MECHANISMS OF ANESTHESIA AND CONSCIOUSNESS-STUDENT.pptx

MECHANISMS OF ANESTHESIA AND CONSCIOUSNESS NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 KEY POINTS • General anesthesia consists of five components: Unconsciousness, amnesia, analgesia, immobility, and attenuation of autonomic response. • An unconscious state consists of alterations in both awaren...

MECHANISMS OF ANESTHESIA AND CONSCIOUSNESS NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 KEY POINTS • General anesthesia consists of five components: Unconsciousness, amnesia, analgesia, immobility, and attenuation of autonomic response. • An unconscious state consists of alterations in both awareness and arousal (wakefulness). • Interaction of the ventrolateral preoptic nucleus and tuberomamillary nucleus creates a sleep-wake cycle which can be altered by anesthetics. • Induction and emergence occur asymmetrically. • The locus coeruleus is the primary source of NE to the cerebral cortex and the nucleus basalis of Meynert, which in turn is the primary source of cholinergic input to the cerebral cortex. The locus coeruleus is the primary site of action of dexmeditomidine. 2 KEY POINTS • Anesthesia generally impairs short-term memory while leaving long-term memory intact. Differentiating these mechanisms is important and discussed in the slides. • Immobility is thought to be mediated primarily at the spinal cord level. • The target for anesthetic action is now thought to be protein rather than lipid. This continues to satisfy the Meyer-Overton Rule. While other sites are believed to contribute, the primary sites of action appear to be at the synapse. • In addition to the ligand gated ion channels (primarily glutamate, GABA and the nAChR mediated channels), the voltage gated Na+, 2 pore K+, and HCN channels also appear to play a role. • The volatile and IV anesthetics work via multiple mechanisms as opposed to our earlier “understanding” of the unitary theory of anesthesia. 3 WHAT IS GENERAL ANESTHESIA? • A drug-induced reversible depression of the CNS resulting in the loss of response to and perception of all external stimuli. • More accurately a group of components: • • • • • Unconsciousness Amnesia Analgesia Immobility Attenuation of autonomic response 4 UNCONSCIOUSNESS • Consciousness • Awareness • Ability to process, integrate, and store information in order to interact with the environment • General anesthetics impair connectivity and integration between cortical structures • A finding similar to what is seen with NREM sleep • Also likely interfere with thalamic input to the cerebral cortex and other subcortical structures • Wakefulness or Arousal • Receptivity to the external environment • Mediated through subcortical structures, in particular the RAS 5 AWARENESS AND AROUSAL (WAKEFULNESS) 6 EVERS SLEEP/WAKE CYCLE 7 BARAS SLEEP/WAKE CYCLE AND ANESTHESIA • The TMN – VLPO acts as a sleep/wake switch • Each inhibits the other when activated • It is not clear what activates the switching from an asleep to awake state • Orexin from the perifornical area activates the: • • • • Thalamus Ventral Tegmental Area (VTA) Locus coeruleus (LC) Tuberomammilary nucleus (TMN) • Orexinergic stimulation of the TMN stabilizes the sleep-wake switch • All of which release neurotransmitters (dopamine, histamine, NE) which stimulate the cerebral cortex • Cholinergic stimulation of the cerebral cortex results from Ach release from the nucleus basalis of Meynert (NBM) in response to histaminergic stimulation from the TMN and 8 noradrenergic stimulation from the LC LIKELY ANESTHETIC TARGETS FOR UNCONSCIOUSNESS 9 • Cerebral cortex • Disruption of information transfer between regions • Looks much like NREM sleep • Thalamus • Likely important in both arousal and awareness, but the mechanisms aren’t clear • Tuberomamillary nucleus (TMN) • Provides the only histaminergic (excitatory) input to the cerebral cortex • Inhibited by GABAergic stimulation BARASH 57 LIKELY ANESTHETIC TARGETS FOR UNCONSCIOUSNESS 10 • Ventrolateral preoptic nucleus (VLPO) • Via inhibition of the TMN • Perifornical area (PF) • Plays an important role in emergence • Orexin stimulation of the TMN • Nucleus basalis of Meynert (NBM) • Primary source of cholinergic input to cortex and thalamus BARASH 57 LIKELY ANESTHETIC TARGETS FOR UNCONSCIOUSNESS 11 • Locus coeruleus (LC) • Inhibited by GABA • Primary source of noradrenergic input to cortex and NBM • Presumed to be the primary site of action of dexmedetomidine • ???? Many things we don’t yet know BARASH 57 AMNESIA • Anesthesia (generally) prevents formation of new memories, but leaves previous memories intact • Short-Term Memory • Explained by post-tetanic potentiation • Long-Term Memory • Dependent on: • Long-term synaptic potentiation • Enhanced synaptic transmission following repeated stimulation of the presynaptic neuron • Structural changes requiring protein transcription and synaptic remodeling • Increased expression of postsynaptic NMDA receptors and VDCCs • Stable 12 AMNESIA • Long-Term Memory • Exact mechanisms of long-term memory formation not known • Critical steps are known to occur in the: • Hippocampus • Amygdala • Not stored in the hippocampus or amygdala • Conversion of short-term to long-term memory • Requires anatomic change in the synapse • Therefore takes time 13 AWARENESS UNDER ANESTHESIA • Memory • Conscious memory (explicit) • Spontaneous recall and recognition memory • Ablated by general anesthesia • 0.45 MAC Isoflurane or 0.6 MAC N2O • Unconscious memory (implicit) • Altered performance or behavior due to experiences that aren’t consciously remembered • + ablated by general anesthesia • 0.6 MAC Isoflurane 14 AWARENESS UNDER ANESTHESIA • Incidence of awareness with recall (conscious memory) • 1-5/1000 general anesthetics • Higher risk groups • Cesarean section 0.4% • Cardiac surgery 1.14% - 1.5% • Major trauma 11% - 43% 15 AWARENESS MONITORING • Based on processed EEG (Fourier transformation) and presence and ratio of burst suppression or somatosensory evoked potentials • BIS (Bispectral Index) assesses: • Beta power • Bispectral coherence • Burst suppression • Results in a dimensionless number between 0 (isoelectric) and 100 (awake) • Range for GA ~ 40-60 • Widely used • Studies have shown the BIS monitor to be no more successful in preventing awareness than a protocol using MAC 16 FOURIER TRANSFORMATION EVERS 17 ANALGESIA • Volatile anesthetics • Biphasic dose response • Appear to increase nocioceptive stimulation at ~10% MAC • At higher concentrations this effect is reduced • Possibly through inhibition of Na+ channels and decreased glutamate release • Opioids • Non-opioids • • • • • • • • α2 agonists Neostigmine Ketamine Barbiturates Nitrous oxide Xenon Adenosine Etc 18 IMMOBILITY • Mediated primarily at the spinal cord level • Various anesthetics work by different mechanisms in the spinal cord affecting: • Afferent pathways • Efferent pathways • Reflex spinal arcs • What is MAC? • MAC of Isoflurane • Brain only 2.9% • Entire body 1.2% • Body excluding brain 0.8% 19 ATTENUATION OF AUTONOMIC RESPONSE • Multiple anesthetics have been shown to impair autonomic homeostatic mechanisms • Respiratory • Cardiac • Temperature regulation • Mediated by the hypothalamus 20 ANESTHETIC TARGET SITES LIPID PROTEIN Neuron Synapse Presynaptic Postsynaptic Ion Channels Voltage dependent Ligand Gated 21 22 ANESTHETIC TARGET SITES-LIPID THEORY • Meyer-Overton Rule • Recognized early on that potency of anesthetic gases was related to their solubility in olive oil • Dissimilar structures all obeyed the rule, so they came up with a presumed single mechanism of anesthesia • Unitary Theory of Anesthesia • The initial belief was that anesthetics, being lipid soluble, dissolved in the lipid bilayer and produced changes in the membrane structure sufficient to induce anesthesia BARASH 51 PROBLEMS WITH THE LIPID THEORY • Similar structure with similar octanol:water partition coefficient with no, or opposite, effect of halogenated anesthetics. • Cutoff effect • Anesthetic potency increases with increasing chain length to a certain point, after which the compound no longer produces anesthesia. • Enantiomers show different anesthetic potency despite identical octanol:water partition coefficient. 23 ANESTHETIC TAGET SITES – PROTEIN THEORY • Best explanation of both the Meyer-Overton Rule and exceptions to it is anesthetic binding of specific lipophilic amino acids. • A similar structure could bind the same binding pocket in a different way that produced no, or different, effect. • The cutoff effect would be explained by a structure becoming to large to fit in the binding pocket. • The different shape of enantiomers could preclude binding with a particular binding site. 24 ANESTHETIC EFFECTS ON THE NERVOUS SYSTEM Neuronal Synaptic Presynaptic Postsynaptic ION CHANNELS Voltage gated Ligand gated Glutamate GABA Other 25 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Neuronal excitability determined by: • Resting membrane potential • Threshold potential • Size of an action potential • Anesthetics have been shown to hyperpolarize nerves and this effect correlates with anesthetic potency • May have some effect, but certainly not the primary mechanism of anesthetics • Likely ion channels involved: • Na+ • K+ (background or “leak” channels) 2P/4TM channels • Volatiles • HCN • Volatiles, propofol, ketamine 26 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Synaptic Effects • Synapse is the most likely primary site of action of general anesthetics • Presynaptic • Volatile anesthetics inhibit release of glutamate (excitatory neurotransmitter) • Likely ion channels involved: • Na+ and 2P/4TM K+ channels • Ca++ questionable • Postsynaptic • Marked potentiation of electrical response to GABA (inhibitory neurotransmitter) • Volatiles, propofol, etomidate, barbiturates, neurosteroids • Ion channel involved • Cl27 28 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • BARASH 5-2 • Need to put on Student and Mine • Postsynaptic potentiation of GABA-activated chloride current. • • • • • Volatiles Propofol Etomidate Barbiturates Neurosteroids 29 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Postsynaptic potentiation of GABA-activated chloride current. • • • • • Volatiles Propofol Etomidate Barbiturates Neurosteroids ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Ion Channels • Voltage Gated • Discussed earlier • Summary • As a whole, not highly sensitive to anesthetics, but Na +, 2P/4TM K+, and HCN channels are likely targets • Ligand Gated • Glutamate • GABA • Other • nAChr, glycine, 5-HT3 (All structurally related to GABA receptors) 30 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Ligand-gated ion channels • Glutamate-activated • AMPA • Kainate • NMDA • Inhibitors of NMDA-activated current • Ketamine* • Nitous oxide • Xenon • Volatiles? 31 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Ligand-gated ion channels • GABA-activated • Primary inhibitory neurotransmitter in CNS • Results in Cl- entry and a more negative resting membrane potential • Types of effect on GABAA receptor channels • Potentiation • Direct gating • Inhibition • Different anesthetics act at different subtypes of the GABA receptor 32 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Effects of anesthetics on the GABA receptor • Potentiation • Create a conformational change in the receptor that increases the affinity of the receptor for GABA • Increases the frequency with which the channel opens or the time it remains open • Results in increased Cl- current in the presence of low concentrations of GABA BARASH 33 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Effects of anesthetics on the GABA receptor • Direct gating • Activation of the GABAA channel in the absence of GABA • Seen at supraclinical concentrations of anesthetic • Inhibition • Ability to prevent GABA from opening the GABAA channel • Typically seen at high anesthetic concentrations • May explain some of the conflicting study results 34 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Ligand-gated ion channels • Other • Nicotinic acetylcholine receptor • nAChR activation enhances higher-order brain function such as learning, memory and attention • Inhibition likely important in the hypnotic and amnestic effects of volatiles • Does not appear to be involved in immobility • 5-HT3 receptor • May play a role, but unclear • Volatiles increase 5-HT3-activated current • Thiopental inhibits current • Propofol – no effect 35 ELECTROPHYSIOLOGIC EFFECTS OF ANESTHETICS • Ligand-gated ion channels • Other • Glycine receptor • Prevalent in brainstem and spinal cord • Anesthetics act via potentiation, increasing the affinity of the receptor for glycine • Activation produces inhibition via opening of a Cl- channel and hyperpolarization • Likely target for immobilization component of anesthesia produced by volatiles • Potentiated by: • Volatiles • Propofol • Barbiturates • Neurosteroid anesthetics (Alphaxolone, Allopregnenalone) • Not potentiated by: • Etomidate – explain graphic slide* • Ketamine 36 GRAPHIC SUMMARY 1 EVERS 37 GRAPHIC SUMMARY 2 BARASH 38 SOURCES • Barash Clinical Anesthesia 8th edition. 2017 • Flood Stoelting’s Pharmacology and Physiology in Anesthetic Practice 6th edition. 2022 • Evers Anesthetic Pharmacology 2nd edition. 2011 39