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

CH3

CH3CH3

CH3

OH

CH3

CH3CH3

CH3

OGlu

40%Urine

CH3

CH3CH3

CH3

OH

OH

CH3

CH3CH3

CH3

OH

OSO3H

CH3

CH3OGluCH3

CH3

OH

CH3

CH3OHCH3

CH3

OGlu

60%

Urine

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!