General Anesthesia Myomi Tse

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

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

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

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!