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
 Chloroform introduced
 James Simpson: 1847
 Nitrous oxide
 Horace Wells
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
 Halothane: 1956
 Team effort between the
British Research Council and
chemists at Imperial
Chemical Industries
 Preferred anesthetic of
choice
 Thiopental: Intravenous
anesthetic
 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
 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 < 36˚C
 Nausea and Vomiting
 Chemoreceptor trigger zone
 Emergence
 Physiological changes
 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
 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, ligand-
gated ion channel in
the mammalian brain
 Located in the post-
synaptic membrane
 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
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
 Action of Propofol
 Positive modulation of inhibitory function of
GABA through GABAA receptors
 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, 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
 Metabolism and Toxicity
 Propofol is extensively CH3 OH CH3
CH3 OGlu CH3

40%

metabolized H3C CH3 H3C CH3 Urine

 88% of an administered
dose appearing in the
urine CH3 OH CH3 CH3 OGlu CH3 CH3 OH CH3

H3C CH3 H3C CH3

H3C CH3

 Eliminated by the
OH OGlu
OH
hepatic conjugation of
the inactive
glucuronide H3C
CH3 OH CH3

CH3
60%
Urine

metabolites which are

OSO 3H

excreted by the kidney

 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
 Mechanicallydriven 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
 Prolongedchanges in behavior; memory and learning
impairments
 Relevance of the animal findings to pediatric
patients is unknown
Thank you!