General Anesthesia

1. General Anesthesia Myomi Tse April 17, 2007 CHEM 5398

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. 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. 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. 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. 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. 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. 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. 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. 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. Structures • Intravenous • Inhalational Ketamine Etomidate Propofol Isoflurane Sevoflurane Halothane

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. 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. Molecular Action: GABAA Receptor

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. 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

17. Mechanism of Propofol • Inhibits the response to painful stimuli by interacting with beta3subunit 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. 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. 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. Metabolism and Toxicity • Propofol is extensively metabolized • 88% of an administered dose appearing in the urine • Eliminated by the hepatic conjugation of the inactive glucuronide metabolites which are excreted by the kidney

21. Adverse Effects of Propofol • Hypotension • Arrhythmia • Myocardial ischemia • Restriction of blood supply • Confusion • Rash • Hyper-salivation • Apnea

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. 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)

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. 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 • Prolonged changes in behavior; memory and learning impairments • Relevance of the animal findings to pediatric patients is unknown

26. Thank you!