Transcript General Anesthesia

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:
Abu al-Qasim al-Zahrawi
Ibn Zuhr
900s- 1000s
Ether:
Accepted in 1846 due to William Morton
-Gilbert Abbot was 1st patient
OR used: “ether dome”
Functions of Anesthesia
Not therapeutic or diagnostic
Facilitates surgery and noxious procedures
1)
2)
3)
4)
5)
6)
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
–
–
–
•
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
–
–
•
Endotracheal tube
Nausea/Vomiting
–
–
–
•
Gag reflex lost
Ventilation commonly needed to create neg. pressure
Watch tidal CO2
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
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.
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
Desflurane (Suprane®)
Enflurane (Ethrane ®)
Isoflurane (Forane®)
Sevoflurane (Ultane ®)
Halothane
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.
Binds to GABAa
receptor
Barbiturate binding to
GABAa receptors
–Concurrent use of
Flurazepam increases
Propofol affinity to its target
receptor. Needs emulsion
Note:opiates and muscle relaxants are commonly used with the anesthetic chosen.
mixture.
Drug Metabolism: Propofol
•
Oxidation
–
–
•
Conjugation
–
–
•
P450 in the liver (P4502B6)
Oxidized here (ring
hydroxylation)
glucuronidation of the parent
drug to form the propofolglucuronide (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.