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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 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
Historical Perspective
Crawford Long: 1842, ether anesthesia James Simpson: 1847 Horace Wells
Chloroform introduced
Nitrous oxide
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 Team effort between the British Research Council and chemists at Imperial Chemical Industries Preferred anesthetic of choice
Halothane: 1956
Anesthetic state
immobility in response to stimulation, attenuation of autonomic responses to painful stimuli, analgesia, and unconsciousness
Minimizing the potentially harmful direct and indirect effects of anesthetic agents and techniques Sustaining physiologic homeostasis during surgical procedures Improving post-operative outcomes
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 < 36C Nausea and Vomiting
Emergence
Mechanism
Early Ideas
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
Cellular Mechanism
Intravenous Anesthetics
Substantial effect on synaptic transmission Smaller effect on action-potential generation or propagation Produce narrower range of physiological effects
inhibitory neurotransmission
Structures
Intravenous
Propofol
Etomidate
Ketamine
Inhalational
Halothane
Isoflurane
Sevoflurane
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, ligandgated ion channel in the mammalian brain Located in the postsynaptic membrane
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 Cterminal chain
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
Can
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 Positive modulation of inhibitory function of GABA through GABAA receptors
Action of Propofol
Mechanism of Propofol
Parenteral anesthetic
Propofol partitions into lipophilic tissues of the brain and spinal cord
Based on its own hydrophobicity and metabolic clearance, Propofols half-life is 1.8 hours Accounts for the quick 2-4 minute distribution to the entire body
Expected
Anesthetic of choice
CH3 H3C
OH
CH3
OGlu
CH3
OH
CH3
OGlu
CH3
OH
CH3 CH3
Eliminated by the hepatic conjugation of the inactive glucuronide metabolites which are excreted by the kidney
OH
OH
OGlu
CH3 H3C
OH
OSO 3H
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?
large number of different subunits (16) allows for a great variety of different types of GABAA receptors that will likely differ in drug sensitivity
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
Prolonged
Thank you!