1. General Anesthesia

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 Propofol Etomidate Ketamine
Halothane
Isoflurane
Sevoflurane

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: 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 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. 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!