Transcript General Anesthesiax

General Anesthesia
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


Chloroform introduced


Crawford Long: 1842,
ether anesthesia
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


Halothane: 1956



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
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 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
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
metabolized


CH3
CH3
CH3
CH3
OH
CH3
CH3
CH3
H3C
OH
CH3
CH3
OGlu
CH3
CH3
60%
OSO 3H
Urine
OH
Urine
CH3
CH3
H3C
OGlu
OH
CH3
H3C
40%
CH3
CH3
H3C
OH
CH3
OGlu
H3C
CH3
H3C
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
OH
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!