Skip to main content
SpringerLink
Log in

Mechanisms of Intravenous Anesthetic Action

  • Chapter
  • First Online:
Total Intravenous Anesthesia and Target Controlled Infusions

  • 2652 Accesses

Abstract

General anesthesia consists of key separable and independent neurobiological end points. Each of these involves distinct but possibly overlapping neuroanatomical and molecular mechanisms that converge to produce the characteristic behavioral end points of anesthesia: amnesia, unconsciousness, and immobility. The potency of various structurally dissimilar general anesthetics correlates with their solubilities in oil (lipophilicity), consistent with critical interactions with hydrophobic molecular targets. The pharmacologically relevant binding sites of general anesthetics are lipophilic cavities in proteins identified by a combination of site-directed mutagenesis and high-resolution structural analysis of anesthetic binding. Specific point mutations render putative target proteins insensitive to certain general anesthetics. Expression of these mutations in mice reduces anesthetic potency for specific end points.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 229.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci. 2004;5:709–20.

    Article  CAS  PubMed  Google Scholar 

  2. Hemmings Jr HC, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci. 2005;26:503–10.

    Article  CAS  PubMed  Google Scholar 

  3. Meyer H. Zur theorie der alkoholnarkose. Arch Exp Pathol Pharmakol. 1899;42:109–18.

    Article  Google Scholar 

  4. Overton C. Studien über die Narkose zugleich ein Beitrag zur allgemeinen Pharmakologie. Jena: Verlag von Gustav Fischer; 1901.

    Google Scholar 

  5. Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature. 1984;310:599–601.

    Article  CAS  PubMed  Google Scholar 

  6. Franks NP, Lieb WR. Seeing the light: protein theories of general anesthesia. 1984. Anesthesiology. 2004;101:235–7.

    Article  CAS  PubMed  Google Scholar 

  7. Hall AC, Lieb WR, Franks NP. Stereoselective and non-stereoselective actions of isoflurane on the GABAA receptor. Br J Pharmacol. 1994;112:906–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology. 1993;79:1244–9.

    Article  CAS  PubMed  Google Scholar 

  9. Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology. 1993;78:707–12.

    Article  CAS  PubMed  Google Scholar 

  10. Stabernack C, Zhang Y, Sonner JM, Laster M, Eger 2nd EI. Thiopental produces immobility primarily by supraspinal actions in rats. Anesth Analg. 2005;100:128–36.

    Article  CAS  PubMed  Google Scholar 

  11. Veselis RA, Reinsel RA, Feshchenko VA. Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence. Anesthesiology. 2001;95:896–907.

    Article  CAS  PubMed  Google Scholar 

  12. Veselis RA, Reinsel RA, Feshchenko VA, Wronski M. The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations. Anesthesiology. 1997;87:749–64.

    Article  CAS  PubMed  Google Scholar 

  13. Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness not equal unconsciousness. Anesthesiology. 2012;116:946–59.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Devor M, Zalkind V. Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain. 2001;94:101–12.

    Article  CAS  PubMed  Google Scholar 

  15. Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci. 2002;5:979–84.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Z, Ferretti V, Guntan I, Moro A, Steinberg EA, Ye Z, Zecharia AY, Yu X, Vyssotski AL, Brickley SG, Yustos R, Pillidge ZE, Harding EC, Wisden W, Franks NP. Neuronal ensembles sufficient for recovery sleep and the sedative actions of alpha2 adrenergic agonists. Nat Neurosci. 2015;18:553–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lakhlani PP, MacMillan LB, Guo TZ, McCool BA, Lovinger DM, Maze M, Limbird LE. Substitution of a mutant alpha2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci U S A. 1997;94:9950–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology. 2000;93:1345–9.

    Article  CAS  PubMed  Google Scholar 

  19. Rampil IJ, Laster MJ. No correlation between quantitative electroencephalographic measurements and movement response to noxious stimuli during isoflurane anesthesia in rats. Anesthesiology. 1992;77:920–5.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang Y, Sonner JM, Eger 2nd EI, Stabernack CR, Laster MJ, Raines DE, Harris RA. Gamma-aminobutyric acidA receptors do not mediate the immobility produced by isoflurane. Anesth Analg. 2004;99:85–90.

    Article  CAS  PubMed  Google Scholar 

  21. Kungys G, Kim J, Jinks SL, Atherley RJ, Antognini JF. Propofol produces immobility via action in the ventral horn of the spinal cord by a GABAergic mechanism. Anesth Analg. 2009;108:1531–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang Y, Guzinski M, Eger EI, Laster MJ, Sharma M, Harris RA, Hemmings HC. Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats. Br J Pharmacol. 2010;159:872–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liao M, Sonner JM, Jurd R, Rudolph U, Borghese CM, Harris RA, Laster MJ, Eger 2nd EI. Beta3-containing gamma-aminobutyric acidA receptors are not major targets for the amnesic and immobilizing actions of isoflurane. Anesth Analg. 2005;101:412–8. Table of contents.

    Article  CAS  PubMed  Google Scholar 

  24. Sonner JM, Werner DF, Elsen FP, Xing Y, Liao M, Harris RA, Harrison NL, Fanselow MS, Eger 2nd EI, Homanics GE. Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane. Anesthesiology. 2007;106:107–13.

    Article  CAS  PubMed  Google Scholar 

  25. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, Lazdunski M. TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J. 2004;23:2684–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Linden AM, Aller MI, Leppa E, Vekovischeva O, Aitta-Aho T, Veale EL, Mathie A, Rosenberg P, Wisden W, Korpi ER. The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists. J Pharmacol Exp Ther. 2006;317:615–26.

    Article  CAS  PubMed  Google Scholar 

  27. Linden AM, Sandu C, Aller MI, Vekovischeva OY, Rosenberg PH, Wisden W, Korpi ER. TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J Pharmacol Exp Ther. 2007;323:924–34.

    Article  CAS  PubMed  Google Scholar 

  28. Westphalen R, Krivitski M, Amarosa A, Guy N, Hemmings H. Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1. Br J Pharmacol. 2007;152:939–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jinks SL, Bravo M, Hayes SG. Volatile anesthetic effects on midbrain-elicited locomotion suggest that the locomotor network in the ventral spinal cord is the primary site for immobility. Anesthesiology. 2008;108:1016–24.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Searle JR. Consciousness. Annu Rev Neurosci. 2000;23:557–78.

    Article  CAS  PubMed  Google Scholar 

  31. Crick F, Koch C. A framework for consciousness. Nat Neurosci. 2003;6:119–26.

    Article  CAS  PubMed  Google Scholar 

  32. Alkire MT, Haier RJ, Fallon JH. Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn. 2000;9:370–86.

    Article  CAS  PubMed  Google Scholar 

  33. Ries CR, Puil E. Mechanism of anesthesia revealed by shunting actions of isoflurane on thalamocortical neurons. J Neurophysiol. 1999;81:1795–801.

    CAS  PubMed  Google Scholar 

  34. Detsch O, Vahle-Hinz C, Kochs E, Siemers M, Bromm B. Isoflurane induces dose-dependent changes of thalamic somatosensory information transfer. Brain Res. 1999;829:77–89.

    Article  CAS  PubMed  Google Scholar 

  35. Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science. 2008;322:876–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010;363:2638–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Varela F, Lachaux JP, Rodriguez E, Martinerie J. The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci. 2001;2:229–39.

    Article  CAS  PubMed  Google Scholar 

  38. Bullmore E, Sporns O. The economy of brain network organization. Nat Rev Neurosci. 2012;13:336–49.

    CAS  PubMed  Google Scholar 

  39. van den Heuvel MP, Sporns O. Rich-club organization of the human connectome. J Neurosci. 2011;31:15775–86.

    Article  PubMed  CAS  Google Scholar 

  40. Ferrarelli F, Massimini M, Sarasso S, Casali A, Riedner BA, Angelini G, Tononi G, Pearce RA. Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A. 2010;107:2681–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dutton RC, Maurer AJ, Sonner JM, Fanselow MS, Laster MJ, Eger 2nd EI. The concentration of isoflurane required to suppress learning depends on the type of learning. Anesthesiology. 2001;94:514–9.

    Article  CAS  PubMed  Google Scholar 

  42. Mashour GA. Fragmenting consciousness. Proc Natl Acad Sci U S A. 2012;109:19876–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Imas OA, Ropella KM, Ward BD, Wood JD, Hudetz AG. Volatile anesthetics enhance flash-induced gamma oscillations in rat visual cortex. Anesthesiology. 2005;102:937–47.

    Article  CAS  PubMed  Google Scholar 

  44. Imas OA, Ropella KM, Wood JD, Hudetz AG. Isoflurane disrupts anterio-posterior phase synchronization of flash-induced field potentials in the rat. Neurosci Lett. 2006;402:216–21.

    Article  CAS  PubMed  Google Scholar 

  45. John ER, Prichep LS, Kox W, Valdes-Sosa P, Bosch-Bayard J, Aubert E, Tom M, di Michele F, Gugino LD. Invariant reversible QEEG effects of anesthetics. Conscious Cogn. 2001;10:165–83.

    Article  CAS  PubMed  Google Scholar 

  46. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2–8.

    Article  CAS  PubMed  Google Scholar 

  47. Alkire MT, Nathan SV. Does the amygdala mediate anesthetic-induced amnesia? Basolateral amygdala lesions block sevoflurane-induced amnesia. Anesthesiology. 2005;102:754–60.

    Article  PubMed  Google Scholar 

  48. Vertes RP. Hippocampal theta rhythm: a tag for short-term memory. Hippocampus. 2005;15:923–35.

    Article  CAS  PubMed  Google Scholar 

  49. Pan WX, McNaughton N. The medial supramammillary nucleus, spatial learning and the frequency of hippocampal theta activity. Brain Res. 1997;764:101–8.

    Article  CAS  PubMed  Google Scholar 

  50. Seidenbecher T, Laxmi TR, Stork O, Pape HC. Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science. 2003;301:846–50.

    Article  CAS  PubMed  Google Scholar 

  51. Pryor KO, Murphy E, Reinsel RA, Mehta M, Veselis RA. Heterogeneous effects of intravenous anesthetics on modulatory memory systems in humans. Anesthesiology. 2007;107:A1218.

    Google Scholar 

  52. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999;401:796–800.

    Article  CAS  PubMed  Google Scholar 

  53. Murphy M, Bruno MA, Riedner BA, Boveroux P, Noirhomme Q, Landsness EC, Brichant JF, Phillips C, Massimini M, Laureys S, Tononi G, Boly M. Propofol anesthesia and sleep: a high-density EEG study. Sleep. 2011;34:283–91A.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tung A, Bergmann BM, Herrera S, Cao D, Mendelson WB. Recovery from sleep deprivation occurs during propofol anesthesia. Anesthesiology. 2004;100:1419–26.

    Article  CAS  PubMed  Google Scholar 

  55. Hentschke H, Schwarz C, Antkowiak B. Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor-mediated inhibition. Eur J Neurosci. 2005;21:93–102.

    Article  PubMed  Google Scholar 

  56. Perouansky M, Hemmings Jr HC. Neurotoxicity of general anesthetics: cause for concern? Anesthesiology. 2009;111:1365–71.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Durieux M, Davis PJ. The safety of key inhaled and intravenous drugs in pediatrics (SAFEKIDS): an update. Anesth Analg. 2010;110:1265–7.

    Article  PubMed  Google Scholar 

  58. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82.

    CAS  PubMed  Google Scholar 

  59. Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, Olney JW. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol. 2005;146:189–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Scallet AC, Schmued LC, Slikker Jr W, Grunberg N, Faustino PJ, Davis H, Lester D, Pine PS, Sistare F, Hanig JP. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci. 2004;81:364–70.

    Article  CAS  PubMed  Google Scholar 

  61. Cattano D, Young C, Straiko MM, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg. 2008;106:1712–4.

    Article  CAS  PubMed  Google Scholar 

  62. Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology. 2007;107:427–36.

    Article  CAS  PubMed  Google Scholar 

  63. Stratmann G. Review article: neurotoxicity of anesthetic drugs in the developing brain. Anesth Analg. 2011;113:1170–9.

    Article  CAS  PubMed  Google Scholar 

  64. Hudson AE, Hemmings Jr HC. Are anaesthetics toxic to the brain? Br J Anaesth. 2011;107:30–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, Fiskum G, Giffard RG, Herold KF, Loepke AW, Ma D, Orser BA, Planel E, Slikker Jr W, Soriano SG, Stratmann G, Vutskits L, Xie Z, Hemmings Jr HC. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth. 2013;111:143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li J, Xiong M, Nadavaluru PR, Zuo W, Ye JH, Eloy JD, Bekker A. Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure. J Neurosurg Anesthesiol. 2016;28:51–64.

    Article  CAS  PubMed  Google Scholar 

  67. Jevtovic-Todorovic V. Anesthesia and the developing brain: are we getting closer to understanding the truth? Curr Opin Anaesthesiol. 2011;24:395–9.

    Article  PubMed  Google Scholar 

  68. Shih J, May LD, Gonzalez HE, Lee EW, Alvi RS, Sall JW, Rau V, Bickler PE, Lalchandani GR, Yusupova M, Woodward E, Kang H, Wilk AJ, Carlston CM, Mendoza MV, Guggenheim JN, Schaefer M, Rowe AM, Stratmann G. Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology. 2012;116:586–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Munk L, Andersen G, Moller AM. Post-anaesthetic emergence delirium in adults: incidence, predictors and consequences. Acta Anaesthesiol Scand. 2016.

    Google Scholar 

  70. Guenther U, Riedel L, Radtke FM. Patients prone for postoperative delirium: preoperative assessment, perioperative prophylaxis, postoperative treatment. Curr Opin Anaesthesiol. 2016.

    Google Scholar 

  71. Djaiani G, Silverton N, Fedorko L, Carroll J, Styra R, Rao V, Katznelson R. Dexmedetomidine versus propofol sedation reduces delirium after cardiac surgery: a randomized controlled trial. Anesthesiology. 2016;124:362–8.

    Article  CAS  PubMed  Google Scholar 

  72. Zurek AA, Bridgwater EM, Orser BA. Inhibition of alpha5 gamma-aminobutyric acid type A receptors restores recognition memory after general anesthesia. Anesth Analg. 2012;114:845–55.

    Article  CAS  PubMed  Google Scholar 

  73. Wan Y, Xu J, Ma D, Zeng Y, Cibelli M, Maze M. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology. 2007;106:436–43.

    Article  PubMed  Google Scholar 

  74. Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, Jonsson Fagerlund M, Charo IF, Akassoglou K, Maze M. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70:986–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tang JX, Mardini F, Caltagarone BM, Garrity ST, Li RQ, Bianchi SL, Gomes O, Laferla FM, Eckenhoff RG, Eckenhoff MF. Anesthesia in presymptomatic Alzheimer’s disease: a study using the triple-transgenic mouse model. Alzheimers Dement. 2011;7:521–31. e1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Avidan MS, Searleman AC, Storandt M, Barnett K, Vannucci A, Saager L, Xiong C, Grant EA, Kaiser D, Morris JC, Evers AS. Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology. 2009;111:964–70.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Avidan MS, Evers AS. Review of clinical evidence for persistent cognitive decline or incident dementia attributable to surgery or general anesthesia. J Alzheimers Dis. 2011;24:201–16.

    PubMed  Google Scholar 

  78. Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms. Br J Anaesth. 2003;91:551–65.

    Article  CAS  PubMed  Google Scholar 

  79. Pagel PS, Hettrick DA, Lowe D, Gowrie PW, Kersten JR, Bosnjak ZJ, Warltier DC. Cardiovascular effects of verapamil enantiomer combinations in conscious dogs. Eur J Pharmacol. 1998;348:213–21.

    Article  CAS  PubMed  Google Scholar 

  80. Vulliemoz Y. The nitric oxide-cyclic 3’,5’-guanosine monophosphate signal transduction pathway in the mechanism of action of general anesthetics. Toxicol Lett. 1998;100–101:103–8.

    Article  PubMed  Google Scholar 

  81. Huneke R, Fassl J, Rossaint R, Luckhoff A. Effects of volatile anesthetics on cardiac ion channels. Acta Anaesthesiol Scand. 2004;48:547–61.

    Article  CAS  PubMed  Google Scholar 

  82. Thompson A, Balser JR. Perioperative cardiac arrhythmias. Br J Anaesth. 2004;93:86–94.

    Article  CAS  PubMed  Google Scholar 

  83. Stuth EA, Krolo M, Tonkovic-Capin M, Hopp FA, Kampine JP, Zuperku EJ. Effects of halothane on synaptic neurotransmission to medullary expiratory neurons in the ventral respiratory group of dogs. Anesthesiology. 1999;91:804–14.

    Article  CAS  PubMed  Google Scholar 

  84. Nieuwenhuijs D, Sarton E, Teppema LJ, Kruyt E, Olievier I, van Kleef J, Dahan A. Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol. Anesthesiology. 2001;95:889–95.

    Article  CAS  PubMed  Google Scholar 

  85. Hoshino Y, Ayuse T, Kurata S, Ayuse T, Schneider H, Kirkness JP, Patil SP, Schwartz AR, Oi K. The compensatory responses to upper airway obstruction in normal subjects under propofol anesthesia. Respir Physiol Neurobiol. 2009;166:24–31.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Nieuwenhuijs DJ, Olofsen E, Romberg RR, Sarton E, Ward D, Engbers F, Vuyk J, Mooren R, Teppema LJ, Dahan A. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology. 2003;98:312–22.

    Article  CAS  PubMed  Google Scholar 

  87. Gueye PN, Borron SW, Risede P, Monier C, Buneaux F, Debray M, Baud FJ. Buprenorphine and midazolam act in combination to depress respiration in rats. Toxicol Sci. 2002;65:107–14.

    Article  CAS  PubMed  Google Scholar 

  88. Venn RM, Hell J, Grounds RM. Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care. Crit Care. 2000;4:302–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hsu YW, Cortinez LI, Robertson KM, Keifer JC, Sum-Ping ST, Moretti EW, Young CC, Wright DR, Macleod DB, Somma J. Dexmedetomidine pharmacodynamics: Part I: Crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 2004;101:1066–76.

    Article  CAS  PubMed  Google Scholar 

  90. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994;367:607–14.

    Article  CAS  PubMed  Google Scholar 

  91. Zeller A, Jurd R, Lambert S, Arras M, Drexler B, Grashoff C, et al. Inhibitory ligand-gated ion channels as substrates for general anesthetic actions. In: Schüttler J, Schwilden H, editors. Modern anesthetics, Handbook of experimental pharmacology, vol. 182. Berlin Heidelberg: Springer; 2008. p. 31–51.

    Google Scholar 

  92. Bertaccini EJ, Trudell JR, Franks NP. The common chemical motifs within anesthetic binding sites. Anesth Analg. 2007;104:318–24.

    Article  CAS  PubMed  Google Scholar 

  93. Eckenhoff RG. Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? Mol Interv. 2001;1:258–68.

    CAS  PubMed  Google Scholar 

  94. Dickinson R, Peterson BK, Banks P, Simillis C, Martin JC, Valenzuela CA, Maze M, Franks NP. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology. 2007;107:756–67.

    Article  CAS  PubMed  Google Scholar 

  95. Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, Corringer PJ. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature. 2011;469:428–31.

    Article  CAS  PubMed  Google Scholar 

  96. Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci. 1999;2:422–6.

    Article  CAS  PubMed  Google Scholar 

  97. Herold KF, Hemmings Jr HC. Sodium channels as targets for volatile anesthetics. Front Pharmacol. 2012;3:50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev. 2004;84:1051–95.

    Article  CAS  PubMed  Google Scholar 

  99. Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA, Harrison NL. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature. 1997;389:385–9.

    Article  CAS  PubMed  Google Scholar 

  100. Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses. Neuron. 1996;16:1077–85.

    Article  CAS  PubMed  Google Scholar 

  101. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology. 1997;86:859–65.

    Article  CAS  PubMed  Google Scholar 

  102. Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology. 1997;86:866–74.

    Article  CAS  PubMed  Google Scholar 

  103. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51:7–61.

    CAS  PubMed  Google Scholar 

  104. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;4:460–3.

    Article  CAS  PubMed  Google Scholar 

  105. Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature. 1998;396:324.

    Article  CAS  PubMed  Google Scholar 

  106. Herold KF, Nau C, Ouyang W, Hemmings HC. Isoflurane inhibits the tetrodotoxin-resistant voltage-gated sodium channel Nav1.8. Anesthesiology. 2009;111:591–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ouyang W, Hemmings H. Depression by isoflurane of the action potential and underlying voltage-gated ion currents in isolated rat neurohypophysial nerve terminals. J Pharmacol Exp Ther. 2005;312:801–8.

    Article  CAS  PubMed  Google Scholar 

  108. Ouyang W, Hemmings H. Isoform-selective effects of isoflurane on voltage-gated Na + channels. Anesthesiology. 2007;107:91–8.

    Article  CAS  PubMed  Google Scholar 

  109. Ratnakumari L, Vysotskaya T, Duch D, Hemmings H. Differential effects of anesthetic and nonanesthetic cyclobutanes on neuronal voltage-gated sodium channels. Anesthesiology. 2000;92:529–41.

    Article  CAS  PubMed  Google Scholar 

  110. Shiraishi M, Harris R. Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels. J Pharmacol Exp Ther. 2004;309:987–94.

    Article  CAS  PubMed  Google Scholar 

  111. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000;16:521–55.

    Article  CAS  PubMed  Google Scholar 

  112. Antognini J, Carstens E, Raines DE, Hemmings HC. Neural mechanisms of anesthesia. Totowa, NJ: Humana Press; 2003.

    Google Scholar 

  113. Hanley PJ, ter Keurs HE, Cannell MB. Excitation-contraction coupling in the heart and the negative inotropic action of volatile anesthetics. Anesthesiology. 2004;101:999–1014.

    Article  PubMed  Google Scholar 

  114. Rithalia A, Hopkins PM, Harrison SM. The effects of halothane, isoflurane, and sevoflurane on Ca2+ current and transient outward K+ current in subendocardial and subepicardial myocytes from the rat left ventricle. Anesth Analg. 2004;99:1615–22. Table of contents.

    Article  CAS  PubMed  Google Scholar 

  115. Huneke R, Jungling E, Skasa M, Rossaint R, Luckhoff A. Effects of the anesthetic gases xenon, halothane, and isoflurane on calcium and potassium currents in human atrial cardiomyocytes. Anesthesiology. 2001;95:999–1006.

    Article  CAS  PubMed  Google Scholar 

  116. Stowe DF, Rehmert GC, Kwok WM, Weigt HU, Georgieff M, Bosnjak ZJ. Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes. Anesthesiology. 2000;92:516–22.

    Article  CAS  PubMed  Google Scholar 

  117. Buljubasic N, Marijic J, Berczi V, Supan DF, Kampine JP, Bosnjak ZJ. Differential effects of etomidate, propofol, and midazolam on calcium and potassium channel currents in canine myocardial cells. Anesthesiology. 1996;85:1092–9.

    Article  CAS  PubMed  Google Scholar 

  118. Yost CS. Potassium channels: basic aspects, functional roles, and medical significance. Anesthesiology. 1999;90:1186–203.

    Article  CAS  PubMed  Google Scholar 

  119. Friederich P, Benzenberg D, Trellakis S, Urban BW. Interaction of volatile anesthetics with human Kv channels in relation to clinical concentrations. Anesthesiology. 2001;95:954–8.

    Article  CAS  PubMed  Google Scholar 

  120. Franks NP, Lieb WR. Volatile general anaesthetics activate a novel neuronal K+ current. Nature. 1988;333:662–4.

    Article  CAS  PubMed  Google Scholar 

  121. Franks NP, Honore E. The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci. 2004;25:601–8.

    Article  CAS  PubMed  Google Scholar 

  122. Patel AJ, Honore E. Anesthetic-sensitive 2P domain K+ channels. Anesthesiology. 2001;95:1013–21.

    Article  CAS  PubMed  Google Scholar 

  123. Sirois JE, Lynch 3rd C, Bayliss DA. Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones. J Physiol. 2002;541:717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chen X, Sirois JE, Lei Q, Talley EM, Lynch 3rd C, Bayliss DA. HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents. J Neurosci. 2005;25:5803–14.

    Article  CAS  PubMed  Google Scholar 

  125. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol. 2003;65:453–80.

    Article  CAS  PubMed  Google Scholar 

  126. Semyanov A, Walker MC, Kullmann DM, Silver RA. Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci. 2004;27:262–9.

    Article  CAS  PubMed  Google Scholar 

  127. Bai D, Zhu G, Pennefather P, Jackson MF, MacDonald JF, Orser BA. Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons. Mol Pharmacol. 2001;59:814–24.

    CAS  PubMed  Google Scholar 

  128. Bieda MC, MacIver MB. Major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol. 2004;92:1658–67.

    Article  CAS  PubMed  Google Scholar 

  129. Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A. 2004;101:3662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Caraiscos VB, Newell JG, You-Ten KE, Elliott EM, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci. 2004;24:8454–8.

    Article  CAS  PubMed  Google Scholar 

  131. Capogna M, Pearce RA. GABA A, slow: causes and consequences. Trends Neurosci. 2011;34:101–12.

    Article  CAS  PubMed  Google Scholar 

  132. Penttonen M, Buzsáki G. Natural logarithmic relationship between brain oscillators. Thalamus Relat Syst. 2003;2:145–52.

    Article  Google Scholar 

  133. Lewis LD, Weiner VS, Mukamel EA, Donoghue JA, Eskandar EN, Madsen JR, Anderson WS, Hochberg LR, Cash SS, Brown EN, Purdon PL. Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness. Proc Natl Acad Sci U S A. 2012;109:E3377–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Steriade M, Nunez A, Amzica F. Intracellular analysis of relations between the slow (<1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J Neurosci. 1993;13:3266–83.

    CAS  PubMed  Google Scholar 

  135. Buzsaki G. Theta oscillations in the hippocampus. Neuron. 2002;33:325–40.

    Article  CAS  PubMed  Google Scholar 

  136. Perouansky M, Hentschke H, Perkins M, Pearce RA. Amnesic concentrations of the nonimmobilizer 1,2- dichlorohexafluorocyclobutane (F6, 2N) and isoflurane alter hippocampal theta oscillations in vivo. Anesthesiology. 2007;106:1168–76.

    Google Scholar 

  137. Bland BH, Bland CE, Colom LV, Roth SH, DeClerk S, Dypvik A, Bird J, Deliyannides A. Effect of halothane on type 2 immobility-related hippocampal theta field activity and theta-on/theta-off cell discharges. Hippocampus. 2003;13:38–47.

    Article  CAS  PubMed  Google Scholar 

  138. Madler C, Keller I, Schwender D, Poppel E. Sensory information processing during general anaesthesia: effect of isoflurane on auditory evoked neuronal oscillations. Br J Anaesth. 1991;66:81–7.

    Article  CAS  PubMed  Google Scholar 

  139. Munglani R, Andrade J, Sapsford DJ, Baddeley A, Jones JG. A measure of consciousness and memory during isoflurane administration: the coherent frequency. Br J Anaesth. 1993;71:633–41.

    Article  CAS  PubMed  Google Scholar 

  140. Sukhotinsky I, Zalkind V, Lu J, Hopkins DA, Saper CB, Devor M. Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABA A-active anesthetics. Eur J Neurosci. 2007;25:1417–36.

    Article  CAS  PubMed  Google Scholar 

  141. Sonner JM, Cascio M, Xing Y, Fanselow MS, Kralic JE, Morrow AL, Korpi ER, Hardy S, Sloat B, Eger 2nd EI, Homanics GE. Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol Pharmacol. 2005;68:61–8.

    CAS  PubMed  Google Scholar 

  142. Jurd R, Arras M, Lambert S, et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J. 2003;17:250–2.

    CAS  PubMed  Google Scholar 

  143. Borghese CM, Xiong W, Oh SI, Ho A, Mihic SJ, Zhang L, Lovinger DM, Homanics GE, Eger 2nd EI, Harris RA. Mutations M287L and Q266I in the glycine receptor alpha1 subunit change sensitivity to volatile anesthetics in oocytes and neurons, but not the minimal alveolar concentration in knockin mice. Anesthesiology. 2012;117:765–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Putzke C, Hanley PJ, Schlichthorl G, Preisig-Muller R, Rinne S, Anetseder M, Eckenhoff R, Berkowitz C, Vassiliou T, Wulf H, Eberhart L. Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1. Am J Physiol Cell Physiol. 2007;293:C1319–26.

    Article  CAS  PubMed  Google Scholar 

  145. Steinberg EA, Wafford KA, Brickley SG, Franks NP, Wisden W. The role of K(2)p channels in anaesthesia and sleep. Pflugers Arch. 2015;467:907–16.

    Article  CAS  PubMed  Google Scholar 

  146. Herold KF, Sanford RL, Lee W, Schultz MF, Ingolfsson HI, Andersen OS, Hemmings Jr HC. Volatile anesthetics inhibit sodium channels without altering bulk lipid bilayer properties. J Gen Physiol. 2014;144:545–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, NY, USA

    Hugh C. Hemmings Jr. MD, PhD, FRCA

  2. Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA

    Karl F. Herold MD, PhD

Authors
  1. Hugh C. Hemmings Jr. MD, PhD, FRCA
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karl F. Herold MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hugh C. Hemmings Jr. MD, PhD, FRCA .

Editor information

Editors and Affiliations

  1. Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Anthony R. Absalom

  2. Department of Anesthesia, Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA

    Keira P. Mason

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Hemmings, H.C., Herold, K.F. (2017). Mechanisms of Intravenous Anesthetic Action. In: Absalom, A., Mason, K. (eds) Total Intravenous Anesthesia and Target Controlled Infusions. Springer, Cham. https://doi.org/10.1007/978-3-319-47609-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-47609-4_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-47607-0

  • Online ISBN: 978-3-319-47609-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation