1. General Anesthesia “Behind the Scenes” Rachel Gambulos
Medicinal Chemistry
March 20, 2008

2. Overview History Functions of anesthesia Side effects
How do they work: mechanism of action
GABAA Receptor
Glycine gated chlorine channels
Inhibition of NMDA
Activation of K+ channels
Commonly used anesthesia
inhaled
intravenous

3. History: Ether: Abu al-Qasim al-Zahrawi Ibn Zuhr 900s- 1000s
Accepted in 1846 due to William Morton
-Gilbert Abbot was 1st patient
OR used: “ether dome”
American civil war amputations 1860s
Anesthesia dripped into sponge/cone fit over mouth/nose.
Ether first discovered in used after William Morton in 1846 showed it worked in dental procedures in Boston.

4. Russo Japanese war 1904-1905 over Korea and Manchuria, china

5. Functions of Anesthesia
Not therapeutic or diagnostic
Facilitates surgery and noxious procedures
Analgesia (pain relief)
Amnesia
Loss of consciousness
Impairment of all skeletal muscle (motionlessness)
Weakened autonomic responses
Reversible
Not all anesthetics bring about all of these. Ex: barbituates are not analgesics, but they will put you to sleep.

6. Side Effects of Anesthesia
Decreased Respiration
Gag reflex lost
Ventilation commonly needed to create neg. pressure
Watch tidal CO2
Nausea/Vomiting
Lower esophageal sphincter is relaxed
Endotracheal tubes used to avoid death by aspiration
Postoperative vomiting due to action on medulla oblongata
Hypothermia
Lowers the set point where vasoconstriction occurs
Preventing this is a major goal of anesthesiologists today
Warming fluids
Anesthesia awareness
Movie Awake explains the phenomenon (1/1000) most of these do not feel pain.
2007 Mortality of General Anesthesia: 5/million
Endotracheal tube

7. How do they work? An early theory: Unitary Theory of Amnesia
Anesthetic potency correlated to solubility in olive oil. Meyer-Overton rule
Implied that the plasma membrane was the nonspecific target
Rare counterexamples: enantiomers
What about hydrophobic pockets of proteins?
Current focus on a wide range of specific protein targets (receptors)
A wide variety of chemical structures cause similar responses, suggesting multisite mode of action.
Different aspects of anesthetic state achieved by different receptors throughout the CNS.
GABAA Receptors
Glycine gated chlorine channels
NMDA receptors
K+ channels

8. Nerve Cell Physiology
Action Potential: a voltage change which induces neurotransmitter release
Concentration gradients
Depolarization to threshold
The cell gets less negative
Repolarization to resting potential
The cell gets more negative

9. GABAA Receptor What is it? How does it help in anesthesia?
A ligand gated chlorine channel
GABA is the ligand that stimulates the GABAA Receptor.
GABAA stands for γ-Aminobutyric acid type A.
How does it help in anesthesia?
Makes it more difficult to stimulate the neuron
Causes IPSP (inhibitory postsynaptic potential)
Makes interior of the cell more negative (hyperpolarized)
Allosteric Agonists for this receptor
Barbituates
Benzodiazepines
Kavalactones
A large variety of drugs target this receptor
Where does the anesthesia bind?
Between the alpha and beta subunits
(Met 236 and Met 286) identified by mutating the protein

10. Glycine Gated Channels
ligand gated chlorine ion channel
very similar to GABAA Receptor
Important in the spinal cord and brain stem
Increased anesthesia causes increased affinity of glycine to the ligand gated channel

11. NMDA Receptor Anesthesia inhibits it It normally depolarizes the cell
A net positive charge goes into the cell
Ca2+ and Na+ enter cell (net increase of +2)
Drugs involved
Xenon
Ketamine
Nitrous Oxide
NMDA stands for N-methyl-D-aspartate

12. Commonly Inhaled Anesthetics
Blood Gas Coefficient: solubility in blood
MAC: minimum alveolar concentration (low MAC means high potency)
Nitrous Oxide
Sevoflurane (Ultane ®)
Enflurane (Ethrane ®)
Desflurane (Suprane®)
Isoflurane (Forane®)
Halothane
Mostly made by Baxter- pharm company and Hospira
Note:opiates and muscle relaxants are commonly used with the anesthetic chosen.

13. Common Intravenous Anesthetics
Propofol (Diprivan® )
Ketamine (Ketalar® )
Methohexital (Brevital®)
Etomidate
analgesic properties (non barbiturate). New class of hypnotic sedativies: diisopropylphenols
Binds GABAa receptor.
Concurrent use of Flurazepam increases Propofol affinity to its target receptor. Needs emulsion mixture.
Binds to GABAa receptor
Astra Zenica does Propofol
Barbiturate binding to GABAa receptors
Note:opiates and muscle relaxants are commonly used with the anesthetic chosen.

14. Drug Metabolism: Propofol
Oxidation
P450 in the liver (P4502B6)
Oxidized here (ring hydroxylation)
Conjugation
glucuronidation of the parent drug to form the propofol-glucuronide (PG)
sulfo-conjugation
Half Life
1.8 hours
Dimeric compounds form and insert into the membrane
88% appears in the urine
Glucoronidation: Glucuronic acid linked with a glycosidic bond

15. The Future Find the specific binding regions on the protein receptors
Cloning genes with point mutations
Synthesize drugs that can minimize side effects
Propofol: salivation, arrhythmias, rash, apnea
Reduce instances of anesthesia awareness

16. Works Referenced:
Campbell, Neil A., and Reece, Jane B. Biology. 6ed. San Francisco, 2002.
Gilman, Goodman. The Pharmacological Basis of Therapeutics. 11Ed. Brunton, Lauren, Lazo, John, and Parker, Keith L. New York 2006.
Hirota, Kazuyoshi. Special Cases: Ketamine, Nitrous Oxide, and Xenon. Journal of Clinical Anesthesiology. Vol 20 (1). P
Lee, A.G Nature (London) 262,
Lerner, Richard A. A hypothesis about the endogenous analogue of general anesthesia. Departments of Chemistry and Molecular Biology. The Scripps Research Institute, and the Skaggs Institute for Chemical Biology. Proceedings of the National Academy of Sciences of the United States of America. Vol 94 p Dec. 1997
Seelig, Dr. Samuel. Anesthesiology.
Tang, P, and Yan Xu. Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: The implication of molecular mechanisms of general anesthesia. Proceedings of the National Academy of Sciences of the United States of America. Vol. 99 (25). Pp December 10, 2002.
Thomas, Shawn. Drug Reference for FDA Approved General Neurotransmitter.net
Oda, Yutaka. Hamoka, N. Hiroi, T., Imaoka, S., Hase, I., Tanaka K., Funae Y., Involvement of Human Liver Cytochrome P4502B6 in the metabolism of Propofol. The British Jounral of Pharmacology
Pictures:
Thomas, Shawn. Drug Reference for FDA Approved General Neurotransmitter.net
nmhm.washingtondc.museum/news/bs101.html
Corbis.com

17. Thanks for your attention
Hopefully I didn’t put you to sleep.