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Anaesthesiology
Mechanisms of Anesthesia and Consciousness
Built from Barash Clinical Anesthesia, 9th Edition
What’s inside
7 sections · 197 slides
Overview
- Scope of this topic
- Reasons anesthetic mechanisms are hard to study
- Framework of the chapter
What Is Anesthesia?
- Limits of a broad definition of general anesthesia
- Components of the anesthetic state
- Anesthesia as a set of behavioural components
- Difficulty of studying anesthesia in simple organisms
- Consciousness as an unsettled concept
- Neural inertia
- Reversal of sedation by arousal pathways
- Minimum alveolar concentration
- Advantages of MAC as a potency measure
- Limitations of MAC
- Dependence of MAC on the chosen endpoint
- Depth of anesthesia monitors
- Case for individualised depth monitoring
Chemical Nature of Anesthetic Target Sites
- Meyer-Overton rule
- Solubility plotted against anesthetic potency
- Octanol/water partition coefficient
- Candidate sites suggested by solvent properties
- Exceptions to the Meyer-Overton rule
- Enantioselectivity of anesthetic potency
- Implication of the exceptions
- Lipid versus protein targets
- Lipid theories of anesthesia
- Membrane nanodomains and renewed interest in lipids
- Current standing of the lipid contribution
- Protein theories of anesthesia
- Why membrane proteins are the likely targets
- Two kinds of anesthetic binding site on membrane proteins
- Site-directed mutagenesis as evidence for binding
- Photoaffinity labelling
- Structure of the GABA-A receptor
- Intersubunit binding sites identified by photolabelling
- Intrasubunit binding sites
- Anesthetic binding sites on the GABA-A receptor
- Reading the receptor images
- Cryo-electron microscopy of anesthetic complexes
- Structural confirmation of GABA-A binding sites
- Hydrogen bonding of neurosteroids to the alpha subunit
- Limitations of structural snapshots
- Prospects for structure-guided anesthetic design
- Standing of the protein binding evidence
- Unanswered questions about anesthetic-protein interaction
Effects on Nerve Cell Function
- Two routes to disrupting neuronal function
- Determinants of neuronal excitability
- Anesthetic hyperpolarization of neurons
- Threshold potential and action potential size
- A small change in spike size with large consequences
- Small excitability effects with clinical significance
- Synaptic transmission as the likely site of action
- Prolongation of inhibitory postsynaptic currents
- Presynaptic inhibition of glutamate release
- Anesthetic effects on inhibitory transmitter release
- Mechanism of reduced transmitter release
- Postsynaptic effects on excitatory transmission
- Postsynaptic effects on inhibitory transmission
- Summary of cellular neurophysiology
Potential Anesthetic Targets
- Criteria for a relevant anesthetic target
- Genetic proof of a functional target
- Value of a targeted point mutation
- Candidate anesthetic target proteins
- Reading the target protein summary
- GABA-A receptors
- Three anesthetic effects on GABA-A channel behaviour
- Significance of potentiation versus direct gating
- Volatile anesthetic potentiation of GABA currents
- Single channel effects of anesthetics
- Increased GABA affinity as the unifying explanation
- Subunit selectivity of different anesthetics
- Chimeric receptors and critical amino acids
- Drug-specific amino acid requirements
- Alpha subunit mouse mutants
- Phenotype of the double mutant alpha-1 strain
- Beta-3 subunit knockin mice
- Loss of anesthetic sensitivity in beta subunit mutants
- Selective effects of the beta-3 mutation on drug side effects
- Forebrain beta-3 and beta-2 subunit evidence
- Status of GABA-A as an anesthetic target
- Hyperpolarization-activated cyclic nucleotide-gated channels
- HCN channel structure and function
- Anesthetic inhibition of HCN currents
- Stereoselective inhibition of HCN1 by ketamine
- HCN channel inhibition and knockout mouse sensitivity
- HCN knockout mouse phenotypes
- Remaining gap in HCN evidence
- Background potassium channels
- Discovery in invertebrate neurons
- Two-pore domain potassium channel family
- Agent-specific responses of TASK and TREK channels
- Volatile anesthetic activation of background potassium channels
- Reading the background potassium channel figure
- TREK-1 knockout mouse phenotype
- Volatile anesthetic resistance without TREK-1
- Presynaptic role of TREK-1
- TASK channel knockout results
- Status of TREK-1 as an anesthetic target
- Voltage-dependent sodium channels
- Evidence that some sodium channel subtypes are sensitive
- Genetic evidence on sodium channels
- Standing of sodium channels as targets
- T-type calcium channels
- Distribution and function of T-type channels
- Knockout evidence for T-type channel isoforms
- Interpretation of the T-type channel data
- Standing of T-type channels
- Voltage-gated potassium channels
- Origin of the Shaker channel name
- Volatile activation of Shaker-family channels
- Genetic and pharmacologic evidence for Shaker channels
- Binding evidence for Kv1.2
- Glutamate-activated ion channels
- NMDA receptor subunit composition
- Selective anesthetic sensitivity of NMDA currents
- Nitrous oxide inhibition of NMDA currents
- Obstacles to NMDA mouse genetics
- Interpretation of the NMDA genetic data
- Nematode evidence for nitrous oxide
- Ketamine bound within the NMDA receptor
- Structural evidence for the ketamine binding site
- Mitochondrial complex I
- Mouse and human complex I sensitivity
- Clinical correlate of complex I sensitivity
- Synaptic vesicle release machinery
- Allelic differences in syntaxin mutants
- Conservation of the syntaxin mechanism
- Binding of anesthetics to the SNARE complex
- Overall standing of the candidate targets
Anatomic Sites of Anesthetic Action
- Where each component of anesthesia is produced
- Spinal cord as the site of immobility
- Goat cerebral circulation experiments
- Spinal mechanisms underlying MAC
- Brainstem control of respiration
- Brainstem cardiovascular reflexes
- Shared circuitry of sleep and anesthesia
- Stages of non-rapid eye movement sleep
- Resemblance of anesthetic EEG to sleep stages
- Limits of the sleep analogy
- Arousal and awareness as components of consciousness
- Sedation contrasted with general anesthesia
- Brain regions implicated in anesthetic-induced unconsciousness
- Reading the network and nuclei diagram
- The reticular activating system
- Reticular formation and arousal
- The sleep switch between wake and sleep nuclei
- Preoptic nuclei and sedation
- Dexmedetomidine and preoptic neurons
- Separation of sleep architecture from anesthetic transition
- The tuberomammillary nucleus
- Genetic evidence linking propofol to the tuberomammillary nucleus
- Orexin and the perifornical area
- Asymmetry between induction and emergence
- The lateral habenula
- Rostral medial tegmental nucleus
- Mesopontine tegmental anesthetic locus
- Ventral tegmental area and locus coeruleus
- Nucleus basalis of Meynert
- Thalamic relay nuclei during anesthesia
- Thalamic reticular and medial nuclei
- Centromedian nuclei and thalamocortical coupling
- Cerebral cortex and awareness
- Disruption of cortical feedback connections
- Human evidence and molecular basis of feedback loss
- Loss of information representation and integration
- Default mode and ventral attention networks
- The anterior insula and conscious access
- Hippocampus and anesthetic amnesia
- Alpha-5 GABA-A receptors and memory suppression
- Extrasynaptic receptors and hippocampal assemblies
- Summary of anatomic sites
Conclusions
- No single anatomic or physiologic locus
- Refutation of the unitary theory of anesthesia
- Outlook for anesthetic mechanism research
- Key points to carry forward
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- Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition