General Anesthesia

Rachel Gambulos

Medicinal Chemistry

March 20, 2008

“Behind the Scenes”

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:

Accepted in 1846 due to William Morton

-Gilbert Abbot was 1st patient

OR used: “ether dome”

Abu al-Qasim al-Zahrawi

Ibn Zuhr

900s- 1000s

Ether:

Functions of Anesthesia

1) Analgesia (pain relief)

2) Amnesia

3) Loss of consciousness

4) Impairment of all skeletal muscle (motionlessness)

5) Weakened autonomic responses

6) Reversible

Not therapeutic or diagnostic

Facilitates surgery and noxious procedures

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 ruleMeyer-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?

– 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

Nitrous OxideEnflurane (Ethrane ®)

Desflurane (Suprane®)HalothaneIsoflurane (Forane®)

Sevoflurane (Ultane ®)

Note:opiates and muscle relaxants are commonly used with the anesthetic chosen.

Blood Gas Coefficient: solubility in blood

MAC: minimum alveolar concentration (low MAC means high potency)

Common Intravenous Anesthetics

Propofol (Diprivan® )

Ketamine (Ketalar® )Methohexital (Brevital®)

–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.

Barbiturate binding to GABAa receptors

Note:opiates and muscle relaxants are commonly used with the anesthetic chosen.

Etomidate

Binds to GABAa receptor

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.