Mechanisms of general anaesthesia. Nick Franks FRCA, FMedSci, FRS Imperial College London

Transcription

1 Mechanisms of general anaesthesia Nick Franks FRCA, FMedSci, FRS Imperial College London

2 Etomidate Thiopental Propofol Halothane Isoflurane Sevoflurane Xenon Nitrous oxide

3 Franks and Lieb Nature (1994)

4 Traditionally, anaesthetic theories focussed on the lipid bilayer

5 Franks and Lieb Nature (1984)

6 Even the simplest anaesthetics bind to small cavities on proteins Franks et al. Biophys. J (1998)

7 Anaesthetics cause no structural changes at their binding sites Bhattacharya et al. JBC 275, (2000) Liu et al. FASEB J.19, 567(2005)

8 General anaesthetic EC 50 concentrations Loss of consciousness (failure to respond to a verbal command) Xenon Isoflurane Thiopental Propofol 1000 μm 90 μm 10 μm 0.4 μm

9 Anaesthetic optical isomers generally differ in potency Ratio of anaesthetic potencies in animals R(+) etomidate S(-) etomidate >10 Tomlin et al. (1998) S(-) thiopental R(+) thiopental 2-4 Andrews & Mark (1982) S(+) isoflurane R(-) isoflurane ~1.5 Dickinson et al. (2000)

10 The three most important anaesthetic targets GABA A receptors Two-pore K + channels NMDA receptors Franks Nature Rev. Neuroscience 9, 370 (2008)

11 GABA A receptors are the principal targets Tomlin et al. Anesthesiology 88, 708 (1998)

12 GABA A receptors are the principal targets Tomlin et al. Anesthesiology 88, 708 (1998)

13 GABA A receptors are the principal targets In vivo and in vitro stereoselectivities match Tomlin et al. Anesthesiology 88, 708 (1998)

14 GABA A receptors are the principal targets Tomlin et al. Anesthesiology 88, 708 (1998)

15 GABA A receptors are the principal targets Enhanced apparent GABA affinity causes prolongation of synaptic currents Tomlin et al. Anesthesiology 88, 708 (1998) Dickinson et al. Anesthesiology 96, 884 (2002)

16 GABA A receptors are the principal targets GLUTAMATE Tomlin et al. Anesthesiology 88, 708 (1998) Dickinson et al. Anesthesiology 96, 884 (2002)

17 Knock-in mice can help determine the relevance of anaesthetic targets & pathways The β3n265m Knock-in mouse Jurd et al. FASEB J (2003)

18 Anaesthetic binding to pre-existing states can explain kinetics GABA b 2 g 2 a 1 a 1 b 2

19 Anaesthetic binding to pre-existing states can explain kinetics Nury et al. Nature 469, 428 (2010)

20 Anaesthetic binding to pre-existing states can explain kinetics

21 Anaesthetic binding to pre-existing states can explain kinetics

22 Anaesthetic binding to pre-existing states can explain kinetics

23 Where do anaesthetics act in the brain? Anaesthetics act on a relatively small number of specific molecular targets Does this selectivity extend to neuronal pathways in the brain?

24 Switch between conciousness and unconsciousness occurs over a narrow range of anaesthetic concentrations Smith et al. Anesthesiology 81, 820 (1994) Katoh et al. Anesthesiology 92, 55 (2000)

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26 1920 We watch closely those who sleep

27 We watch closely those who sleep Safe in sleep Association of Anaesthetists of Great Britain and Ireland

28 It is divine to alleviate pain Royal College of Anaesthetists Safety while we watch College of Anaesthetists of Ireland

29 Neuronal pathways of sleep and arousal Inhibition of the ascending arousal system in the brain stem, hypothalamus and basal forebrain Activation of the sleeppromoting systems in the hypothalamus and basal forebrain

30 Anaesthesia and sleep - functional brain imaging Propofol Kaisti et al (2003) nonrem sleep Kajimura et al (1999) Sevoflurane Kaisti et al (2003)

31 Selective anatomical targets - Cortex Cortical connectivity is disrupted at LOC Hudetz et al Anesthesiology 111:231-9 (2009)

32 Selective anatomical targets - Cortex Cortical connectivity is disrupted at LOC with midazolam and sleep Cortical connectivity is disrupted at LOC Ferrarelli et al PNAS 107: (2010)

33 The role of the thalamus in corticocortical communication Guillery and Sherman Neuron 33: (2002)C

34 Selective anatomical targets - Cortex Cortical connectivity is disrupted at LOC Hudetz et al Anesthesiology 111:231-9 (2009)

35 Selective thalamic inhibition eliminates late somatosensory potentials mimicking the effects of anesthetics Midline and intralaminar nuclei project widely to the cortex as well to the striatum and limbic areas O Brien & Rosenblum J. Neurophysiol 37, 430 (1974)

36 Key points Despite their diversity, anaesthetics act by binding directly to specific ion channel/receptor targets Anaesthetics bind to some states of the channel preferentially and this shifts the equilibrium between open and closed states For the intravenous anaesthetics, the GABA A receptor is overwhelmingly the most important target It seems probable that anaesthetics act preferentially on some neuronal circuits to depress consciousness, and the initial state of loss of consciousness resembles deep sleep

37 Thanks for listening