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PubMed2004

Characteristics of anesthetic agents used for induction and maintenance of general anesthesia.

PURPOSE: The characteristics of ideal intravenous (i.v.) and inhaled anesthetic agents; the rationale for inducing anesthesia with i.v. anesthetics (particularly propofol); the rationale for inducing and maintaining anesthesia with inhaled anesthetics; and the advantages and disadvantages of specific inhaled anesthetics, namely, nitrous oxide, desflurane, halothane, isoflurane, and sevoflurane, are discussed. SUMMARY: Propofol has many characteristics of the ideal i.v. anesthetic, including a rapid, smooth induction of anesthesia and rapid clearance from the body. The use of an i.v. anesthetic such as propofol avoids the claustrophobia associated with the inhaled route. Inhaled anesthetics are preferred for maintenance of anesthesia because they allow a more precise control of the anesthetic state and do so at low cost. The ideal inhaled anesthetic agent has ample potency and a low solubility in blood and tissues (rapid recovery from anesthesia), resists physical and metabolic degradation, and protects and does not injure vital tissues. It also does not cause seizures, respiratory irritation, or circulatory stimulation or deplete the ozone layer. It has a low acquisition cost. Nitrous oxide potency is too small to produce anesthesia by itself. Halothane is too soluble and poses a risk of severe hepatotoxicity. Desflurane, isoflurane, and sevoflurane are preferred because they have an adequate potency, appropriate solubility, and minimal to no risk for hepatotoxicity. CONCLUSION: The utilization choice among desflurane, isoflurane, and sevoflurane is made by weighing specific advantages and disadvantages of each agent. The primary determining factors for use are anesthetic potency and control, rate of anesthesia induction, clearance from the body, and adverse effects.

Anesthesia, General↗
PubMed2001

Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels.

BACKGROUND: General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols. METHODS: The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp. RESULTS: ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. CONCLUSIONS: G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents.

Amino Acid Sequence↗
PubMed2007

Local anesthetics.

Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. This chapter, on the analgesic aspects of local anesthetics, reviews their broad actions that affect many different molecular targets and disrupt their functions in pain processing. Application of local anesthetics to peripheral nerve primarily results in the blockade of propagating action potentials, through their inhibition of voltage-gated sodium channels. Such inhibition results from drug binding at a site in the channel's inner pore, accessible from the cytoplasmic opening. Binding of drug molecules to these channels depends on their conformation, with the drugs generally having a higher affinity for the open and inactivated channel states that are induced by membrane depolarization. As a result, the effective potency of these drugs for blocking impulses increases during high-frequency repetitive firing and also under slow depolarization, such as occurs at a region of nerve injury, which is often the locus for generation of abnormal, pain-related ectopic impulses. At distal and central terminals the inhibition of voltage-gated calcium channels by local anesthetics will suppress neurogenic inflammation and the release of neurotransmitters. Actions on receptors that contribute to nociceptive transduction, such as TRPV1 and the bradykinin B2 receptor, provide an independent mode of analgesia. In the spinal cord, where local anesthetics are present during epidural or intrathecal anesthesia, inhibition of inotropic receptors, such as those for glutamate, by local anesthetics further interferes with neuronal transmission. Activation of spinal cord mitogen-activated protein (MAP) kinases, which are essential for the hyperalgesia following injury or incision and occur in both neurons and glia, is inhibited by spinal local anesthetics. Many G protein-coupled receptors are susceptible to local anesthetics, with particular sensitivity of those coupled via the Gq alpha-subunit. Local anesthetics are also infused intravenously to yield plasma concentrations far below those that block normal action potentials, yet that are frequently effective at reversing neuropathic pain. Thus, local anesthetics modify a variety of neuronal membrane channels and receptors, leading to what is probably a synergistic mixture of analgesic mechanisms to achieve effective clinical analgesia.

Anesthesia, Epidural↗
PubMed1998

Effects of halothane, enflurane, isoflurane, and sevoflurane on slowly adapting pulmonary stretch receptor activity in anesthetized dogs.

The aim of this study was to evaluate the effects of halothane, enflurane, isoflurane, and sevoflurane on slowly adapting pulmonary stretch receptor (SAR) activity in dogs. Eight beagles were anesthetized with an intravenous injection of a mixture of urethane and alpha-chloralose as a basal anesthesia, then vagotomized, artificially ventilated, and chest opened. Single afferent activities from SARs were recorded from the peripheral nerve cut end of the left vagus. Changes in SAR activities with inhalation of halothane, enflurane, isoflurane, and sevoflurane at 1, 1.5, and 2 times the minimal alveolar anesthetic concentration (MAC) were measured, and differences in the discharges within and among four anesthetics were evaluated. As a result, two different types of SARs, low threshold SARs and high threshold SARs, were detected in this study. In all anesthetics, expiratory discharges of low threshold SARs decreased significantly in a dose-dependent manner, whereas inspiratory discharges did not change significantly at any anesthetic level. Discharges of high threshold SARs tended to decrease with increasing anesthetic level; however, no statistical significance was observed at any anesthetic level. Only one exception to these changes was observed at 1 MAC of halothane where no significant decrease in the expiratory discharge of low threshold SARs or significant increase in the discharge of high threshold SARs was induced against a control value. In conclusion, recent inhalation anesthetics, except for halothane at the light anesthetic level, tended to decrease SAR activities depending on the anesthetic level, suggesting attenuation of the Hering-Breuer inflation reflex.

Action Potentials↗
PubMed1985

Multiequilibrium binding of a spin-labeled local anesthetic in phosphatidylcholine bilayers.

The equilibria among spin-labeled amine local anesthetic species in dioleoylphosphatidylcholine liposomes at an anesthetic: lipid mole ratio of 1:100 are investigated. Electron spin resonance (ESR) spectra demonstrate that anesthetic mobility within the bilayer is charge-dependent, with the uncharged species the more mobile. Partition coefficient measurements confirm ESR evidence that changes in anesthetic mobility represent anesthetic-phospholipid interaction and not changes in bilayer fluidity. Spin-exchange attenuation experiments show that anesthetics within the bilayer are accessible to the aqueous medium. Dependence of tertiary-amine anesthetic pK on dielectric constant has been used to estimate the interfacial pK. We propose a model of equilibria among species of the tertiary amine anesthetic in the aqueous medium and those intercalated in the bilayer, including a species electrostatically bound to the lipid phosphate. Using experimentally determined equilibrium constants, the model provides the binding constant between the electrostatically bound and unbound cationic anesthetics within the bilayer. The model stimulates the pH dependence of the mobile fraction of total anesthetic population determined by subtraction techniques on experimental ESR spectra.

Anesthetics, Local↗
PubMed2000

Effect of local anesthetics on the bilayer membrane of dipalmitoylphosphatidylcholine: interdigitation of lipid bilayer and vesicle-micelle transition.

The phase transitions of dipalmitoylphosphatidylcholine (DPPC) bilayer membrane were observed by means of differential scanning calorimetry (DSC) as a function of the concentration of local anesthetics, dibucaine (DC x HCl), tetracaine (TC x HCl), lidocaine (LC x HCl) and procaine hydrochlorides (PC x HCl). LC x HCl and PC x HCl depressed monotonously the temperatures of the main- and pre-transition of DPPC bilayer membrane. The enthalpy changes of both transitions decreased slightly with an increase in anesthetic concentration up to 160 mmol kg(-1). In contrast, the addition of TC x HCl or DC x HCl, having the ability to form a micelle by itself, induced the complex phase behavior of DPPC bilayer membrane including the vesicle-to-micelle transition. The depression of both temperatures of the main- and pre-transition, which is accompanied with a decrease in enthalpy, was observed by the addition of TC x HCl up to 21 mmol kg(-1) or DC x HCl up to 11 mmol kg(-1). The pretransition disappeared when these concentrations of anesthetic were added, and the interdigitated gel phase appeared above these concentrations. The appearance of the interdigitated gel phase, instead of the ripple gel phase, brings about the stabilization of the gel phase by 1.8-2.4 kcal mol(-1). In the concentration range of 70-120 mmol kg(-1) TC x HCl (or 40-60 mmol kg(-1) DC x HCl), the enthalpy of the main transition exhibited a drastic decrease, resulting in the virtual disappearance of the main transition. This process includes the decrease in vesicle size with increasing anesthetic concentration, resulting in the mixed micelle of DPPC and anesthetics. Therefore, in this range of anesthetic concentration, the DPPC vesicle solubilized an anesthetic which coexists with the DPPC-anesthetic mixed micelle. Above the concentration of 120 mmol kg(-1) TC x HCl (or 60 mmol kg(-1) DC x HCl), there exists the DPPC-anesthetic mixed micelle. Two types of new transitions concerned with the mixed micelle of DPPC and micelle-forming anesthetics were observed by DSC.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

The nitric oxide-cyclic 3',5'-guanosine monophosphate signal transduction pathway in the mechanism of action of general anesthetics.

(1) The nitric oxide-cyclic 3',5'-guanosine monophosphate (NO-cGMP) system is a major signaling transduction pathway implicated in a wide range of physiologic and pathophysiologic functions of the cardiovascular, respiratory, gastrointestinal, nervous or immune systems. (2) Evidence is provided that, at anesthetic concentrations, volatile and intravenous anesthetics interact with the NO-cGMP system. They have been shown to produce a decrease in cGMP in neuronal and vascular tissue. (3) Inhibition of NO synthesis produces a dose-dependent reversible decrease in the minimum anesthetic requirement and in the ED50 for the loss of righting reflex induced by general anesthetics. Volatile anesthetics also inhibit the NO-mediated relaxation in many vascular beds. (4) The selective alpha-2 adrenergic agonist, dexmedetomidine, which has potent sedative/hypnotic, anesthetic sparing and analgesic properties, produces a dose-dependent, reversible decrease in cGMP in mouse cerebellum at concentrations that decrease the anesthetic requirement of volatile anesthetics or induce a loss of righting reflex, an effect eliminated when NO synthase is inhibited. The site and mechanism by which the anesthetics interact with the NO-cGMP system is not yet clear and may vary with the anesthetic.

Anesthetics, General↗
PubMed1997

Effects of gas flow management on postintubation end-tidal anesthetic concentration and operating room pollution.

STUDY OBJECTIVE: To study how different anesthetic practices during the transition from anesthetic delivery by mask to endotracheal intubation affect end-tidal postintubation anesthetic concentration and operating room (OR) pollution. DESIGN: Prospective study. SETTING: Anesthesia research laboratory. MEASUREMENTS AND MAIN RESULTS: We studied four gas flow management practices: practice vaporizer off, only the anesthetic vaporizer was turned off; all off, oxygen (O2), nitrous oxide (N2O), and the vaporizer were turned off; gas off: O2 and N2O were turned off; and all on: neither the gas flows nor the vaporizer were turned off. A model of inhalational anesthetic induction was simulated by using an adult circle system attached to a reservoir bag ("artificial lung"). By using a fixed gas flow, we achieved an end-tidal N2O (ETN2O) concentration of 70% and end-tidal halothane (ETHal) concentration of 3%, then stopped mechanical ventilation and performed the four practices for a 30-second "intubation" period. During this time, the reservoir bag was disconnected from the circuit, and the gas volume exiting the circuit (pollution volume) was measured. After this 30-second disconnect period, the bag was reconnected to the anesthetic circuit, and the original ventilation, gas flows, and vaporizer setting were resumed. The anesthetic concentrations were measured at 10, 20, and 30 seconds after reconnection. For the vaporizer off practice, ETHal was low and did not return to equilibrium within 30 seconds (p < 0.05); ETN2O clinically was unaltered. In the all off practice, anesthetic concentrations were below equilibrium at 10, 20, and 30 seconds (p < 0.05). For the gas off practice, ETHal was slightly below equilibrium at all times; ETN2O was below equilibrium at 10, 20, and 30 seconds (p < 0.05). In the all on practice, end-tidal anesthetic concentrations were unchanged when compared with equilibrium (p > 0.05). Pollution volumes in the vaporizer off and all on practices were ten-fold higher than in the all off and gas off practices (p < 0.05). CONCLUSION: In a mechanical model of anesthetic induction, turning the gas flows off before "intubation" and leaving the vaporizer on (the gas off practice) maintained "postintubation" end-tidal drug concentrations close to "preintubation" equilibrium and minimized OR pollution.

Air Pollution, Indoor↗
PubMed1987

Limited nerve impulse blockade by "leashed" local anesthetics.

To measure the depth of the local anesthetic binding site within the neuronal membrane, biotin-containing polyethylene glycols having zero, three, and six ethylene glycol subunits were added to the p-amino termini of tetracaine and procaine, thereby interposing a pharmacologically inert "spacer" molecule between the local anesthetic and the biotin moiety. These biotinyl-local anesthetic derivatives produced "tonic" inhibition of the compound action potential of split, desheathed frog sciatic nerves in a concentration-dependent, reversible manner. However, no inhibition of the action potential occurred when sufficient avidin, a 66,000-MW protein that binds four biotins, was present to bind and anchor the biotin-containing end of each derivative outside the plasma membrane. Increasing the "leashed" anesthetic derivative's concentration to 4 times that which reduced impulse height by 50% in the absence of avidin still produced no detectable block when equimolar avidin was present. Apparently, the "spacer" in the derivative compound was too short to permit the avidin-complexed anesthetic to reach its site of action on the sodium channel. In a similar fashion, the local anesthetic derivatives produced "use-dependent" block when drug-treated nerves were stimulated at 40 Hz in the absence of equimolar avidin, but failed to produce "use-dependent" block when equimolar avidin was present. In common with others, we assume that tertiary amine local anesthetics may reach their binding site via hydrophobic (transmembrane) pathways without necessarily entering the cytoplasm. Thus, since our longest local anesthetic derivative, that containing six ethylene glycol subunits, placed the local anesthetic group a maximum of 15-18 A from the surface of the avidin moiety, we conclude that the local anesthetic binding site for block of sodium channels of amphibian nerve must be greater than or equal to 15 A from the outer surface of the plasma membrane.

Action Potentials↗
PubMedDate not supplied

Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients.

BACKGROUND AND OBJECTIVES: Over the past 10 years, several studies have suggested that the addition of certain opiates to the local anesthetic used for brachial block may provide effective, long-lasting postoperative analgesia. One of these studies indicated that the agonist-antagonist, buprenorphine, added to bupivacaine provided a longer period of postoperative analgesia than the traditional opiates, but in this study, it is impossible to determine the relative contributions of the local anesthetic and the opiate to the postoperative analgesia because of the extremely long duration of the anesthesia provided by the local anesthetic, bupivacaine. By repeating the study using a local anesthetic of a shorter duration, the present study delineates more clearly the contribution of the buprenorphine to postoperative analgesia when added to a shorter-acting local anesthetic. METHODS: Forty, healthy, consenting adult patients scheduled for upper extremity surgery were enrolled in the study. Premedication was provided by intravenous midazolam 2 mg/70 kg and anesthesia by a subclavian perivascular brachial plexus block. The patients were assigned randomly to 1 of 2 equal groups based on the agents used for the blocks. The patients in group I received 40 mL of a local anesthetic alone, while those in group II received the same local anesthetic plus buprenorphine 0.3 mg. The study was kept double-blind by having 1 anesthesiologist prepare the solutions, a second anesthesiologist perform the blocks, and a third anesthesiologist monitor the anesthesia and analgesia thereafter, up to and including the time of the first request for an analgesic medication. The data were reported as means (+/- SEM), and differences between groups were determined using repeated measures of analysis of variance (ANOVA) and chi(2), followed by the Fisher exact test for post hoc comparison. A P value of less than.05 was considered to be statistically significant. RESULTS: The mean duration of postoperative pain relief following the injection of the local anesthetic alone was 5.3 (+/- 0.15) hours as compared with 17.4 (+/- 1.26) hours when buprenorphine was added, a difference that was statistically (and clinically) significant (P <.0001). CONCLUSIONS: The addition of buprenorphine to the local anesthetic used for brachial plexus block in the present study provided a 3-fold increase in the duration of postoperative analgesia, with complete analgesia persisting 30 hours beyond the duration provided by the local anesthetic alone in 75% of the patients. This practice can be of particular benefit to patients undergoing ambulatory upper extremity surgery by providing prolonged analgesia after discharge from the hospital.

Adolescent↗
PubMed2002

Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: the implication of molecular mechanisms of general anesthesia.

Interactions of volatile anesthetics with the central nervous system are characterized by low yet specific binding affinities. Although neurotransmitter-gated ion channels are considered the primary anesthetic targets, the mechanism of action at the molecular level remains elusive. We consider here the theoretical implications of channel dynamics on anesthetic action in a simplified membrane-channel system. Large-scale 2.2-ns all-atom molecular dynamics simulations were performed to study the effects of halothane, a clinical anesthetic, on a gramicidin A (gA) channel in a fully hydrated dimyristoyl phosphatidylcholine membrane. In agreement with experimental results, anesthetics preferentially target the anchoring residues at the channel-lipid-water interface. Although the anesthetic effect on channel structure is minimal, the presence of halothane profoundly affects channel dynamics. For 2.2-ns simulation, the rms fluctuation of gA backbone in the lipid core increases from approximately equal 1 A in the absence of anesthetics to approximately equal 1.5 A in the presence of halothane. Autocorrelation analysis reveals that halothane (i) has no effect on the subpicosecond librational motion, (ii) prolongs the backbone autocorrelation time in the 10- to 100-ps time scale, and (iii) significantly decreases the asymptotic values of generalized order parameter and correlation time of nanosecond motions for the inner but not the outer residues. The simulation results discount the viewpoint of a structure-function paradigm that overrates the importance of structural fitting between general anesthetics and yet-unidentified hydrophobic protein pockets. Instead, the results underscore the global, as opposed to local, effects of anesthetics on protein dynamics as the underlying mechanisms for the action of general anesthetics and possibly of other low-affinity drugs.

Anesthesia, General↗
PubMed1983

Local anesthetic-membrane interaction: a multiequilibrium model.

We report the detection of electrostatic interactions between local anesthetics and membrane phospholipids and proteins. A spin-labeled local anesthetic was used to study how membrane-bound tertiary amine anesthetics interact with major molecular components in the membrane. The nitroxyl reporter group of this spin label is located at the polar end of the amphiphilic local anesthetic; it is therefore a uniquely suitable probe for detecting immobilization of the anesthetic due to binding interactions at the polar regions of the bilayer. The binding properties of this spin-labeled anesthetic to human erythrocyte membranes and to vesicles made from human erythrocyte lipids were studied. Lipid vesicle-bound spin labels give rise to a composite electron spin resonance spectrum from which two subcomponent spectra were resolved. Both components are membrane-bound; the first component has a narrower linewidth, indicating a greater mobility of the nitroxyl moiety of the anesthetic probe. The second component has a broader linewidth, indicating a population of constrained spin labels. We infer from the experimental results that electrostatic binding between cationic anesthetics and anionic phosphate of phospholipids produced the constrained component. In similar studies using erythrocyte ghost membranes, both a mobile (nonelectrostatic) component and a constrained (electrostatic) component were resolved from the composite spectrum. However, the constrained component in this case is much broader than the corresponding constrained component from the vesicles. We interpret this broad component in the erythrocyte membrane as an electrostatic interaction of cationic anesthetic probes with phospholipids and with membrane proteins. We conclude that membrane-bound tertiary amine anesthetics in cationic form do interact selectively with phospholipids and proteins.

Anesthetics, Local↗
PubMed2002

Volatile anesthetics affect nutrient availability in yeast.

Volatile anesthetics affect all cells and tissues tested, but their mechanisms and sites of action remain unknown. To gain insight into the cellular activities of anesthetics, we have isolated genes that, when overexpressed, render Saccharomyces cerevisiae resistant to the volatile anesthetic isoflurane. One of these genes, WAK3/TAT1, encodes a permease that transports amino acids including leucine and tryptophan, for which our wild-type strain is auxotrophic. This suggests that availability of amino acids may play a key role in anesthetic response. Multiple lines of evidence support this proposal: (i) Deletion or overexpression of permeases that transport leucine and/or tryptophan alters anesthetic response; (ii) prototrophic strains are anesthetic resistant; (iii) altered concentrations of leucine and tryptophan in the medium affect anesthetic response; and (iv) uptake of leucine and tryptophan is inhibited during anesthetic exposure. Not all amino acids are critical for this response since we find that overexpression of the lysine permease does not affect anesthetic sensitivity. These findings are consistent with models in which anesthetics have a physiologically important effect on availability of specific amino acids by altering function of their permeases. In addition, we show that there is a relationship between nutrient availability and ubiquitin metabolism in this response.

Amino Acid Transport Systems↗
PubMed1998

The effect of anesthetic duration on kinetic and recovery characteristics of desflurane versus sevoflurane, and on the kinetic characteristics of compound A, in volunteers.

UNLABELLED: This study documents the differences in kinetics of 2 h (n = 7) and 4 h (n = 9) of 1.25 minimum alveolar anesthetic concentration (MAC) of desflurane (9.0%) versus (on a separate occasion) sevoflurane (3.0%), both administered in a fresh gas inflow of 2 L/min. These data are extensions of our previous 8-h (n = 7) studies of these anesthetics. By 10 min of anesthetic administration, average inspired (F(I)) and end-tidal concentration (F(A)) (F(I)/F(A); the inverse of the more commonly used F(A)/F(I)) decreased to less than 1.15 for both anesthetics, with the difference from 1.0 nearly twice as great for sevoflurane as for desflurane. During all sevoflurane administrations, F(A)/F(I) for Compound A [CH2F-O-C(=CF2) (CF3); a vinyl ether resulting from the degradation of sevoflurane by Baralyme] equaled approximately 0.8, and the average inspired concentration equaled approximately 40 ppm. Compound A is of interest because at approximately 150 ppm-h, it can induce biochemical and histological evidence of glomerular and tubular injury in rats and humans. During elimination, F(A)/F(A0) for Compound A (F(A0) is the last end-tidal concentration during anesthetic administration) decreased abruptly to 0 after 2 h and 4 h of anesthesia and to approximately 0.1 (F(A) approximately 3 ppm) after 8 h of anesthesia. In contrast, F(A)/F(A0) for desflurane and sevoflurane decreased in a conventional, multiexponential manner, the decrease being increasingly delayed with increasing duration of anesthetic administration. F(A)/F(A0) for sevoflurane exceeded that for desflurane for any given duration of anesthesia, and objective and subjective measures indicated a faster recovery with desflurane. Times (mean +/- SD) to initial response to command (2 h 10.9 +/- 1.2 vs 17.8 +/- 5.1 min, 4 h 11.3 +/- 2.1 vs 20.8 +/- 4.8 min, 8 h 14 +/- 4 vs 28 +/- 8 min) and orientation (2 h 12.7 +/- 1.6 vs 21.2 +/- 4.6 min, 4 h 14.8 +/- 3.1 vs 25.3 +/- 6.5 min, 8 h 19 +/- 4 vs 33 +/- 9 min) were shorter with desflurane. Recovery as defined by the digit symbol substitution test, P-deletion test, and Trieger test results was more rapid with desflurane. The incidence of vomiting was greater with sevoflurane after 8 h of anesthesia but not after shorter durations. We conclude that for each anesthetic duration, F(I) more closely approximates F(A) with desflurane during anesthetic administration, F(A)/F(A0) decreases more rapidly after anesthesia with desflurane, and objective measures indicate more rapid recovery with desflurane. Finally, it seems that after 2-h and 4-h administrations, all Compound A taken up is bound within the body. IMPLICATIONS: Regardless of the duration of anesthesia, elimination is faster and recovery is quicker for the inhaled anesthetic desflurane than for the inhaled anesthetic sevoflurane. The toxic degradation product of sevoflurane, Compound A, seems to bind irreversibly to proteins in the body.

Adult↗
PubMed1999

Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis.

UNLABELLED: The Meyer-Overton hypothesis predicts that the potency of conventional inhaled anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) x the olive oil/gas partition coefficient equals a constant of approximately 1.82 +/- 0.56 atm (mean +/- SD), whereas MAC x the octanol/gas partition coefficient equals a constant of approximately 2.55 +/- 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC x the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 +/- 0.072 atm) is one-tenth that found for conventional anesthetics, whereas the product for MAC x the octanol/gas partition coefficient (1.72 +/- 1.19) is similar to that for conventional anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC x olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 +/- 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC x the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. IMPLICATIONS: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity--i.e., a greater polarity.

Alcohols↗
PubMed1999

Hypothesis: volatile anesthetics produce immobility by acting on two sites approximately five carbon atoms apart.

UNLABELLED: All series of volatile and gaseous compounds contain members that can produce anesthesia, as defined by the minimum alveolar anesthetic concentration (MAC) required to produce immobility in response to a noxious stimulus. For unhalogenated n-alkanes, cycloalkanes, aromatic compounds, and n-alkanols, potency (1 MAC) increases by two-to threefold with each carbon addition in the series (e.g., ethanol is twice as potent as methanol). Total fluorination (perfluorination) of n-alkanes essentially eliminates anesthetic potency: only CF4 is anesthetic (MAC = 66.5 atm), which indicates that fluorine atoms do not directly influence sites of anesthetic action. Fluorine may enhance the anesthetic action of other moieties, such as the hydrogen atom in CHF3 (MAC = 1.60 atm), but, consistent with the notion that the fluorine atoms do not directly influence sites of anesthetic action, adding -(CF2)n moieties does not further increase potency (e.g., CHF2-CF3 MAC = 1.51 atm). Similarly, adding -(CF2)n moieties to perfluorinated alkanols (CH2OH-[CF2]nF) does not increase potency. However, adding a second terminal hydrogen atom (e.g., CHF2-CHF2 or CH2OH-CHF2) produces series in which the addition of each -CF2- "spacer" in the middle of the molecule increases potency two- to threefold, as in each unhalogenated series. This parallel stops at four or five carbon atom chain lengths. Further increases in chain length (i.e., to CHF2[CF2]4CHF2 or CHF2[CF2]5CH2OH) decrease or abolish potency (i.e., a discontinuity arises). This leads to our hypothesis that the anesthetic moieties (-CHF2 and -CH2OH) interact with two distinct, spatially separate, sites. Both sites must be influenced concurrently to produce a maximal anesthetic (immobility) effect. We propose that the maximal potency (i.e., for CHF2[CF2]2CHF2 and CHF2[CF2]3CH2OH) results when the spacing between the anesthetic moieties most closely matches the distance between the two sites of action. This reasoning suggests that a distance equivalent to a four or five carbon atom chain, approximately 5 A, separates the two sites. IMPLICATIONS: Volatile anesthetics may produce immobility by a concurrent action on two sites five carbon atom lengths apart.

Anesthetics, Inhalation↗
PubMed1985

Effect of anesthetics and a convulsant on normal and mutant Caenorhabditis elegans.

The authors have developed a method for studying the action of volatile anesthetics in Caenorhabditis elegans (C.e.), a free living nematode. C.e. appears to be a useful model for the study of the influence of genetics on susceptibility to anesthetics. This worm has a small, completely defined nervous system, easily manipulated genetics, and a large number of nervous system mutants. Under normal conditions C.e. moves almost constantly. When exposed to anesthetics there is an initial phase of increased locomotion, followed by uncoordinated motion that progresses to immobility. Motion returns quickly when the nematodes are removed from the anesthetic. The authors called loss of locomotion "anesthesia." The ED50S of various anesthetics with C.e. are as follows: methoxyflurane 0.45%, chloroform 1.25%, halothane 2.7%, enflurane 4.2%, isoflurane 5.6%, fluroxene 9.9%. The authors also studied the action of a convulsant, flurothyl, on C.e. Flurothyl has anesthetizing properties in these animals with an ED50 of 8.1%. No convulsant activity was noted. However, mixtures of halothane and flurothyl were antagonistic in their effects, while halothane and enflurane were additive. Furthermore, the authors isolated a mutant strain (HS1) of C.e. that shows altered responses to several anesthetics and a convulsant. HS1 is uncoordinated when not exposed to anesthetics. Like the normal strain (N2) HS1 loses mobility when exposed to anesthetics. The ED50S for various anesthetics in HS1 were as follows: methoxyflurane 0.04%, chloroform 0.52%, halothane 0.85%, isoflurane 4.9%, enflurane 6.0%, fluroxene 10.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMed1993

Inhibition of plasma membrane Ca(2+)-ATPase activity by volatile anesthetics.

BACKGROUND: The precise sites and mechanisms of action of volatile anesthetics remain unknown. Recently, several integral membrane proteins have been suggested as potential targets to which anesthetics can bind at hydrophobic regions. Impairment of cell Ca2+ homeostasis has been postulated as one of the possible mechanisms of anesthetic action. To test these hypotheses, the authors selected the human erythrocyte Ca(2+)-ATPase as a model membrane protein. This enzyme is an integral membrane protein that is instrumental in maintaining Ca2+ homeostasis in the cell in which it is the sole Ca(2+)-transporting system. Thus, any functional alteration of the Ca(2+)-ATPase by anesthetics may lead to serious perturbations in Ca(2+)-regulated processes in the cell. METHODS: The Ca(2+)-ATPase activity was measured as a function of increased concentration of four volatile anesthetics: halothane, isoflurane, enflurane, and desflurane. RESULTS: All four anesthetics significantly inhibited the Ca(2+)-ATPase activity in a dose-dependent manner. The half-maximal inhibition occurred at anesthetic concentrations from 0.3 to 0.7 vol% at 37 degrees C, which, except for desflurane, is a clinically relevant concentration range. The greater the clinical potency of the volatile anesthetics studied, the less was the concentration required to inhibit the Ca(2+)-ATPase activity. The inhibition was less at 25 degrees C than at 37 degrees C, which is consistent with direct interactions of the nonpolar interfaces of the enzyme with the nonpolar of the portions of the anesthetics. CONCLUSIONS: The authors' findings indicate that the Ca(2+)-ATPase is a suitable model for investigating the mechanism of action of volatile anesthetics on the integral membrane protein, and that this inhibition may be specific.

Administration, Inhalation↗