General Anesthesia Myomi Tse



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General Anesthesia

  • Myomi Tse

  • April 17, 2007

  • CHEM 5398


Overview of Discussion

  • Historical Perspective

  • What is General Anesthesia?

    • Definition
  • Principles of Surgical Anesthesia

    • Hemodynamic and Respiratory Effects
    • Hypothermia
    • Nausea and Vomiting
    • Emergence
  • Mechanisms of Anesthesia

  • Molecular Actions: GABAA Receptor

  • Mechanism of Propofol (Diprivan®)

  • Adverse Affects of Propofol

  • Remaining Questions Concerning the GABAA Receptor

  • Latest Discoveries and Current Events



Historical Perspective

  • Original discoverer of general anesthetics

    • Crawford Long: 1842, ether anesthesia
  • Chloroform introduced

    • James Simpson: 1847
  • Nitrous oxide

    • Horace Wells


Historical Perspective

  • William Morton

    • October 16, 1846
    • Gaseous ether
    • Public demonstration gained world-wide attention
    • Public demonstration consisted of an operating room, “ether dome,” where Gilbert Abbot underwent surgery in an unconscious state at the Massachusetts General Hospital
  • Ether no longer used in modern practice, yet considered to be the first “ideal” anesthetic



Historical Perspective

  • Cyclopropane: 1929

    • Most widely used general anesthetic for the next 30 years
  • Halothane: 1956

    • Team effort between the British Research Council and chemists at Imperial Chemical Industries
    • Preferred anesthetic of choice
  • Thiopental: Intravenous anesthetic



Definition of General Anesthesia

  • Reversible, drug-induced loss of consciousness

    • Depresses the nervous system
  • Anesthetic state

    • Collection of component changes in behavior or perception
      • Amnesia, immobility in response to stimulation, attenuation of autonomic responses to painful stimuli, analgesia, and unconsciousness


Principles of General Anesthesia

  • Minimizing the potentially harmful direct and indirect effects of anesthetic agents and techniques

  • Sustaining physiologic homeostasis during surgical procedures

  • Improving post-operative outcomes



The Body and General Anesthesia

  • Hemodynamic effects: decrease in systemic arterial blood pressure

  • Respiratory effects: reduce or eliminate both ventilatory drive and reflexes maintaining the airway unblocked

  • Hypothermia: body temperature < 36˚C

  • Nausea and Vomiting

    • Chemoreceptor trigger zone
  • Emergence

    • Physiological changes


Mechanism

  • Early Ideas

    • Unitary theory of anesthesia
      • Anesthesia is produced by disturbance of the physical properties of cell membranes
      • Problematic: theory fails to explain how the proposed disturbance of the lipid bilayer would result in a dysfunctional membrane protein
        • Inhalational and intravenous anesthetics can be enantio-selective in their action
  • Focus on identifying specific protein binding sites for anesthetics



Cellular Mechanism

  • Intravenous Anesthetics

    • Substantial effect on synaptic transmission
    • Smaller effect on action-potential generation or propagation
    • Produce narrower range of physiological effects
  • Actions occur at the synapse

    • Effects the post-synaptic response to the released neurotransmitter
      • Enhances inhibitory neurotransmission


Structures

  • Intravenous

  • Inhalational



Molecular Actions: GABAA Receptor

  • Ligand-gated ion channels

    • Chloride channels gated by the inhibitory GABAA receptor
      • GABAA receptor mediates the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain
        • GABAA receptor found throughout the CNS
          • Most abundant, fast inhibitory, ligand-gated ion channel in the mammalian brain
          • Located in the post-synaptic membrane


Molecular Actions: GABAA Receptor

  • GABAA receptor is a 4-transmembrane (4-TM) ion channel

    • 5 subunits arranged around a central pore: 2 alpha, 2 beta, 1 gamma
      • Each subunit has N-terminal extracellular chain which contains the ligand-binding site
      • 4 hydrophobic sections cross the membrane 4 times: one extracellular and two intracellular loops connecting these regions, plus an extracellular C-terminal chain


Molecular Action: GABAA Receptor



Molecular Action: GABAA Receptor

  • Receptor sits in the membrane of its neuron at the synapse

  • GABA, endogenous compound, causes GABA to open

  • Receptor capable of binding 2 GABA molecules, between an alpha and beta subunit

    • Binding of GABA causes a conformational change in receptor
      • Opens central pore
      • Chloride ions pass down electrochemical gradient
    • Net inhibitory effect, reducing activity of the neuron


Mechanism of Propofol

  • Action of anesthetics on the GABAA receptor

    • Binding of anesthetics to specific sites on the receptor protein
    • Proof of this mechanism is through point mutations
      • Can eliminate the effects of the anesthetic on ion channel function
    • General anesthetics do not compete with GABA for its binding on the receptor


Mechanism of Propofol

  • Inhibits the response to painful stimuli by interacting with beta3 subunit of GABAA receptor

  • Sedative effects of Propofol mediated by the same GABAA receptor on the beta2 subunit

    • Indicates that two components of anesthesia can be mediated by GABAA receptor
  • Action of Propofol



Mechanism of Propofol

  • Parenteral anesthetic

    • Small, hydrophobic, substituted aromatic or heterocyclic compound
  • Propofol partitions into lipophilic tissues of the brain and spinal cord

    • Produces anesthesia within a single circulation time


Metabolism and Toxicity

  • Recovery after doses/infusion of Propofol is fast

  • Half-life is “context-sensitive”

    • Based on its own hydrophobicity and metabolic clearance, Propofol’s half-life is 1.8 hours
    • Accounts for the quick 2-4 minute distribution to the entire body
      • Expected for a highly lipid-soluble drug
  • Anesthetic of choice



Metabolism and Toxicity

  • Propofol is extensively metabolized

  • Eliminated by the hepatic conjugation of the inactive glucuronide metabolites which are excreted by the kidney



Adverse Effects of Propofol

  • Hypotension

  • Arrhythmia

  • Myocardial ischemia

    • Restriction of blood supply
  • Confusion

  • Rash

  • Hyper-salivation

  • Apnea



Remaining Questions

  • At the molecular level, where are the binding sites on the GABAA receptor?

  • Which neuronal structures are most important for the anesthetic end points of interest?



Latest Discoveries: Implications for the Medicinal Chemist

  • Explosion of new information on the structure and function of GABAA receptors

    • Cloning and sequencing multiple subunits
      • Advantageous: large number of different subunits (16) allows for a great variety of different types of GABAA receptors that will likely differ in drug sensitivity
    • Propofol delivery technology
      • Mechanically driven pumps
      • Computer-controlled infusion systems
        • “target controlled infusion” (TCI)


Latest Discoveries: Implications for the Medicinal Chemist

  • Findings collectively enhance the understanding on the mechanism of action of Propofol

  • Allows the medicinal chemist to rationally design analogues with better pharmacological profiles



Current News

  • March 30, 2007

  • The Wall Street Journal: “FDA Wants More Research on Anesthesia Risk to Kids”

    • Anesthesia can be harmful to the developing brain, studies on animals suggest, raising concerns about potential risks in putting young children under for surgery
    • Relevance of the animal findings to pediatric patients is unknown


Thank you!




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