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

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

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 1842- used after William Morton in 1846 showed it worked in dental procedures in Boston.

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

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.

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. www.video.aol.com/video-detail/awake-movie-based-on-anesthesia-awareness/691529866 2007 Mortality of General Anesthesia: 5/million Endotracheal tube

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

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

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

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

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

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.

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.

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

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

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. 69-79. 2006. Lee, A.G. 1976. Nature (London) 262, 545-548. 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. 13375-13377. Dec. 1997 Seelig, Dr. Samuel. Anesthesiology. http://www.videojug.com/tag/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 16035-16040. December 10, 2002. Thomas, Shawn. Drug Reference for FDA Approved General Anesthetics @ Neurotransmitter.net. 2007. 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. 51. 281-285. 2001. Pictures: Thomas, Shawn. Drug Reference for FDA Approved General Anesthetics @ Neurotransmitter.net. 2007. nmhm.washingtondc.museum/news/bs101.html Corbis.com

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