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PubMed2005

Anesthetic effects of progesterone are undiminished in progesterone receptor knockout mice.

Progesterone has sedative and anesthetic effects but the underlying molecular mechanisms remain unclear. The two possible mechanisms by which progesterone affects the function of the brain include binding to intracellular progesterone receptors (PR) and metabolism to GABA(A) receptor-modulating neurosteroids. In this study, PR knockout (PRKO) mice were used as model to study the role of PRs in the anesthetic activity of progesterone. The progesterone-induced anesthetic activity was undiminished in female PRKO mice (ED50, 172 mg/kg) as compared to their wild-type littermates (ED50, 167 mg/kg). The progesterone-induced anesthetic activity was highly correlated with increased plasma allopregnanolone levels. Pretreatment of PRKO mice with the 5alpha-reductase inhibitor finasteride significantly reduced the progesterone-induced anesthetic activity. Allopregnanolone also evoked dose-dependent anesthetic activity in PRKO mice, which was similar to those of wild-type mice. Thus, the anesthetic activity of progesterone is not mediated by its interaction with PRs. The neurosteroid allopregnanolone partially mediates the anesthetic activity of progesterone by potentiation of GABA(A) receptor function.

Analysis of Variance↗

PubMedDate not supplied

Maximum recommended doses of local anesthetics: a multifactorial concept.

The current recommendations regarding maximum doses of local anesthetics presented in textbooks, or by the responsible pharmaceutical companies, are not evidence based (ie, determined by randomized and controlled studies). Rather, decisions on recommending certain maximum local anesthetic doses have been made in part by extrapolations from animal experiments, clinical experiences from the use of various doses and measurement of blood concentrations, case reports of local anesthetic toxicity, and pharmacokinetic results. The common occurrence of central nervous system toxicity symptoms when large lidocaine doses were used in infiltration anesthesia led to the recommendation of just 200 mg as the maximum dose, which has remained unchanged for more than 50 years. In most cases, there is no scientific justification for presenting exact milligram doses or mg/kg doses as maximum dose recommendations. Instead, only clinically adequate and safe doses (ranges) that are block specific are justified, taking into consideration the site of local anesthetic injection and patient-related factors such as age, organ dysfunctions, and pregnancy, which may influence the effect and the pharmacokinetics of the local anesthetic. Epinephrine in concentrations of 2.5 to 5 microg/mL should be added to the local anesthetic solution when large doses are administered, providing there are no contraindications for the use of epinephrine. As a rule, conditions (eg, end-stage pregnancy, high age in epidural, or spinal block) or diseases (uremia) that may increase the rate of the initial uptake of the local anesthetic are indications to reduce the dose in comparison to one normally used for young, healthy, and nonpregnant adults. On the other hand, the reduced clearance of local anesthetics associated with renal, hepatic, and cardiac diseases is the most important reason to reduce the dose for repeated or continuous administration. The magnitude of the reduction should be related to the expected influence of the pharmacodynamic or pharmacokinetic change.

Age Factors↗

PubMed2005

Emerging molecular mechanisms of general anesthetic action.

General anesthetics are essential to modern medicine, and yet a detailed understanding of their mechanisms of action is lacking. General anesthetics were once believed to be "drugs without receptors" but this view has been largely abandoned. During the past decade significant progress in our understanding of the mechanisms of general anesthetic action at the molecular, cellular and neural systems levels has been made. Different molecular targets in various regions of the nervous system are involved in the multiple components of anesthetic action, and these targets can vary between specific anesthetics. Neurotransmitter-gated ion channels, particularly receptors for GABA and glutamate, are modulated by most anesthetics, at both synaptic and extrasynaptic sites, and additional ion channels and receptors are also being recognized as important targets for general anesthetics. In this article, these developments, which have important implications for the development of more-selective anesthetics, are reviewed in the context of recent advances in ion channel structure and function.

Anesthesia, General↗

PubMed2002

Propofol, a general anesthetic, promotes the formation of fluid phase domains in model membranes.

The molecular site of anesthetic action remains an area of intense research interest. It is not clear whether general anesthetics act through direct binding to proteins or by perturbing the membrane properties of excitable tissues. Several studies indicate that anesthetics affect the properties of either membrane lipids or proteins. However, gaps remain in our understanding of the molecular mechanism of anesthetic action. Recent developments in membrane biology have led to the concept of small-scale domain structures in lipid and lipid--protein coupled systems. The role of such domain structures in anesthetic action has not been studied in detail. In the present study, we investigated the effect of anesthetics on lipid domain structures in model membranes using the fluorescent spectral properties of Laurdan (6-dodecanoyl-2-dimethylamino naphthalene). Propofol, a general anesthetic, promoted the formation of fluid domains in model membranes of dipalmitoyl phosphatidyl choline (DPPC) or mixtures of lipids of varying acyl chains (DPPC:DMPC dimyristoyl phosphatidyl choline 1:1). The estimated size of these domains is 20--50 A. Based on these studies, we speculate that the mechanism of anesthetic action may involve effects on protein--lipid coupled systems through alterations in small-scale lipid domain structures.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2000

The alpha and gamma subunit-dependent effects of local anesthetics on recombinant GABA(A) receptors.

Although convulsions due to local anesthetic systemic toxicity are thought to be due to inhibition of GABA(A) receptor-linked currents in the central nervous system, the mechanism of action remains unclear. We therefore examined the effects of local anesthetics on gamma-aminobutyric acid (GABA)-induced currents using recombinant GABA(A) receptors with specific combinations of subunits. Murine GABA(A) receptors were expressed by injection of cRNAs encoding each subunit into Xenopus oocytes. The effects of local anesthetics (lidocaine, bupivacaine, procaine and tetracaine) on GABA-induced currents of receptors expressing different subunit combinations (alpha1beta2, alpha1beta2gamma2s, alpha4beta2gamma2s and beta2) were examined via the two electrode voltage clamp method. At alpha1beta2, alpha1beta2gamma2s and alpha4beta2gamma2s GABA(A) receptors, all local anesthetics inhibited GABA-induced currents in a dose-dependent manner. The presence of the gamma2s subunit resulted in a greater inhibition by all local anesthetics, but the presence of the alpha4 subunit resulted in less inhibition. At beta2 homomeric receptors, local anesthetics directly induced an outward current similar to that of picrotoxin. These data indicated that (1) the alpha and gamma subunits of GABA(A) receptors modulated the inhibitory effects of local anesthetics on GABA(A) function, and (2) local anesthetics can activate the beta2 subunit and may block the GABA(A) receptor channel pore.

Anesthetics, Local↗

PubMed1988

Pain reduction in local anesthetic administration through pH buffering.

The effects of pH buffering on the pain of administration and efficacy of three local anesthetics (1% lidocaine, 1% lidocaine with 1:100,000 epinephrine, and 1% mepivacaine) were investigated in a randomized, prospective, double-blind study of 25 adult volunteers. Plain and buffered solutions of the three local anesthetics were prepared, and a 0.5 intradermal injection of each was administered. Pain of anesthetic infiltration was rated from zero to ten. The area of anesthetized skin surrounding each injection site was measured at time intervals following each injection. Buffering the local anesthetics significantly reduced the mean quantitative pain estimates compared to the nonbuffered controls: 1) 1% lidocaine compared with buffered 1% lidocaine, 4.9 +/- 0.4 versus 1.1 +/- 0.2 (P less than 10(-6)); 2) 1% lidocaine with epinephrine compared with buffered 1% lidocaine with epinephrine, 5.1 +/- 0.4 versus 1.8 +/- 0.4 (P less than 10(-6)); and 3) 1% mepivacaine compared with buffered 1% mepivacaine, 5.1 +/- 0.4 versus 0.9 +/- 0.2 (P less than 10(-6)). Onset, extent, and duration of skin anesthesia were not statistically altered by pH buffering. The pain of local anesthetic administration can be dramatically reduced by buffering the local anesthetic prior to its infiltration. Anesthetic efficacy is not compromised, and patient acceptance may be significantly increased.

Adult↗

PubMed2006

Kinetics of anesthetic-induced conformational transitions in a four-alpha-helix bundle protein.

Inhaled anesthetics are thought to alter the conformational states of Cys-loop ligand-gated ion channels (LGICs) by binding within discrete cavities that are lined by portions of four alpha-helical transmembrane domains. Because Cys-loop LGICs are complex molecules that are notoriously difficult to express and purify, scaled-down models have been used to better understand the basic molecular mechanisms of anesthetic action. In this study, stopped-flow fluorescence spectroscopy was used to define the kinetics with which inhaled anesthetics interact with (Aalpha(2)-L1M/L38M)(2), a four-alpha-helix bundle protein that was designed to model anesthetic binding sites on Cys-loop LGICs. Stopped-flow fluorescence traces obtained upon mixing (Aalpha(2)-L1M/L38M)(2) with halothane revealed immediate, fast, and slow components of quenching. The immediate component, which occurred within the mixing time of the spectrofluorimeter, was attributed to direct quenching of tryptophan fluorescence upon halothane binding to (Aalpha(2)-L1M/L38M)(2). This was followed by a biexponential fluorescence decay containing fast and slow components, reflecting anesthetic-induced conformational transitions. Fluorescence traces obtained in studies using sevoflurane, isoflurane, and desflurane, which poorly quench tryptophan fluorescence, did not contain the immediate component. However, these anesthetics did produce the fast and slow components, indicating that they also alter the conformation of (Aalpha(2)-L1M/L38M)(2). Cyclopropane, an anesthetic that acts with unusually low potency on Cys-loop LGICs, acted with low apparent potency on (Aalpha(2)-L1M/L38M)(2). These results suggest that four-alpha-helix bundle proteins may be useful models of in vivo sites of action that allow the use of a wide range of techniques to better understand how anesthetic binding leads to changes in protein structure and function.

Anesthetics, Inhalation↗

PubMed1998

Methane influences infrared technique anesthetic agent monitors.

OBJECTIVE: During closed-circuit anesthesia, anesthetic vapor analysis by infrared absorption at 3.3 microm can be influenced by the concentration of accumulated methane, resulting in inaccurate readings of anesthetic concentrations. The current study examined the influence of different known methane concentrations on the analysis of halothane or isoflurane concentrations by the infrared absorption technique. METHODS: Three different gas mixtures containing 100, 500 and 1000 ppm methane were given through an experimental sampling bar. Four infrared technique anesthetic agent monitors were examined: (1) the Ultima (Datex), (2) the Andros analyzer (Cato anesthesia machine, Driger), (3) the anesthetic gas monitor 1304 (Brüel & Kjaer) and (4) the mainstream analyzer Irina (Drager). All devices, except the Brüel & Kjaer anesthetic gas monitor, function at 3.3 microm wavelength. The Brüel & Kjaer apparatus functions at 10.3-13 microm wavelength. The readings were recorded with and without addition of halothane (or isoflurane) at a halothane (or an isoflurane) dedicated sensitivity after application of methane. RESULTS: At the two highest methane concentrations (500 and 1000 ppm) all studied devices except the Brüel & Kjaer anesthetic gas monitor 1304 displayed inaccurate anesthetic concentrations. This was more pronounced at halothane than at isoflurane sensitivity. Introduction of halothane (0.8%) or isoflurane (0.8%) vapor into the experimental sampling bar resulted in values that were additive to the falsely recorded ones. CONCLUSIONS: In closed circuit or low-flow anesthesia, in which methane can accumulate, infrared measuring techniques for potent inhalation anesthetics that do not use the 3.3 microm wavelength appear to be preferable.

Anesthesia, Closed-Circuit↗

PubMed2004

Interaction of serotonin1A receptors from bovine hippocampus with tertiary amine local anesthetics.

1. We have examined the interaction of tertiary amine local anesthetics with the bovine hippocampal serotonin1A (5-HT1A) receptor, an important member of the G-protein-coupled receptor superfamily. 2. The local anesthetics inhibit specific agonist and antagonist binding to the 5-HT1A receptor at a clinically relevant concentration range of the anesthetics. This is accompanied by a concomitant reduction in the binding affinity of the 5-HT1A receptor to the agonist. Interestingly, the extent of G-protein coupling of the receptor is reduced in the presence of the local anesthetics. 3. Fluorescence polarization measurements using depth-dependent fluorescent probes show that procaine and lidocaine do not show any significant change in membrane fluidity. On the other hand, tetracaine and dibucaine were found to alter fluidity of the membrane as indicated by a fluorescent probe which monitors the headgroup region of the membrane. 4. The local anesthetics showed inhibition of agonist binding to the 5-HT1A receptor in membranes depleted of cholesterol more or less to the same extent as that of control membranes in all cases. This suggests that the inhibition in ligand binding to the 5-HT1A receptor brought about by local anesthetics is independent of the membrane cholesterol content. 5. Our results on the effects of the local anesthetics on the ligand binding and G-protein coupling of the 5-HT1A receptor support the possibility that G-protein-coupled receptors could be involved in the action of local anesthetics.

Amines↗

PubMedDate not supplied

Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia.

BACKGROUND AND OBJECTIVES: Buprenorphine added to local anesthetic solutions for supraclavicular block was found to triple postoperative analgesia duration in a previous study when compared with local anesthetic block alone. That study, however, did not control for potentially confounding factors, such as the possibility that buprenorphine was affecting analgesia through intramuscular absorption or via a spinal mechanism. To specifically delineate the role of buprenorphine in peripherally mediated opioid analgesia, the present study controlled for these 2 factors. METHODS: Sixty American Society of Anesthesiologists (ASA) P.S. I and II, consenting adults for upper extremity surgery, were prospectively assigned randomly in double-blind fashion to 1 of 3 groups. Group I received local anesthetic (1% mepivacaine, 0.2% tetracaine, epinephrine 1:200,000), 40 mL, plus buprenorphine, 0.3 mg, for axillary block, and intramuscular (IM) saline. Group II received local anesthetic-only axillary block, and IM buprenorphine 0.3 mg. Group III received local anesthetic-only axillary block and IM saline. Postoperative pain onset and intensity were compared, as was analgesic medication use. RESULTS: The mean duration of postoperative analgesia was 22.3 hours in Group I; 12.5 hours in group II, and 6.6 hours in group III. Differences between groups I and II were statistically significant (P =.0012). Differences both between groups I and III and II and III were also statistically significant (P <.001). CONCLUSIONS: Buprenorphine-local anesthetic axillary perivascular brachial plexus block provided postoperative analgesia lasting 3 times longer than local anesthetic block alone and twice as long as buprenorphine given by IM injection plus local anesthetic-only block. This supports the concept of peripherally mediated opioid analgesia by buprenorphine.

Adult↗

PubMed1993

Volatile anesthetics compete for common binding sites on bovine serum albumin: a 19F-NMR study.

There is controversy as to the molecular nature of volatile anesthetic target sites. One proposal is that volatile anesthetics bind directly to hydrophobic binding sites on certain sensitive target proteins. Consistent with this hypothesis, we have previously shown that a fluorinated volatile anesthetic, isoflurane, binds saturably [Kd (dissociation constant) = 1.4 +/- 0.2 mM, Bmax = 4.2 +/- 0.3 sites] to fatty acid-displaceable domains on serum albumin. In the current study, we used 19F-NMR T2 relaxation to examine whether other volatile anesthetics bind to the same sites on albumin and, if so, whether they vary in their affinity for these sites. We show that three other fluorinated volatile anesthetics bind with varying affinity to fatty acid-displaceable domains on serum albumin: halothane, Kd = 1.3 +/- 0.2 mM; methoxyflurane, Kd = 2.6 +/- 0.3 mM; and sevoflurane, Kd = 4.5 +/- 0.6 mM. These three anesthetics inhibit isoflurane binding in a competitive manner: halothane, K(i) (inhibition constant) = 1.3 +/- 0.2 mM; methoxyflurane, K(i) = 2.5 +/- 0.4 mM; and sevoflurane, K(i) = 5.4 +/- 0.7 mM--similar to each anesthetic's respective Kd of binding to fatty acid displaceable sites. These results illustrate that a variety of volatile anesthetics can compete for binding to specific sites on a protein.

Anesthetics↗

PubMed1999

Amino acid volume and hydropathy of a transmembrane site determine glycine and anesthetic sensitivity of glycine receptors.

Two specific amino acid residues in transmembrane segments (TM) 2 and 3 are critical for the enhancement of glycine receptor (GlyR) function by volatile anesthetics. To determine which physicochemical characteristics of these sites determine their roles in anesthetic actions, an extensive series of single amino acid mutations at amino acid residue 288 (Ala-288) in TM3 of the alpha1 GlyR subunit was tested for modulation by volatile anesthetics. The mutations changed the apparent affinities of receptors for glycine; replacements with larger volumes and less hydropathy exhibited higher affinities for glycine. Potentiation by anesthetics was reduced by specific mutations at Ala-288. The molecular volume of the substituents was negatively correlated with the extent of potentiation by isoflurane, enflurane, and 1-chloro-1,2,2-trifluorocyclobutane, whereas there was no correlation between anesthetic enhancement and polarity, hydropathy, or hydrophilicity of substituents. In contrast to anesthetics, no correlation was found between the effects of the nonanesthetics 1,2-dichlorohexafluorocyclobutane or 2, 3-dichlorooctafluorobutane and any physicochemical property of the substituent. These results suggest that the molecular volume and hydropathy of the amino acid at position 288 in TM3 regulate glycine and anesthetic sensitivity of the GlyR and that this residue might represent one determinant of an anesthetic binding site.

Alanine↗

PubMed2000

A transmembrane site determines sensitivity of neuronal nicotinic acetylcholine receptors to general anesthetics.

Neuronal nicotinic acetylcholine receptors (nAChRs) are potential targets for a wide variety of general anesthetics. We recently showed that alpha(4)beta(2) nAChRs are more sensitive than alpha(4)beta(4) receptors to the gaseous anesthetics nitrous oxide and xenon. The present study examines chimeric and point mutant rat nAChRs expressed in Xenopus oocytes and identifies a single amino acid residue (beta(2)-Val(253) or beta(4)-Phe(255)) near the middle of the second transmembrane segment (TM2) that determines gaseous anesthetic sensitivity. Mutations of this residue in beta subunits and the homologous residue of alpha(4) subunits (alpha(4)-Val(254)) showed that this position also determines sensitivities of nAChRs to acetylcholine, isoflurane, pentobarbital, and hexanol. In contrast, these mutations did not affect actions of ketamine. The positively charged sulfhydryl-specific reagent methanethiosulfonate ethylammonium reacted with a cysteine introduced at alpha(4)-Val(254) or beta(2)-Val(253), and irreversibly reduced anesthetic sensitivities of nAChRs. Propyl methanethiosulfonate is an anesthetic analog that covalently binds to a TM2 site of gamma-aminobutyric acid(A) and glycine receptors and irreversibly enhances receptor function. However, propyl methanethiosulfonate reversibly inhibited cysteine-substitution mutants at alpha(4)-Val(254) or beta(2)-Val(253) of nAChRs, and did not affect anesthetic sensitivity. Thus, residues alpha(4)-Val(254) and beta(2)-Val(253) alter channel gating and determine anesthetic sensitivity of nAChRs, but are not likely to be anesthetic-binding sites.

Amino Acid Sequence↗

PubMed1997

A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect.

Bispectral analysis (BIS) of the electroencephalogram (EEG) has been shown in retrospective studies to predict whether patients will move in response to skin incision. This prospective multicenter study was designed to evaluate the real-time utility of BIS in predicting movement response to skin incision using a variety of general anesthetic techniques. Three hundred patients from seven study sites received an anesthetic regimen expected to give an approximately 50% movement response at skin incision. EEG was continuously recorded via an Aspect B-500 monitor and BIS was calculated in real time from bilateral frontocentral channels displayed on the monitor. Half of the patients were randomized to a treatment group in which anesthetic drug doses were increased to produce a lower BIS. In the control group, BIS was recorded, but no action taken on the data displayed. A determination of movement in response to skin incision was made in the 2 min succeeding incision. Retrospective pharmacodynamic modeling was performed using STANPUMP to estimate effect-site concentrations of intravenously administered anesthetics. BIS values were significantly higher in the control group (66 +/- 19) versus the BIS-guided group, in which additional anesthesia was administered to produce a lower BIS (51 +/- 19). The movement response rate was significantly higher in the control group at 43% compared with 13% in the BIS-guided group, but response rates were low at sites which used larger doses of opioids. Logistic regression analysis showed that BIS, estimated opioid effect-site concentrations, and heart rate (in that order) were the best predictors of movement at skin incision. This study demonstrates that dosing anesthetic drugs to lower BIS values achieves a lower probability of movement in response to surgical stimulation. BIS is a significant predictor of patient response to incision, but the utility of the BIS depends on the anesthetic technique being used. When drugs such as propofol or isoflurane are used as the primary anesthetic, changes in BIS correlate with the probability of response to skin incision. When opioid analgesics are used, the correlation to patient movement becomes much less significant, so that patients with apparently "light" EEG profiles may not move or otherwise respond to incision. Therefore, the adjunctive use of opioid analgesics confounds the use of BIS as a measure of anesthetic adequacy when movement response to skin incision is used as the primary end point.

Adult↗

PubMed1997

Maturation decreases ethanol minimum alveolar anesthetic concentration in mice as previously demonstrated in rats: there is no species difference.

The potency of conventional inhaled anesthetics increases with maturation: the 50% effective dose (minimum alveolar anesthetic concentration [MAC]) for conventional inhaled anesthetics in the neonatal rat or human exceeds MAC in the young adult. This increase also applies to ethanol in rats tested using MAC as the measure of anesthesia. However, the converse appears to be true for studies in mice assessed with the righting reflex; that is, adult mice are six times more resistant than neonates to the effects of ethanol. These disparate findings imply that maturation in rats and mice may produce opposing changes in the quantity or sensitivity of one or more receptors that mediate the actions of anesthetics that lead to the anesthetic state. Such a finding would be important for two reasons. First, both rodents are widely used in studies of anesthetic effects, and, thus, a species-dependent divergence in anesthetic effects has immediate experimental implications. Second, confirmation of such a species difference would supply an opportunity to test which receptors might be crucial to anesthetic mechanisms. Accordingly, we investigated whether maturation decreased ethanol potency in mice, using MAC as the measure of anesthesia. Applying standard techniques, we tested MAC for ethanol in 15 CF-1 mice aged 10 days (6-8.5 g) and in 13 mice aged 77-84 days (34-39 g). MAC decreased with maturation, and the decrease was indistinguishable from that found in our previous studies of rats.

Aging↗

PubMed1997

Structure-affinity relationships and stereospecificity of several homologous series of local anesthetics for the beta2-adrenergic receptor.

UNLABELLED: Local anesthetics inhibit binding of ligands to beta2-adrenergic receptors (beta2ARs), and, as a consequence, inhibit intracellular cAMP production. We hypothesized that among homologous local anesthetics, their avidity at inhibiting binding of tritiated dihydroalprenolol (3H-DHA) to beta2ARs would increase with increasing length of alkyl substituents and would demonstrate stereospecificity. Specific binding of 3H-DHA to human beta2ARs was assayed in the presence of six different members of the 1-alkyl-2,6-pipecoloxylidide class of local anesthetics (including mepivacaine, ropivacaine, and bupivacaine), the R(+) and S(-) bupivacaine enantiomers, lidocaine, prilocaine, etidocaine, procaine, and tetracaine. Avidity of binding to beta2ARs increased with increasing length of the alkyl chain (pKi values = 2.4, 3.6, 4.3, 4.1, 4.1, 5.9 for the methyl [mepivacaine], ethyl, S(-)propyl [ropivacaine], butyl [bupivacaine], pentyl, and octyl derivatives, respectively). We found no evidence for bupivacaine stereospecificity (pKi values = 4.3 and 4.9 for the S(-) and R(+) isomers, respectively). Other amide and ester local anesthetics also showed increasing potency with increasing length of alkyl substituents (pKi values = 3.6, 3.8, and 4.3 for lidocaine, prilocaine, and etidocaine; 4.2 and 5.6 for procaine and tetracaine, respectively). The correlation between increased inhibition of beta2AR binding and alkyl chain length resembles the correlation between local anesthetic potency at nerve block and increased alkyl chain length. The lack of clear stereospecificity is consistent with the relatively low potency these agents demonstrate at inhibition of beta2AR binding. Finally, the relatively potent inhibition of beta2ARs by etidocaine, tetracaine, and bupivacaine suggests that their propensity for cardiovascular depression after accidental intravenous overdose could result from beta2AR or beta1AR blockade and inhibition of cAMP production. IMPLICATIONS: Local anesthetics demonstrate a rank order of avidity for displacing ligands from beta2-adrenergic receptors such that larger molecules displace ligands at lower concentrations than smaller local anesthetic molecules. This relationship between molecular size and receptor avidity could explain the greater propensity for cardiovascular toxicity of relatively large local anesthetics such as bupivacaine.

Adrenergic beta-2 Receptor Antagonists↗

PubMed1997

Context-sensitive half-times and other decrement times of inhaled anesthetics.

UNLABELLED: The length of anesthetic administration influences the rate at which concentrations of anesthetics decrease after their discontinuation. This is true for both intravenous (I.V.) and inhaled anesthetics. This has been explored in detail for I.V. anesthetics using computer simulation to calculate context-sensitive half-times (the time needed for a 50% decrease in anesthetic concentration) and other decrement times (such as the times needed for 80% or 90% decreases in anesthetic concentration). However, decrement times have not been reported for inhaled anesthetics. In this report, published pharmacokinetic parameters and computer simulation were used to compare the context-sensitive half-times and the 80% and 90% decrement times of the expected central nervous system concentrations for enflurane, isoflurane, sevoflurane, and desflurane. The context-sensitive half-times for all four anesthetics are small (<5 min) and do not increase significantly with increasing duration of anesthesia. The 80% decrement times of both sevoflurane and desflurane are also small (<8 min) and do not increase significantly with duration of anesthesia. However, the 80% decrement times of isoflurane and enflurane increase significantly after approximately 60 min of anesthesia, reaching plateaus of approximately 30 and 35 min. The 90% decrement time of desflurane increased slightly from 5 min after 30 min of anesthesia to 14 min after 6 h of anesthesia. It remained significantly less than the 90% decrement times of sevoflurane, isoflurane, and enflurane, which reached values of 65 min, 86 min, and 100 min, respectively, after 6 h of anesthesia. IMPLICATIONS: The major differences in the rates at which desflurane, sevoflurane, isoflurane, and enflurane are eliminated occur in the final 20% of the elimination process.

Adipose Tissue↗

PubMed1998

Drug-specific effects of volatile anesthetics on Ca2+ sensitization in airway smooth muscle.

UNLABELLED: Halothane directly relaxes airway smooth muscle, partly by decreasing the Ca2+ sensitivity during membrane receptor stimulation. The effects of other volatile anesthetics on Ca2+ sensitivity are unclear. In the current study, we compared the ability of halothane, sevoflurane, and isoflurane to inhibit increases in Ca2+ sensitivity during muscarinic receptor stimulation. Beta-escin-permeabilized canine tracheal smooth muscle strips were used. Anesthetics were applied during contractions induced by 3 microM acetylcholine and 10 microM guanosine 5'-triphosphate at a constant cytosolic Ca2+ concentration of 0.3 microM. Effects were evaluated as a percent relaxation from initial force corrected for time. Halothane significantly decreased force at both low (0.76 minimum alveolar anesthetic concentration [MAC]) and high (1.8 MAC) concentrations in a concentration-dependent manner. Sevoflurane also decreased force, significantly so at a high concentration (1.7 MAC). Isoflurane did not significantly affect force even at a high concentration (1.7 MAC). Halothane's relaxing effect was significantly greater than that of the other two anesthetics at each corresponding MAC concentration. Among these three volatile anesthetics compared at equipotent anesthetic concentrations, halothane was the most potent in reducing Ca2+ sensitivity during muscarinic receptor stimulation in canine tracheal smooth muscle. This may contribute to halothane's greater relaxing effect compared with isoflurane at the same MAC concentrations in intact airway smooth muscle. IMPLICATIONS: In this study, we showed that three volatile anesthetics (halothane, sevoflurane, and isoflurane) compared at equipotent anesthetic concentrations differed in their ability to inhibit Ca2+ sensitivity during muscarinic receptor stimulation in airway smooth muscle. The potency order was halothane > sevoflurane > or = isoflurane.

Acetylcholine↗