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.     

Partition coefficients for sevoflurane in human blood, saline, and olive oil

The purpose of this study was to determine partition coefficients for a new, rapid-acting inhaled anesthetic, sevoflurane. Blood samples were taken from 19 ASA physical status I-III patients ranging in age from 21 to 77 yr who were scheduled for elective surgery. At 37 degrees C, we found a blood/gas partition coefficient of 0.686 +/- 0.047 (mean +/- SD), a saline/gas partition coefficient of 0.370 +/- 0.016; and an oil/gas partition coefficient of 47.2 +/- 2.7. These values are consistent with the clinical observation that sevoflurane is a potent inhaled anesthetic that produces a rapid induction of and recovery from anesthesia.     

The anesthetic potencies of alkanethiols for rats: relevance to theories of narcosis

Meyer and Overton suggested that anesthetic potency correlates inversely with lipophilicity. Thus, MAC times the olive oil/gas partition coefficient equals an approximately constant value of 1.82 +/- 0.56 atm (mean +/- SD). MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC times the olive oil/gas partition coefficient also equals an approximately constant value for normal alkanols from methanol through octanol, the value (0.156 +/- 0.072 atm) is 1/10th that found for conventional anesthetics. We hypothesized that substitution of sulfur for the oxygen in n-alkanols would decrease their saline/gas partition coefficients (i.e., decrease polarity) while sustaining lipid/gas partition coefficients. Further, we hypothesized that these changes would produce products of MAC times olive oil partition coefficients that approximate those of conventional anesthetics. To test these predictions, we measured MAC in rats, and saline and olive oil solubilities for the series H(CH(2))(n)SH, comparing the results with the series H(CH(2))(n)OH for compounds having three to six carbon atoms. As hypothesized, the alkanethiols had similar oil/gas partition coefficients, 1000-fold smaller saline gas partition coefficients, and MAC values 30 times greater than for comparable alkanols. Such findings are consistent with the notion that the greater potency of many alkanols (greater than would be predicted from conventional inhaled anesthetics and the Meyer-Overton hypothesis) results from their greater polarity. Implications: The in vivo anesthetic potency of alkanols and alkanethiols correlates with their lipophilicity and hydrophilicity.     

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

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.     

Partition coefficients of I-653 in human blood, saline, and olive oil

The purpose of this study was to determine partition coefficients for a new, inhaled anesthetic, I-653. Blood samples were taken from 11 patients scheduled for elective surgery who were ASA physical status I-III and ranged in age from 25 to 76 yr. At 37 degrees C, we found a blood/gas partition coefficient of 0.424 +/- 0.024 (mean +/- SD); a saline/gas partition coefficient of 0.225 +/- 0.002; and an oil/gas partition coefficient of 18.7 +/- 1.1. These values indicate that I-653 will have a minimum alveolar concentration (MAC) required for anesthesia that is four to five times that of isoflurane and that I-653 will produce a rapid induction of and recovery from anesthesia.     

The general anesthetic potency of propofol and its dependence on hydrostatic pressure.

Although plasma concentrations of propofol during anesthesia are well known, the free concentration remains unknown because of uncertainties regarding plasma protein binding, interaction with other protein-bound substances, the level of binding to its lipid carrier, and the use of adjuvants. At elevated surrounding pressure, all general anesthetics require higher concentrations to reach adequate levels of anesthesia. To determine the anesthetic potency of propofol at equilibrium conditions and to study the effects of pressure on propofol-induced anesthesia, Rana pipiens tadpoles were exposed to different concentrations of pure, not emulsified, propofol in aqueous solution. Anesthesia was defined as loss of the righting reflex. Ten animals per concentration were used, and each experiment was conducted twice. Pressure experiments were performed with nonanesthetized tadpoles and urethane-anesthetized tadpoles as control groups. Propofol concentrations were measured spectrophotometrically. At 1 atmosphere absolute (atm abs), a semilogarithmic sigmoidal concentration-response curve was obtained with a half-maximal effect of propofol at 2.2 +/- 0.22 microM (EC50; mean +/- SE). Increased pressure shifted the concentration-response curve to the right. The EC50 increased linearly with increasing pressure up to 121 atm abs (EC50 at 121 atm abs = 4.1 +/- 0.41 microM). For pressure greater than 121 atm abs, an increased excitability of the tadpoles made it difficult to distinguish the righting reflex from involuntary movements. The saturated solubility of propofol in aqueous solution was found to be 1.0 +/- 0.02 mM (mean +/- SD), and the octanol/water partition coefficient was 4,300 +/- 280. Propofol adhered to the correlation between anesthetic potency and octanol/water partition coefficient exhibited by other general anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

The minimum alveolar anesthetic concentration of 2-, 3-, and 4-alcohols and ketones in rats: relevance to anesthetic mechanisms

The Meyer-Overton hypothesis predicts that anesthetic potency correlates inversely with lipophilicity; e.g., MAC times the olive oil/gas partition coefficient equals a constant of approximately 1.82 +/- 0.56 atm (mean +/- sd) for conventional inhaled anesthetics. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. In contrast to conventional inhaled anesthetics, MAC times the olive oil/gas partition coefficient for normal alcohols from methanol through octanol equals a constant one tenth as large as that for conventional inhaled anesthetics. The alcohol (C-OH) group causes a great affinity of alcohols to water, and the C-OH may tether the alcohol at the hydrophobic-hydrophilic interface where anesthetics are thought to act. We hypothesized that the position of the C-OH group determined potency, perhaps by governing the maximum extent to which the acyl portion of the molecule might extend into a hydrophobic phase. Using the same reasoning, we added studies of ketones with similar numbers of carbon atoms between the C=O group and the terminal methyl group. The results for both alcohols and ketones showed the predicted correlation, but the correlation was no better than that with carbon chain length regardless of the placement of the oxygen. The oil/gas partition coefficient predicted potency as well as, or better than, either chain length or oxygen placement. Hydrophilicity, as indicated by the saline/gas partition coefficient, also seemed to influence potency.     

Solubility of desflurane (I-653), sevoflurane, isoflurane, and halothane in human blood

The blood/gas partition coefficients for the new volatile anesthetic agent desflurane (I-653), sevoflurane, isoflurane, and halothane were determined, simultaneously, in 8 human volunteers to compare the solubilities of these agents in blood. The blood/gas partition coefficient for desflurane [0.49 +/- 0.03 (mean +/- SD)] was smallest, followed by sevoflurane (0.62 +/- 0.04), isoflurane (1.27 +/- 0.06), and halothane (2.46 +/- 0.09). Differences among the anesthetic agents were significant (P less than 0.001). The results of this study confirm that among these agents the solubility of desflurane in human blood is the smallest. The results suggest that the washin and washout of desflurane will be more rapid than that of sevoflurane, isoflurane, and halothane, and the washin and washout of sevoflurane will be more rapid than that of isoflurane and halothane.     

Hypothermia decreases ethanol MAC in rats

Despite the known capacity of hypothermia to increase anesthetic potency (decrease the partial pressure required to produce anesthesia), many in vitro studies examine the effects of ethanol and other anesthetics in oocytes or isolated neurons at room temperature. We tested whether, as predicted for potent inhaled anesthetics, a proportionate increase in solubility with hypothermia matched a decrease in ethanol minimum alveolar concentration (MAC), and thereby made the use of a single anesthetic concentration appropriate regardless of temperature. We determined ethanol MAC in normothermic (37.3°C) and hypothermic (28.5°C) rats, and, at the two temperatures, also determined ethanol solubilities in olive oil and saline. Ethanol MAC decreased, while olive oil/gas and saline/gas partition coefficients increased. However, the increase in the saline/gas partition coefficient did not match the decrease in MAC, and thus the aqueous-phase partial pressure producing absence of movement in 50% of rats (EC₅₀) values for ethanol decreased by 17%. Although this decrease is not large, it may be important for comparative estimates of the in vitro effects of ethanol at different temperatures.     

Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues

Tissue/blood partition coefficients of anesthetics are important indicators of the rate of tissue wash-in and wash-out, and wash-in and wash-out are determinants of the rates of induction of and recovery from anesthesia. In the present study of human tissues, we found that the tissue/blood partition coefficients (for brain, heart, liver, kidney, muscle, and fat) for the new anesthetic I-653 were smaller than those for isoflurane, sevoflurane, and halothane (anesthetics listed in order of increasing tissue/blood partition coefficients). For example, the respective brain/blood partition coefficients were 1.29 +/- 0.05 (mean +/- SD); 1.57 +/- 0.10; 1.70 +/- 0.09; and 1.94 +/- 0.17. This indicates that induction of and recovery from anesthesia with I-653 should be more rapid than with the other agents. The finding of a lower tissue/blood partition coefficient for I-653 parallels the previous finding of a lower blood/gas partition coefficient.     

Polyhalogenated methyl ethyl ethers: solubilities and anesthetic properties.

The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82+/-0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. IMPLICATIONS: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.     

Effect of age on the solubility of volatile anesthetics in human tissues

To determine the effect of age on the solubility of volatile anesthetics in human tissues, the authors measured the solubilities of isoflurane, enflurane, halothane, and methoxyflurane in vitro at 37 degrees C in 35 postmortem human tissue specimens. Specimens were taken from neonates, and young (20-50 yr), middle-aged (50-70 yr), and elderly adults (greater than 70 yr). Brain/gas, heart/gas, and liver/gas partition coefficients for all four anesthetics increased significantly (P less than 0.05) between birth and adulthood, although brain/gas partition coefficients in young adults tended to be higher than those in middle-aged and elderly adults. Heart/gas and liver/gas partition coefficients tended to increase with aging. Muscle/gas partition coefficients for the four anesthetics increased linearly with age. Fat/gas partition coefficients did not change significantly with age. Tissue/blood solubilities for the four anesthetics were of the same order of magnitude for a given tissue and age group. Tissue/blood solubilities for enflurane were 30% lower than those for isoflurane in the same tissue and age group. In summary: the solubility of volatile anesthetics in human tissues increases with age; the lower solubility of anesthetics in neonates partially explains the more rapid increase of alveolar and tissue anesthetic partial pressures in neonates; despite the higher blood solubility of enflurane, its lower tissue solubility may explain a rate of recovery comparable with that of isoflurane.     

Increase in anesthetic uptake, excretion, and blood solubility in man after eating

Blood-gas partition coefficients of N2O, enflurane, halothane, methoxyflurane, and isoflurane were measured on blood samples from 12 healthy male volunteers before and after eating. The solubility values determined while volunteers fasted substantiate previously reported blood-gas partition coefficients for enflurane, isoflurane, and halothane. Solubility values for methoxyflurane and N2O were slightly greater and smaller, respectively, than accepted values. The uptake and excretion of N2O, enflurane, halothane, and methoxyflurane also were measured in 6 of these subjects in the fasted and postprandial states. Subjects breathed a constant, inspired mixture containing trace concentrations of all 4 gases. Eating increased blood solubility by 17 to 24 percent for all agents except N2O. Accordingly, the rates of rise of the end-tidal enflurane, halothane, and methoxyflurane concentrations were 7 to 8 percent below control, and the rates of anesthetic uptake increased 20 to 23 percent. Simulation studies showed that the increased ventilation induced by eating opposed and, therfore, minimized the impact of increased blood solubility and cardiac output on the rate of end-tidal anesthetic rise. Changes in blood solubility did not correlate with levels of plasma triglycerides and cholesterol.     

Crystalloid hemodilution, hypothermia, and halothane blood solubility during cardiopulmonary bypass

Sequential determinations of halothane blood solubility were determined in 8 patients undergoing cardiac surgical procedures with cardiopulmonary bypass (CPB), hypothermia, and crystalloid hemodilution. The mean temperature-corrected blood/gas partition coefficient (B/G) at the end of surgery (2.4) was lower than preceding induction (2.7). The greatest mean B/G (2.9) occurred after induction of anesthesia. The halothane B/G did not increase significantly at the inception of CPB but decreased from a mean 2.7 to 1.6 as the patients were rewarmed. The maximum range of B/G for a single patient was 1.4 to 3.1. For halothane, the increased blood solubility due to hypothermia was initially antagonized by the crystalloid hemodilution. This antagonism would also be anticipated for methoxyflurane, enflurane, and isoflurane. For N2O and diethyl ether, the increased blood solubility due to hypothermia would be unopposed by simultaneous crystalloid hemodilution.     

The effect of Fluosol-DA on induction of inhalation anesthesia

The liquid/gas partition coefficients of three inhalation anesthetics in Fluosol-DA 20% (Fluosol), a perfluorocarbon blood substitute, were determined in vitro. The high values found (6.68 for halothane, 7.54 for enflurane, and 7.20 for isoflurane) suggested that induction with these agents would be prolonged in patients treated with Fluosol. Induction of isoflurane anesthesia (as a representative agent) at constant inspired concentration was studied in five mongrel dogs before and after replacement of about 25% of each animal's blood volume with Fluosol. Inspired and end-tidal isoflurane and carbon dioxide concentrations were recorded breath by breath, together with cardiac output. There was a significant delay in rise of end-tidal isoflurane concentration after Fluosol infusion. However, because cardiac output could not be held constant during each experiment, and because cardiac output also affects the rate of rise of alveolar anesthetic concentration, a physiological computer model was used to compare the isoflurane blood/gas partition coefficients that must have existed to account for the observed end-tidal levels before and after Fluosol infusion, while taking cardiac output variation into account. Post-Fluosol blood/gas partition coefficients calculated in this way (2.59 +/- 0.51 SD) were significantly different (P less than 0.001) from pre-Fluosol levels (1.45 +/- 0.15 SD) and were not significantly different from post-Fluosol partition coefficients calculated by volume-weighted averaging (2.91 +/- 0.36 SD). This indicates that the delay observed was attributable in large part to increased solubility of isoflurane in blood after addition of Fluosol. Based on their similar liquid/gas partition coefficients in Fluosol, similar delays should occur with halothane and enflurane.     

MAC of desflurane in 60% nitrous oxide in infants and children.

Desflurane, an inhaled anesthetic, may be useful for outpatient procedures in pediatric patients because its blood solubility (similar to that of nitrous oxide and less than that of commercially available potent inhaled anesthetics) may facilitate emergence and recovery from anesthesia. Although the MAC of desflurane without nitrous oxide has been determined in pediatric patients, it is likely that clinicians will administer desflurane with nitrous oxide. To determine the potency of desflurane administered with 60% nitrous oxide in pediatric patients, the authors determined the minimum alveolar concentration that prevents movement in 50% of subjects (MAC) in 12 infants aged 17 weeks-12 months and 12 children aged 1-5 yr. Anesthesia was induced with desflurane in oxygen; nitrous oxide was not administered during induction of anesthesia to minimize the likelihood of hypoxia if laryngospasm occurred. Following tracheal intubation, nitrous oxide and desflurane were administered and maintained at target concentrations for a minimum of 10 min before surgical incision. No additional anesthetic, sedative/hypnotic, or analgesic drugs were administered prior to incision. Following surgical incision, anesthesia was maintained with nitrous oxide, desflurane, and fentanyl, 4 +/- 1 micrograms/kg (mean +/- SD). MAC, determined using a modification of Dixon's "up-and-down" technique, was 7.5 +/- 0.1% (mean +/- SE) for infants and 6.4 +/- 0.2% for children; similar values were obtained using logistic regression (7.5 +/- 0.01% and 6.3 +/- 0.03%, respectively). Time from discontinuation of anesthesia to eye-opening and tracheal extubation was 5.4 +/- 3.6 min (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of age and anesthetic solubility on anesthetic-induced opisthotonus in mice

In our previous report which indicated volatile anesthetics-induced opisthotonus in mice, we hypothesized that opisthotonus might relate with the rapidity of anesthetic induction, i.e., the blood/gas partition coefficient of the agent. To confirm this, we determined the incidence of opisthotonus induced by four different halogenated ethers (2.0% sevoflurane, 1.3% isoflurane, 2.0% enflurane, and 0.5% methoxyflurane) and 1.0% halothane, a haloalkane, in male ddN mice. The effect of age on opisthotonus was also evaluated by using young (10 ± 2 weeks), middle-aged (6 ± 1 mouths), and elderly (12 ± 1 months) groups of male ddN mice. In each age group, the incidence of opisthotonus occurred in the following order: sevoflurane > isoflurane > enflurane > methoxyflurane > halothane. This partly supports our hypothesis as far as halogenated ethers are concerned. Halothane rarely produced opisthotonus. In the sevoflurane, isoflurane, and methoxyflurane groups, incidence was lower in middle-aged than in young or elderly mice, while incidence increased with age in the enflurane group.(Komatsu H, Ohara T, Nogaya J, et al.: The effects of age and anesthetic solubility on anesthetic-induced opisthotonus in mice. J Anesth 5: 228–232, 1991)     

The effect of temperature on solubility of volatile anesthetics in human tissues.

Hypothermia often occurs during surgery, a factor influencing anesthetic pharmacokinetics through its influence on solubility. Information on the tissue solubility of volatile anesthetics under hypothermia is limited. The present study supplies this information for the solubility of volatile anesthetics in human tissues. Tissue specimens of brain, heart, liver, muscle, and fat were obtained from 10 postmortem males (27 +/- 8 yr). Tissue/gas partition coefficients of desflurane, sevoflurane, enflurane, isoflurane and halothane were measured at 37 degrees C, 33 degrees C, 29 degrees C, 25 degrees C, 21 degrees C, and 17 degrees C. For each given tissue, the order of tissue/gas partition coefficient was halothane >enflurane >isoflurane >sevoflurane >desflurane. Tissue/gas partition coefficients at 37 degrees C differed significantly (P < 0.05) across drugs, except that liver/gas partition coefficients for isoflurane and enflurane did not differ. The logarithm of all tissue/gas partition coefficients increased linearly with decreasing temperature (P < 0.05). In conclusion, hypothermia increases tissue/gas partition coefficients of volatile anesthetics. The increases are proportional to those for blood/gas partition coefficients, and therefore tissue/blood partition coefficients will not change during hypothermic conditions. Implications: Volatile anesthetics are often used during hypothermic conditions, and tissue solubility of volatile anesthetics is an important determinant for the wash-in and washout of the anesthetics in tissue. Tissue/gas partition coefficients during hypothermia have implications for understanding the pharmacokinetics of volatile anesthetics at hypothermic conditions.     

Actions of general anesthetics on acetylcholine receptor-rich membranes from Torpedo californica

The molecular mechanisms by which general anesthetics act on postsynaptic membranes can only be worked out in a highly purified, homogeneous system. The nicotinic acetylcholine receptor-rich membranes from the electric tissue of Torpedo californica are currently the only postsynaptic membranes that fulfill this condition. Is this peripheral synapse acted on with a pharmacologic specificity similar to that for general anesthesia, and how much less sensitive is it to anesthetic action than the unknown central site? To answer these questions, the authors studied the effects of 13 anesthetic compounds, including volatile general anesthetics, alkanols, and urethane, on the equilibrium binding of 3H-acetylcholine to these nicotinic receptors. As the anesthetic concentration was raised, all the agents first increased acetylcholine binding steeply and then, with few exceptions, decreased it again at higher concentrations. Anesthetics increased acetylcholine binding by decreasing acetylcholine's dissociation constant without changing the Hill coefficient or the number of sites. To a first approximation, the relative ability of these agents to increase 3H-acetylcholine binding parallels that of anesthesia in vivo as predicted by the Meyer-Overton lipid solubility rule. On average, they produced half maximal increases in acetylcholine binding (EC50) at about four times the concentration that causes loss of righting reflex in one-half of a group of animals (ED50). However, a few agents deviated from this relationship. They were the agents with greatest general anesthetic potency in both the volatile anesthetic series (thiomethoxyflurane) and the normal alcohol series (octanol), and required up to 17 times their ED50s to achieve a half effect on acetylcholine binding. Although the concentrations required were high, these effects were reversible.(ABSTRACT TRUNCATED AT 250 WORDS)     

Age and the solubility of volatile anesthetics in ovine tissues

To determine the effect of age on the solubility of volatile anesthetics in tissues, we measured the blood/gas and tissue/gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane in vitro at 37 degrees C in newborn lambs and postpartum adult sheep. The tissue specimens examined were brain, heart, liver, kidney, muscle, and fat. Hematocrit and serum concentrations of albumin, globulin, cholesterol, and triglycerides were measured. The blood/gas partition coefficients, hematocrit, and the serum concentrations of albumin, globulin, cholesterol, and triglycerides in the newborn lambs did not differ from those in the adult sheep. The tissue/blood partition coefficients [the ratio of (tissue/gas)/(blood/gas)] in newborn lambs were 28% [mean value for the four anesthetics] less than those in the adults. The tissue/blood partition coefficients for enflurane and methoxyflurane in newborn tissues were significantly less (P less than 0.05) than those for halothane and isoflurane. We conclude that the blood/gas partition coefficients in sheep do not change significantly with age, and that the time required for equilibration of volatile anesthetics (particularly enflurane and methoxyflurane) in newborn tissues is probably less than in adult sheep.