Handbook of Clinical Anesthesia

Chapter 5

Mechanisms of Anesthesia and Consciousness

Despite the importance of general anesthesia and more than 100 years of active research, the molecular mechanisms responsible for anesthetic action remain one of the unsolved mysteries of pharmacology (Evers AS, Crowder CM: Mechanisms of anesthesia and consciousness. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 93–114). Molecular and genetic tools are becoming available that should allow for major insights into anesthetic mechanisms in the next decade. A wide variety of structurally unrelated compounds (steroids to elemental xenon) are capable of producing anesthesia, suggesting that multiple molecular mechanisms may be operative.

  1. What is Anesthesia?
  2. The components of the anesthetic state include unconsciousness, amnesia, analgesia, immobility, and attenuation of autonomic nervous system responses to noxious stimulation.
  3. Anesthesia is always defined by drug-induced changes in behavior or perception. As such, anesthesia can only be defined and measured in the intact organism.
  4. Central to the mechanism of sleep is a set of hypothalamic nuclei that appear to form an awake/sleep switch mechanism.
  5. The thalamus and cortex maintain wakefulness and consciousness through complex interactions that may involve intrinsic oscillators and widespread synaptic communication.
  6. Awareness and consciousness are thought to emerge from communication between the prefrontal cortex and multiple cortical and subcortical areas that have distributed representations of perception.

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  1. How is Anesthesia Measured?
  2. To study the pharmacology of anesthetic action, a quantitative measurement of anesthetic potency is essential. This is provided in the concept of minimum alveolar concentration (MAC).
  3. MAC is defined as the alveolar partial pressure (PA) of a gas (end-tidal concentration) at which 50% of humans will not move in response to a surgical skin incision (or in animals, in response to a noxious stimulus such as a tail clamp).
  4. MAC is the standard for determining the potency of volatile anesthetics.
  5. MAC is reproducible and constant over a wide range of species.
  6. The quantal nature of MAC (either anesthetized or not anesthetized with no partially anesthetized data point possible) makes it difficult to compare MAC measurements with concentration–response curves obtained in vitro.
  7. A MAC equivalent for intravenous (IV) anesthetics is the plasma concentration of the drug required to prevent movement in response to a noxious stimulus in 50% of subjects.
  8. The PA is an accurate reflection of the anesthetic concentration in the plasma and brain tissue at 37°C.
  9. Because of the limitations of MAC, monitors that measure some correlate of anesthetic depth have been introduced into clinical practice. These monitors convert spontaneous electroencephalogram (EEG) waveforms into a single value that correlates with anesthetic depth for some general anesthetics.
  10. Anesthetic depth monitors may reduce the incidence of awareness during anesthesia (estimated incidence, 0.1 to 0.2%), reduce the amount of anesthetic used, and hasten emergence and recovery room discharge.
  11. It is controversial whether anesthetic depth monitors are superior to MAC, to standardized dosing of IV anesthetics, or to clinical indicators of anesthetic depth.

III. Where in the Central Nervous System do Anesthetics Work?

  1. Plausible sites of action of general anesthetics include the spinal cord, brainstem, and cerebral cortex. Peripheral

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sensory receptors are not important sites of anesthetic action.

  1. Spinal Cord
  2. The spinal cord is probably the site at which anesthetics act to inhibit purposeful responses to noxious stimulation (end point for determination of MAC).
  3. Anesthetic actions at the spinal cord cannot explain either amnesia or unconsciousness.
  4. Brainstem, Hypothalamic, and Thalamic Arousal Systems
  5. It has long been speculated that the reticular activating system, a diffuse collection of brainstem neurons, is involved in the effects of general anesthetics on consciousness.
  6. A role for the brainstem in anesthetic action is supported by changes in somatosensory evoked potentials (increased latency and decreased amplitude indicating that anesthetics inhibit information transfer through the brainstem).
  7. Within the reticular formation is a set of pontine noradrenergic neurons (locus coeruleus) that innervates a number of targets in basal forebrain and cortex. It is likely that the tuberomammillary nucleus and associated pathways is a site of sedative action of anesthetics (propofol, barbiturates) that act on γ-aminobutyric acid (GABA) receptors.
  8. Increasing evidence indicates that inhalational anesthetics can depress the excitability of thalamic neurons, thus blocking thalamocortical communication and potentially resulting in the loss of consciousness.
  9. Cerebral Cortex.Anesthetics alter cortical electrical activity as evidenced by the consistent changes in surface EEG patterns recorded during anesthesia. Anesthetics produce a variety of effects on inhibitory transmission in the cortex.
  10. How do Anesthetics Interfere with the Electrophysiologic Function of the Nervous System?

There are multiple mechanisms by which anesthetics may inhibit vital central nervous system (CNS) functions.

  1. Pattern Generators.Evidence that clinical concentrations of anesthetics have effects on pattern-generating neuronal circuits in the CNS is provided by the observation that most anesthetics exert profound effects on the frequency

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and pattern of breathing (respiratory pattern generators in the brainstem).

  1. Neuronal Excitability.Evidence indicates that anesthetics can hyperpolarize (i.e., create a more negative resting membrane potential) spinal motor neurons and cortical neurons.
  2. Synaptic functionis widely considered to be the most likely subcellular site of general anesthetic action.

Neurotransmission across both excitatory and inhibitory synapses is markedly altered by general anesthetics.

  1. Enhancement of inhibitory transmission is observed with propofol, etomidate, and inhalational anesthetics.
  2. Clinical concentrations of general anesthetics can depress inhibitory postsynaptic potentials in the hippocampus and spinal cord.
  3. Presynaptic Effects.Neurotransmitter release from glutamatergic synapses is inhibited by clinical concentrations of volatile anesthetics.
  4. Postsynaptic Effects.A wide variety of anesthetics (barbiturates, etomidate, propofol, volatile anesthetics) affect synaptic function by enhancing the postsynaptic response to GABA.
  5. Anesthetic Actions on Ion Channels

The notion that voltage-dependent sodium channels are insensitive to anesthetics may be incorrect.

  1. Anesthetic Effects on Voltage-Dependent Ion Channels.A variety of ion channels can sense a change in membrane potential and respond by either opening or closing their pores.
  2. Voltage-dependent calcium channelsserve to couple electrical activity to specific cellular functions, usually by opening to allow calcium to enter the cell and by activating calcium-dependent secretion of neurotransmitters into the synaptic cleft. Anesthetics inhibit these channels at concentrations estimated to be two to five times those necessary to produce anesthesia. This insensitivity makes these channels unlikely major targets of anesthetic action.
  3. Potassium channelsinclude voltage-gated

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second messenger and ligand-activated inward rectifying channels. High concentrations of volatile and IV anesthetics are required to affect the function of voltage-gated potassium channels. Rectifying potassium channels are relatively insensitive to sevoflurane and barbiturates.

  1. Anesthetic Effects on Ligand-Gated Channels.Selective effects of anesthetics on these channels may influence excitatory and inhibitory neurotransmission in the CNS.
  2. Glutamate-activated ion channelsinclude N-methyl-D-aspartate (NMDA) receptors to which ketamine (not other anesthetics) selectively binds, suggesting that this receptor may be the principal molecular target for the anesthetic actions of this drug.
  3. GABA-activated ion channelsmediate the postsynaptic response to GABA (the most important inhibitory neurotransmitter in the CNS) by selectively allowing chloride ions to enter and thereby hyperpolarizing neurons (inhibition).
  4. Data are most consistent with the idea that clinical concentrations of anesthetics produce a change in the conformation of GABAAreceptors.
  5. Despite the similar effects of many anesthetics on GABAAreceptor function, evidence suggests that various anesthetics do not act by binding to a single binding site on the channel protein.
  6. Anesthetic Effects on Background Potassium Ion Channels
  7. Certain potassium channels (background or leak channels) are activated by both volatile and gaseous anesthetics.
  8. These channels tend to open at all voltages, producing a leak current that may regulate the excitability of neurons (their role in producing anesthesia is suggested by genetic evidence).
  9. What is the Chemical Nature of Anesthetic Target Sites?
  10. The Meyer-Overton Rule
  11. Although there is a consensus that anesthetics act by affecting the function of ion channels, considerable controversy remains as to the molecular interactions underlying these functional effects.
  12. Because a wide variety of structurally unrelated compounds obey the Meyer-Overton rule (the potency of anesthetic gases is correlated to their solubility in olive oil), it has been reasoned that all anesthetics are likely to act at the same molecular site (unitary theory of anesthesia).

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  1. The anesthetic site is likely to be amphipathic (i.e., having both polar and nonpolar characteristics).
  2. Exceptions to the Meyer-Overton Rule
  3. Halogenated compounds (e.g., flurothyl) exist that are structurally similar to the inhaled anesthetics but are convulsants rather than anesthetics.
  4. In the series of n-alkanols, anesthetic potency increases from methanol dodecanol, and all longer alkanols lack anesthetic properties (cutoff effect).
  5. Compounds that deviate from the Meyer-Overton rule suggest that anesthetic target sites are also defined by other properties, including size and shape.
  6. The fact that enantiomers of anesthetics differ in their potency as anesthetics argues against the Meyer-Overton rule and favors a protein-binding site.
  7. Pressure Reversal.Evidence indicates that pressure reverses anesthesia by producing excitation that physiologically counteracts depression rather than by acting as an anesthetic antagonist at the anesthetic site of action.
  8. Lipid versus Protein Targets.Anesthetics may interact with several possible molecular targets to produce their effects on the function of ion channels and other proteins. Anesthetics may dissolve in the lipid bilayer, causing physiochemical changes in the membrane structure that alter the ability of membrane proteins to undergo conformational changes important for their function. Alternatively, anesthetics may bind directly to proteins (either ion channel or modulatory proteins) to interfere with binding of a neurotransmitter or the ability of the protein to undergo conformational changes important for its function.
  9. Lipid Theories of Anesthesia
  10. The lipid theory of anesthesia postulates that anesthetics dissolve in lipid bilayers of biologic membranes and produce anesthesia when they reach a critical concentration in the membrane. (Membrane–gas solubility coefficients of anesthetic gases in pure lipids correlate with anesthetic potency.)
  11. The magnitude of membrane perturbations produced by clinical concentrations of anesthetics is small and unlikely to disrupt nervous system function. As a result, most investigators do not consider membranes or lipids as the most likely targets of general anesthetics.

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  1. Protein Theories of Anesthesia.The Meyer-Overton rule may also be explained by the interaction of anesthetics with hydrophobic sites on protein. Direct interactions of anesthetic molecules with proteins would also provide explanations for exceptions from this rule because any protein-binding site is likely to be defined by properties such as size and shape in addition to its solvent properties.
  2. Evidence for Anesthetic Binding to Proteins.A variety of physical techniques (e.g., nuclear magnetic resonance spectroscopy) have confirmed that anesthetic molecules can bind in the hydrophobic core of proteins and the size of the binding site can account for the cutoff effect.
  3. Current evidence strongly supports proteins rather than lipids as the molecular targets for anesthetic action.

VII. How are the Effects of Anesthetics on Molecular Targets Linked to Anesthesia in the Intact Organism?

  1. It is likely that anesthetics affect the function of a number of ion channels and signaling proteins, probably via direct anesthetic–protein interactions. A number of approaches have been used to try to link anesthetic effects observed at a molecular level to anesthesia in intact animals.
  2. Pharmacologic Approaches
  3. α2-Agonists decrease halothane MAC but also have their own inherent CNS depressant effects.
  4. Development of a specific antagonist for anesthetics would provide a useful tool for linking anesthetic effects at the molecular level to anesthesia in the intact organism.
  5. Evidence is consistent with the conclusion that volatile anesthetics affect the function of a large number of important neuronal proteins and that no one target is likely to mediate all of the effects of these drugs.
  6. Genetic Approaches
  7. In mammals, the most powerful genetic model organism is the mouse in which techniques have been developed to alter any gene of interest. The GABAAreceptor has been extensively studied using mouse genetic techniques (e.g., gene knockouts, gene knockins).
  8. Results from both invertebrate and vertebrate genetics indicate that multiple proteins control volatile anesthetic sensitivity.

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  1. The NMDA glutamate receptor is a likely primary target of nitrous oxide.
  2. The GABAAreceptor is the primary mediator for immobilization by etomidate, propofol, and pentobarbital.

VIII. Conclusions

  1. Anesthetic actions cannot be localized to a specific anatomic site in the CNS; rather, different components of the anesthetic state may be mediated by actions at disparate sites.
  2. Anesthetics preferentially affect synaptic function as opposed to action potential propagation.
  3. At a molecular level, it is likely that anesthetic effects are mediated by direct protein–anesthetic interactions.
  4. Numerous proteins are involved, suggesting that the unitary theory of anesthesia is incorrect and that there are at least several mechanisms of anesthesia.
  5. Different anesthetic targets may mediate different components of the anesthetic state.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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