MAC of an inhaled anesthetic is defined as that concentration at 1 atmosphere that prevents skeletal muscle movement in response to a supramaximal painful stimulus (surgical skin incision) in 50% of patients.55 MAC is an anesthetic 50% effective dose (ED50). Immobility produced by inhaled anesthetics as measured by MAC is mediated principally by effects of these drugs on the spinal cord and only a minor component of immobility results from cerebral effects.56 For example, in animals, MAC for isoflurane is 1.2% when delivered to the intact animal but delivery of inhaled anesthetic only to the brain results in isoflurane MAC increasing to nearly 3%.57 Further evidence that MAC reflects effects of the inhaled anesthetics at the spinal cord is the observation that decerebration does not change MAC (Fig. 4-18).58 MAC is among the most useful concepts in anesthetic pharmacology as it establishes a common measure of ­potency (partial pressure at steady state) for inhaled anesthetics. Th s concept is used to provide uniformity in dosages of inhaled anesthetics, to establish relative amounts of inhaled anesthetics to reach specific endpoints (­MACawake), and to guide the search for mechanisms responsible for mechanisms of anesthetic action.59 A unique feature of MAC is its consistency varying only 10% t o 15% among individuals. This small degree of pharmacodynamic variability for inhaled anesthetics is unique in pharmacology. The use of equally potent doses (comparable MAC concentrations) of inhaled anesthetics is mandatory for comparing effects of these drugs not only at the FIGURE 4-18 Decerebration does not change the minimum alveolar anesthetic concentration of isoflurane in rats confirming that the effects of volatile anesthetics on the spinal cord determine MAC. (From Rampil IJ, Mason P, Singh H. Anesthetic potency [MAC] is independent of forebrain structures in the rat. Anesthesiology. 1993;78:707–712, with permission.) spinal cord but also at all other organs (Table 4-5). For example, similar MAC concentrations of inhaled ­anesthetics produce equivalent depression of the spinal cord, whereas effects on cardiopulmonary parameters may be different for each drug (see Chapter 2). This emphasizes that MAC represents only one point on the dose-response curve of effects produced by inhaled anesthetics and that these dose-response curves are not parallel. It is remarkable though that MACawake, the concentration of anesthetic that prevents consciousness in 50% of persons, is reliably about half of MAC and that MACmemory, the concentration of anesthetic that is associated with amnesia in 50% of patients, is signifi antly less than MACawake. If this were not the case, an ED50 would not be satisfactory endpoint for clinical anesthesia! A surgeon may tolerate 50% of his or her patients moving but having 50% of patients have awareness under anesthesia would clearly not be acceptable. Table 4-5 Comparative Minimum Alveolar Concentration of Inhaled Anesthetics Nitrous oxidea Halothane Enfl rane Isoflurane Desflurane Sevoflurane Xenon MAC (%, 30 to 55 Years Old at 37°C, Pb 760 mm Hg) 104 0.75 1.63 1.17 6.6 1.80 63–71 a Determined in a hyperbaric chamber in males 21 to 55 years old. MAC, minimum alveolar concentrationChapter 4 • Inhaled Anesthetics 113 Factors that Alter Minimal Alveolar Concentration Inhalation anesthetic requirements are remarkably uni- form in humans, mainly being affected by age and body temperature. MAC allows a quantitative analysis of the effect, if any, of various physiologic and pharmacologic factors on anesthetic requirements (Table 4-6).60,61 For e ­xample, increasing age results in a progressive decrease in MAC of about 6% per decade that is similar for all in- haled anesthetics (Figs. 4-19 and 4-20).62,63 MAC is de- creased nearly 30% during pregnancy and in the early Table 4-6 Impact of Physiologic and Pharmacologic Factors on Minimum Alveolar Concentration Increases in MAC Hyperthermia Excess pheomelanin production (red hair) Drug-induced increases in central nervous system cate- cholamine levels Cyclosporine Hypernatremia Decreases in MAC Hypothermia Increasing age Preoperative medication Drug-induced decreases in central nervous system cate- cholamine levels a-2 agonists Acute alcohol ingestion Pregnancy Postpartum (returns to normal in 24–72 hours) Lithium Lidocaine Neuraxial opioids (?) Ketanserin Pao2 ,38 mm Hg Mean blood pressure ,40 mm Hg Cardiopulmonary bypass Hyponatremia No change in MAC Anesthetic metabolism Chronic alcohol abuse Gender Duration of anesthesia (?) Paco 2 15–95 mm Hg Pao2 .38 mm Hg Blood pressure .40 mm Hg Hyperkalemia or hypokalemia Thyroid gland dysfunction MAC, minimum alveolar concentration. FIGURE 4-19 Effect of age on minimum alveolar concen- tration (MAC). (From Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J Anaesth. 1996;76:179–185, with permission.) FIGURE 4-20 Minimum alveolar anesthetic concentra- tion (MAC) (as a fraction of MAC at 40 years of age) with increasing age. (From Eger EI. Age, minimum alveolar an- esthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg. 2001;93:947–953, with permission.)114 Part II • Neurologic System Men Move No move Women Move No move 5.5 6.0 6.5 7.0 [Desflurane] (%) FIGURE 4-21 End-tidal concentrations of desflurane were tested for “Move” or “No move” in men and women. MAC for desflurane in men was 6.0% to 0.3% and in women it was 6.2% to 0.4%. P 5 0.31 (mean 2 SD). (From Wadhwa A, Durrani J, Sengupta P, et al. Women have the same desflu- rane minimum alveolar concentration as men: a prospective study. Anesthesiology. 2003;99:1062–1065, with ­permission.) postpartum period, returning to normal values in 12 to 72 hours.64,65 Nevertheless, gender does not influence MAC (Fig. 4-21).66,67 MAC is increased in women with natural red hair, presumably reflecting mutations of the melano- cortin-1 receptor gene and increased pheomelanin con- centrations (Fig. 4-22).68 Although most reports describe MAC as independent of the duration of anesthesia, there is evidence that MAC for isoflurane decreases during the administration of anesthesia and the performance of sur- gery (Fig. 4-23).69 The effect of cardiopulmonary bypass 7 FIGURE 4-23 Preoperative (60 minutes) and postoperative (180 to 300 minutes) individual minimum alveolar concen- tration (MAC) determinations using continuous electrical stimulation (MAC tetanus). Each line represents an individ- ual patient. (From Petersen-Felix S, Zbinden AM, Fischer M, et al. Isoflurane minimum alveolar concentration decreases during anesthesia and surgery. Anesthesiology. 1993;79: 959–965, with permission.) on MAC is uncertain, with some studies showing a de- crease, whereas others fail to demonstrate any change.47 Despite prolongation of sleeping times in animals, cy- closporine increases rather than decreases isoflurane MAC.70 MAC is defined by the response to a surgical inci- sion, which is considered to be a supramaximal stimulus. MAC values may vary with the type of stimulus; tetanic stimulation and trapezius squeeze are considered nonin- vasive stimulation patterns that are relatively equivalent to surgical skin incision, although in contrast to skin inci- sion, these events can be repeated (Fig. 4-24).71 Tracheal intubation requires the highest MAC to prevent skeletal muscle ­responses and may represent a true supramaximal stimulation (see Fig. 4-24).71 MAC values for inhaled anesthetics are additive.72 For 6 5 example, 0.5 MAC of nitrous oxide plus 0.5 MAC isoflu- rane has the same effect at the brain as does a 1 MAC con- centration of either anesthetic alone. The strict additivity of the interactions among inhaled anesthetics implies either a common site of action or that anesthetic action occurs with only a small fraction of the binding sites occupied.73 Opioids synergistically decrease anesthetic require- 4 Dark hair Red hair FIGURE 4-22 Anesthetic requirements for individual par- ticipants (circles) with group means (squares). The des- flurane requirement in redheads (6.2%) was significantly greater than in dark-haired women (5.2%) (From Liem ER, Lin C-M, Suleman M-I, et al. Anesthetic requirement is in- creased in redheads. Anesthesiology. 2004;101:279–283, with permission.) ments for volatile anesthetics. For example, 25 minutes after the administration of fentanyl, 3 mg/kg or 6 mg/kg IV, MAC for desflurane is decreased 48% and 68%, respec- tively.74 Similar decreases in isoflurane MAC are also pro- duced by these doses of fentanyl.75 Dose-response curves for inhaled anesthetics, al- though not parallel, are all steep. This is emphasized by the fact that a 1 MAC dose prevents skeletal muscle move- ment in response to a painful stimulus in 50% of patients, whereas a modest increase to about 1.3 MAC prevents movement in at least 95% of patients. [Desflurane] (%)Chapter 4 • Inhaled Anesthetics 115 conductance. Evidence supporting distortion of sodium channels by dissolved anesthetic molecules is the observation that high pressures (40 to 100 atm) partially antagonize the action of inhaled anesthetics (pressure reversal), presumably by returning (compressing) lipid membranes and their sodium channels to their “awake” contour.76 The most compelling evidence against the Meyer-Overton theory of anesthesia is the fact that effects of inhaled anesthetics on the fluidity of lipid bilayers is implausibly small and can generally be mimicked by temperature changes of 1°C.77 Furthermore, not all lipid-soluble drugs are anesthetics, and, in fact, some are convulsants. For example, the observation that, among n-alcohols, dodecanol is anesthetic and decanol is not (for n-alkanes the cutoff is after octane) suggests that anesthetic binding to protein pockets or clefts and not lipid membranes is important in the mechanism of anesthesia. Based on these negative observations, lipid theories have been refined to postulate that specialized domains in membranes (boundary membranes surrounding proteins) are not only particularly sensitive to anesthetics but also are critical to membrane function. ­Indeed, either binding to proteins or dissolving in lipids can account for the Meyer-Overton correlation. FIGURE 4-24 Responses (movement [horizontal line above]) or no movement (horizontal line below) to preoperative stimulation represented by tracheal intubation (IN), skin incision (SI), response to a continuous (tetanus) electrical stimulation (TE), direct laryngoscopy (LA), and trapezius muscle squeeze (TZ). The probability of response versus end-tidal isoflurane concentration is plotted. (From Zbinden AM, Maggiorini M, Peterson-Felix S, et al. Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. I. Motor reactions. Anesthesiology. 1994; 80:253–260, with permission This is from stoeltings Pharmacology. Without missing important points, give a brief notes on this text in bullet points