General anesthesia


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General anesthesia

  1. 1. General Anesthesia Myomi Tse April 17, 2007 CHEM 5398
  2. 2. 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  Early Ideas  Cellular Mechanisms  Structures  Molecular Actions: GABAA Receptor  Mechanism of Propofol (Diprivan®)  Metabolism and Toxicity  Adverse Affects of Propofol  Remaining Questions Concerning the GABAA Receptor  Latest Discoveries and Current Events
  3. 3. Historical Perspective  Original discoverer of general anesthetics  Crawford Long: 1842, ether anesthesia  Chloroform introduced  James Simpson: 1847  Nitrous oxide  Horace Wells 19th Century physician administering chloroform
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. Structures  Intravenous Propofol Etomidate Ketamine  Inhalational Halothane Isoflurane Sevoflurane
  12. 12. 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
  13. 13. 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
  14. 14. Molecular Action: GABAA Receptor
  15. 15. 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
  16. 16. 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  Caneliminate the effects of the anesthetic on ion channel function  General anesthetics do not compete with GABA for its binding on the receptor
  17. 17. 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  Positive modulation of inhibitory function of GABA through GABAA receptors
  18. 18. 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
  19. 19. 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
  20. 20. Metabolism and Toxicity  Propofol is extensively CH3 OH CH 3 CH 3 OGlu CH 3 40% metabolized H3C CH 3 H 3C CH 3 Urine  88% of an administered dose appearing in the urine CH 3 OH CH 3 CH3 OGlu CH 3 CH3 OH CH3 H3C CH 3 H3C CH 3 H 3C CH 3  Eliminated by the OGlu OH OH hepatic conjugation of the inactive glucuronide H 3C CH3 OH CH 3 CH 3 60% Urine metabolites which are OSO 3H excreted by the kidney
  21. 21. Adverse Effects of Propofol  Hypotension  Arrhythmia  Myocardial ischemia  Restriction of blood supply  Confusion  Rash  Hyper-salivation  Apnea
  22. 22. 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?
  23. 23. 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  Mechanicallydriven pumps  Computer-controlled infusion systems  “target controlled infusion” (TCI)
  24. 24. 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
  25. 25. 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  Prolongedchanges in behavior; memory and learning impairments  Relevance of the animal findings to pediatric patients is unknown
  26. 26. Thank you!
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