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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 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

Original discoverer of general anesthetics

Crawford Long: 1842, ether anesthesia James Simpson: 1847 Horace Wells

Chloroform introduced

Nitrous oxide

19th Century physician administering chloroform

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

Thiopental: Intravenous anesthetic

Definition of General Anesthesia

Reversible, drug-induced loss of consciousness

Depresses the nervous system Collection of component changes in behavior or perception


Amnesia,

Anesthetic state

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 < 36C Nausea and Vomiting

Chemoreceptor trigger zone


Physiological changes

Emergence

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 enantioselective 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

Propofol

Etomidate

Ketamine

Inhalational

Halothane

Isoflurane

Sevoflurane

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, ligandgated ion channel in the mammalian brain Located in the postsynaptic membrane

Molecular Actions: GABAA Receptor

GABAA receptor is a 4-transmembrane (4TM) 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 Cterminal 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 Positive modulation of inhibitory function of GABA through GABAA receptors

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, Propofols 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

CH3 H3C

OH

CH3 CH3 H3C

CH3

OGlu

CH3 CH3 40% Urine

88% of an administered dose appearing in the urine


H3C

CH3

OH

CH3 CH3 H3C

CH3

OGlu

CH3 CH3 H3C

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

CH3 60% CH3 Urine

OSO 3H

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
Prolonged

changes in behavior; memory and learning impairments

Relevance of the animal findings to pediatric patients is unknown

Thank you!

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