sodium influx and inositol phosphate accumulation. Local anesthetics also inhibited inositol phosphate accumulation that was induced by carbamylcholine through both a tetrodotoxin-sensitive and tetrodotoxin-insensitive pathway. Certain local anesthetics, such as dibucaine, inhibited the tetrodotoxin-sensitive pathway with higher potency than for the tetrodotoxin-insensitive pathway, while others, such as quinacrine, inhibited tetrodotoxin-sensitive and tetrodotoxin-insensitive pathways with equal potency. Diphenhydramine and chlorpromazine appeared to inhibit carbamylcholine-elicited phosphoinositide breakdown through blockade of muscarinic cholinergic receptors rather than because of local anesthetic activity of inhibitory effects on phospholipase C.

Anesthetics, Local↗

PubMed1987

[Enhanced stability of isolated muscles and actomyosin due to the action of anesthetics in subnarcotic concentrations].

Subnarcotic concentrations of anesthetics and model anesthetics prolong the survival time of isolated living frog skeletal muscles, the time of contractile ability of the same glycerinated muscles, and the time of frog skeleton muscle actomyosin denaturation. The mode of anesthetic action involves hydrophobic interactions of anesthetics with the investigated biosystems. According to the quantitative analysis, physico-chemical parameters of the anesthetic-binding sites are identical in muscle and in muscle models. This result is interpreted as an evidence that anesthetic-evoked rising of contractile protein stability may be involved in the mechanism of stabilization of isolated muscles.

Actomyosin↗

PubMed1980

Membrane and cellular actions of anesthetic agents.

It is generally accepted that anesthetics affect most biological cells in a nonspecific fashion. A similar or unitary mechanism of action has been proposed for all anesthetics. This may be the rule for general anesthesia; however, evidence exists which suggests that all anesthetics may not act via the same mechanism or at the same site. It is well recognized that various anesthetic agents can affect peripheral systems in a selective manner that is often clinically relevant. In addition to the nonspecific requirement of lipid solubility, specific molecular structure may determine the selectivity of an anesthetic and thus its pattern of anesthesia. Recent studies on an isolated neuronal preparation, the stretch receptor of the crayfish, are presented which demonstrate that anesthetics can differentially alter neuronal behavior in addition to producing biphasic effects of excitation and depression. It is yet to be resolved whether these effects are relevant to the mechanism of anesthesia.

Action Potentials↗

PubMed1978

[The influence of local anesthetics on corneal epithelium. A scanning electron microscopic study (author's transl)].

The effect of different local anesthetics (Cocain 4%, Lidocaine 2%, Proparacain) on the corneal epithelium in rabbits was examined under scanning electron microscope. The experiment was divided into three groups. Group 1 received one application of two drops of the given local anesthetic for a reaction time of 5 minutes. Group 2 received two drops of the given anesthetic after 0, 5 and 10 minutes. The cornea was excised after 15 minutes. Group 3 were measured after a single application of Proparacain using a Schiötz or hand applanation tonometer according to Draeger. After a single dose of a local anesthetic principally the same changes in the surface of the cornea were observed with all the preparations used: a distinct decrease in the number of microvilli and microplicae, disruption of the intercellular spaces and the prominence of the cell nuclei which under normal conditions are not visible. After several applications the greater toxicity of Cocain compared with the other preparations was clearly seen through the disruption of the plasma membrane and the cytoplasm. The damage effected several layers of cells. Tonometry when correctly performed causes no additional damage to the cell surface.- The effect of local anesthetics on the cell membrane can only take place after the disruption of the tear film. The results emphasize that local anesthetics should only be applied when absolutely essential.

Anesthetics, Local↗

PubMed1994

Potentiation of gamma-aminobutyric acidA receptor Cl- current correlates with in vivo anesthetic potency.

Ten general anesthetics of varying structure and potency were investigated for possible modulatory effects on gamma-aminobutyric acid, (GABAA) receptors, using the voltage clamp technique. All 10 anesthetics studied were observed to prolong the duration of responses to exogenously applied GABA recorded in cultured rat hippocampal neurons. These modulatory effects of the anesthetics occurred at pharmacologically relevant concentrations. An excellent correlation exists between drug potency as modulators of the GABAA receptor and anesthetic potency in vivo. These data suggest an alternative interpretation of the historical association between anesthetic potency and lipophilicity. It is proposed that hydrophobic binding sites on ligand-gated ion channel proteins, such as the GABAA receptors, constitute a molecular target site for many general anesthetics.

Anesthetics, General↗

PubMedDate not supplied

[EMLA. A new topical anesthetic].

The method most widely used at present for cutaneous analgesia is local anesthetic infiltration. Pain occurs when the needle penetrates and when the anesthetic is deposited and diffuses. The procedure is not risk-free. It is therefore not surprising that many attempts have been made to develop an anesthetic formula that is effective when applied topically to intact skin. Early efforts were unsuccessful due to either low analgesic efficacy or side effects. The problem was solved several years ago in the European market by the EMLA (Eutetic Mixture of Local Anesthetics) cream. The EMLA cream has been shown to be useful as a topical anesthetic on either intact or damaged skin. Its clinical profile is safe, with a low incidence of side effects. We feel it is a useful tool for preventing pain in a variety of procedures that call for cutaneous analgesia. It may also be used as premedication for perineural injection of anesthetics, providing greater comfort for the patient. This article describes the main pharmacological principles that make EMLA an effective topical analgesic, as well as indications for its use in the clinical practice of anesthesiology.

Anesthetics, Local↗