General Anesthesia - Smu
Transcript of General Anesthesia - Smu
General AnesthesiaMyomi Tse
April 17, 2007CHEM 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 Wells19th 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
Inhalational
Propofol Etomidate Ketamine
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 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
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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!