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General Anesthesia: A more complex mechanism

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Common mechanism with aspects of consciousness ... Gar. Garrett and Grisham 3rd Edition. K Background (Leak) Channel Excitation ... – PowerPoint PPT presentation

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Title: General Anesthesia: A more complex mechanism


1
General AnesthesiaA more complex mechanism
The Meyer-Overton correlation and new research
into the mechanism of action of general
anesthesia.
2
Purposes of General Anesthesia(Inhaled and
Intravenous)
  • Amnesia
  • Analgesia
  • Immobility (muscle relaxation)
  • Loss of consciousness
  • Hypnosis
  • Suppression of noxious reflexes

3
Pharmacological Manipulation of the Neuronal Nexus
  • Various areas of CNS mediate desired effects
  • Unconsciousness
  • Common mechanism with aspects of consciousness
  • Cerebral cortex, thalamus, and reticular
    formation
  • High density of ?-aminobutyric acid (GABA-A),
    N-methyl-D-aspartate (NMDA) and acetylcholine
    (Ach) receptors
  • Subject to input from subcortical arousal systems

4
  • Amnesia
  • Hippocampus, amygdala and prefrontal cortex
  • Implicit memory recalled unconsciously (target
    of anesthesia)
  • Explicit memory recalled consciously
  • Use NMDA and non-NMDA receptors
  • Respond to NT glutamate and serotonergic
    interneurons

5
  • Immobility
  • Sensory and motor neurons
  • GABA-A receptor
  • Glutamate receptors for NMDA, alpha-amino-5-methyl
    -3-hydroxy-4-isoxazole propionic acid (AMPA) and
    kainite
  • Analgesia
  • Nocioception
  • Blocking occurs at glutamate, GABA-A or (micro)
    receptors in spinal cord

6
Meyer-Overton Correlation
  • Has been used to describe the mechanism of
    volatile anesthetics
  • Linear relationship between potency and lipid
    solubility
  • No longer accepted universally
  • Does appear in different levels of CNS
    integration
  • Molecular, subcellular and cellular mainly

7
Current Views of Anesthetic Mechanism
  • Solubilization within the neuronal membrane
  • Redistribution of lateral pressures
  • Alters conformation of membrane proteins (i.e.
    Na pump)
  • Anesthetics interact with many hydrophobic sites
  • Protein structures that form ion channels

8
  • Inhaled anesthetics act at lipid bilayer-protein
    interface
  • Weak electrostatic forces between membrane
    protein and anesthetic
  • Stimulation of K leak channels (neuronal
    hyperpolarization)
  • Ca2 sensitivity to general anesthesia

9
Presynaptic Inhibition
  • Three mechanisms of presynaptic inhibition
  • Mediating neuron causes Ca2 channels of
    presynaptic neuron to close (lt release of NT)
  • Ligand-gated receptors inhibit NT release
  • Ca2 independent (botulinum/tetanus)
  • Activate GABA-A gated Cl- channels
  • Also evidence that background K current (upon
    anesthetic induction) hyperpolarizes both
    pre/postsynaptic neurons

10
Postsynaptic Inhibition
  • Mediating neuron hyperpolarizes another neuron
  • Agonist binds to postsynaptic GABA-A receptor

11
Inhibitory Pathways
  • GABA
  • Key inhibitory NT within the brain
  • Two types (A and B)
  • GABA-A receptors increase Cl- conductance
    (postsynaptic)
  • Analogous ligands (agonists) aside from GABA
    interact with GABA receptors
  • Benzodiazepines, barbiturates, anesthetic
    steriods, volatile anesthetics and ethanol

12
GABA-A/B/C
  • GABA-A individual expression of the GABA-A
    receptor subunit composition and subunit isoforms
    can modify response to anesthetic
  • GABA-B linked via G proteins to K channels
  • ActivatedGABA-B receptors decrease Ca2
    conductance and inhibit cAMP production
  • No KNOWN association with anesthesia
  • GABA-C also ligand-gated Cl- channels

13
GABA-A Receptor
  • GABA-A receptors contain various subunits within
    the predominate structure
  • 1-6 a, 1-4 ß, 1-4 ?, d, e, 1-2 ?
  • 70-70 kDa glycoprotein
  • Contains 12 hydrophobic membrane-spanning domains
  • Two other GABA receptors (B and C)

14
GABA-A Receptor
Voet and Voet 2nd Edition
15
GABA-A Inhibition
  • Increase in Cl ion conductance after activation
    of GABA-A receptors by anesthesia
  • Causes localized hyperpolarization of the
    neuronal membrane
  • Increased threshold to depolarize (to form AP)
  • Increased conductance is due to an increase in
    the mean open time of the Cl ion channel

16
Formation of GABA
  • Initial step utilizes a-ketoglutarate (Krebs)
  • Transamination of a-ketoglutarate to form
    a-oxoglutarate transaminase (GABA-T or glutamate)
  • Glutamate is decarboxylated to form GABA by
    glutamate decarboxylase (GAD)

17
Degradation of GABA
  • Metabolized by GABA-T to form succinic
    semialdehyde
  • Glutamate is regenerated if in the presence of
    a-ketoglutarate
  • If not, succinic semialdehyde is oxidized by
    SSADH then succinic acid returns to Krebs cycle

18
Off Topic ?
  • GAD is also present in ß cells of pancreatic
    islets
  • GAD plays role in pancreatic endocrine function
  • Insulin and GAD coexist in the ß cells
  • Antibodies of the 64-kDa (GAD) occur in almost
    all patients with insulin-dependent diabetes
  • Presence of GAD antibodies appear to precede the
    clinical onset of the disease
  • GAD and development of Type-1 diabetes???

19
Glycine Receptor
  • Ogliomeric transmembrane protein composed of 3 a
    and 2 ß subunits
  • Agonists ß-alanine and taurine as well as
    ß-aminobutyric acid, ethanol and anesthetics as
    well as strychnine
  • Isofluorane and propofol are also allosteric
    effectors
  • Similar in structure to GABA-A receptor
  • GLYT-1 and GLYT-2

20
  • Receptor consists of two polypeptide subunits
  • 48 kDa (a) and 58 kD (ß)
  • Glycine binding site is located on a
  • Each subunit has 4 hydrophobic membrane-spanning
    sequences

Garrett and Grisham 3rd Edition
21
Glycine a-1 Transmembrane Domain
Protein Data Bank
22
Glycine Receptor
Gar
Garrett and Grisham 3rd Edition
23
K Background (Leak) Channel Excitation
  • Leak channels influence both resting membrane
    potential and repolarization
  • These channels are opened by volatile anesthetics
  • Hyperpolarization of the membrane
  • Suppresses action potential generation
  • Partially responsible for suppressing the hypoxic
    drive during general anesthesia

24
Hypoxic Drive
  • Lung damage
  • Alveolar ventilation is inadequate
  • Abnormal arterial blood gases.
  • Chemoreceptors become tolerant of a high pp of
    CO2 kidneys compensate for the respiratory
    acidosis by retaining bicarbonate (HCO3 )
  • Keeps arterial pH normal
  • If Too much oxygen respiratory drive will be lost
  • Not breathe adequately,
  • Pp of CO2 in arterial blood will rise (loss of
    consciousness)

25
Disruption of Ligand Diffusion Chreodes
  • A proposed mechanism of action for inhaled
    anesthetics

26
Diffusion ChreodesWhat the are Chreodes you
ask?
  • Protein cavities are targeted by anesthetic
    molecules
  • This disrupts the normal function of the protein
  • Amino acids outside the active site act as
    promoters
  • These chreodes created in the landscape of the
    receptor are invoked to account for a type of
    facillitated diffusion of a ligand to that
    receptor
  • Exit of ligand from active site may be mediated
    by another set of chreodes

27
Chreodes
  • It is believed that the viscosity of water near
    the protein surface is higher (due to the
    intermolecular forces between the amino acid side
    chains and the water molecules) than the bulk
    water
  • This ordering of layers of water could
    facilitate faster diffusion of the solute
    (ligand) near the protein surface
  • These paths for the ligand are always changing
    until (over time) they continue to return to an
    ordering that promotes fastest diffusion and
    stability
  • A molecule could potentially disrupt the ordering
    of water and amino acid side chains disrupting
    the chreodes

28
And Finally (I know youre happy) Chreodes and
Anesthesia
  • Inhalational anesthetics (IA) are approximately
    equal in size to the AA side chains
  • IA have lipophilicities very close to those of
    lipophilic side chains
  • The presence of IA in or near a chreode could
    alter the unique path adopted by the receptor,
    disrupting the normal diffusion of the ligand to
    the receptor

29
Partition Coefficients of AA Side Chains and
Volatile Anesthetic Drugs
  • Tryptophan 2.25 Sevoflurane 2.34
  • Isoleucine 1.80 Phenylalanine 1.8 Desflurane
    1.80
  • Leucine 1.70 Halothane 1.70
  • Tyrosine 0.96 Ether 0.89
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