anesthetics anna final

8/13/2019 Anesthetics Anna Final

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Anesthetics and mechanisms of general anesthesia

Anna Kuznetsova


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Volatile anesthetics

And Elemental noble gases: He, Ar

Morton 1846

Anesthetics are a mainstay of modern medicine, but their molecular mechanismof action is still not known

Anesthetics are structurally very different and have weak affinity for their targets

However, the mechanism will provide the key to making the perfect anesthetic!


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http://www.doctorspiller.com/local_anesthetics_4.htm

Nerve impulse is the key to sensation

Synapse -contact between nervecells

i m p u l s e

impulse


4/15http://www.doctorspiller.com/local_anesthetics_4.htm

Depolarisation process for impulse generation and conductance

Restingpotential

Depolarization(impulse)


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1. Inhibit ing the depolarization by reducing the influof sodium ions into cytoplasm so that threshold

necessary for sensation is not reached

Threshold of sensitivity

Current theory suggests anesthetics block impulse by:

2. decreasing resting potential(hyperpolarization) by increaseK+ conductance of membrane or

increasing Cl-conductance

To affect ion channels, theanesthetic molecules mustactually enter membrane ofthe nerve. And herein lies thedifference in the potency, timeof onset and duration of thevarious anesthetics.


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This correlation is accurate for a broad range of general anesthetics:alkanols , volatile

agents, and barbiturates. Also, volatile anesthetics are generally additive in theireffects: a mixture of a half dose of two different volatile anesthetics was in fact equalto a full dose of either d rug in isolation.

The Meyer-Overton rule correlation for anestheticsThe more the drug is soluble in olive oil the more potent as an anesthetic!!!

http://www.anes.upmc.edu/anesnews/volume/2003winter_spring/articles/focus.html

1901
http://www.anes.upmc.edu/anesnews/volume/2003winter_spring/articles/focus.htmlhttp://www.anes.upmc.edu/anesnews/volume/2003winter_spring/articles/focus.htmlhttp://www.anes.upmc.edu/anesnews/volume/2003winter_spring/articles/focus.html


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1) First Nonspecific unitary theory of

narcosis: distortion of the lipid bilayeris caused by accumulation ofanesthetic molecules in the neuronalcell membrane providing anesthetic

effect. Chemical structure ofanesthetics per se doesnt matter!!

Theoretical interpretations of Meyer-Overton empiric rule

2) Lipid Hypothesis: Inhibition of neuronal conduction by generalanesthetics is due to changes in membrane density (critical volumehypothesis) and membrane fluidity (Suezaki, 1990)

1954

Expansion of the membrane concept: Meyer-Overton rule can be improved ifmolecular volumes that anesthetics occupy in the membrane are taken into

consideration.The more space within membrane is occupied by anesthetic - the greater theanesthetic effect, because membrane thickening reversibly alters gatingmechanisms of ion flux into the cell.The idea was supported by pressure reversal effect - Anesthetic effect isreversed by increases in atmospheric pressure.

1990s


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Changes in density and fluidity of membrane are so small that smallincreases in temperature can mimic these effects on membranefluidity and density without causing anesthesia.

Objections to Lipid Hypothesis:

Exception to Meyer-Overton rule: the anomalous lack of anesthetic

potency of n -alkanols above a cutoff chain length

Cutoff Thus the molecular volume ofthe alkanol at the cutoff length

provides a measure of thevolume of the putative bindingsite.

Anomaly can be explained by

binding of anesthetics directly toprotein hydrophobic pockets ofwell-defined volumes


9/15http://www.chemcases.com/alcohol/alc-13.htm

When anesthetics bind to hydrophopic pockets on membrane proteinswhich undergo conformational changes and alter ion flux. So volatileanesthetics mediate their actions through direct interaction withmembrane proteins rather than lipids (Franks and Lieb, 1998)

GABA A receptors,glutamate receptors

Theoretical interpretations of Meyer-Overton empiric rule:3) Protein Hypothesis (specific interactions)

1998
http://www.chemcases.com/alcohol/alc-13.htmhttp://www.chemcases.com/alcohol/alc-13.htm


10/15http://sophia.smith.edu/~ahall/research.html

Currently no single protein or channel has emerged as the likely anesthetic targetto the exclusion of all others.

Receptors often exhibit differential modulation by the individual stereoisomers ofoptically active anesthetics


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4)Bilayer mediate interactions of anesthetic and channel (new)

Although the lipid and protein theories have not been proved ordisproved, current evidence suggests that lipid solubility and/orprotein perturbations are not the sole mechanisms involved

anesthetic

Anesthetic is solubilized in the bilayer, causing redistributionof membrane lateral pressures, which shifts conformationalequilibrium of integral proteins such as ligand-gated ionchannels

It is largely the positional and orientational distribution within thebilayer of the segments and bonds of the anesthetic molecule thatdetermines its potency

Anomalous lack of anesthetic potency of n alkanols above a


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Anomalous lack of anesthetic potency of n -alkanols above a cutoff chain length (exception to Meyer-Overton rule):

O

H

O H

In short alkanols , flexible hydrocarbon chain segments reside in

hydrocarbon region of bilayer but very close to hydroxyl grouptethered to the aqueous interfacial region

Short hydrocarbon chainredistr ibutes lateralstresses from the bilayerinterior toward the

aqueous interface!!!

For alkanols with longer chain , thehydrocarbon tails penetrate deeper intothe bilayer, reducing the magnitude ofthe effect until , for sufficiently longchains, no pressure redistribution ispredicted and anesthetic potency islost.

OH OH OHOH

Polyhydric alkanols were suggested to have anesthetic effectsimilar to 1-alkanols. And indeed polyhydroxyalkanes 1,6,11,16-hexadecanetetraol and 2,7,12,17-octadecanetetraol exhibitedsignificant anesthetic potency.

J. Med. Chem. , 2005, 48 (12), pp 41724176

Oleamide induced closure of gap junction membrane channels


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Richard A. Lerner PNAS Vol. 94, pp. 1337513377, 1997

On treatment with endogenous anestheticoleamide (red triangles), this lipid ring is

fluidized and becomes disordered,promoting a conformational change in theconnexon oligomer and leads to closure.

Oleamide-induced closure of gap junction membrane channels

A mixture of phospholipids (greencircles) and cholesterol (yellow

squares) form a well-ordered lipidring surrounding the gap junctionconnexon (blue).

Endogenous anesthetic oleamide (amide of oleic acid) potentiates sleep andlowers temperature through closing gap junction channels. AnestheticIsoflurane was showed to cause flickering of the acetylcholine receptor


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http://www.nematodes.org/Caenorhabditis/C_elegans_genome/Celegans_acedb.shtml

Identification of genes of anesthetic targets in C. Elegance

The whole genome (~1000 genes) completely solved!!


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P.G. Morgan, E.-B. Kayser, M.M. Sedensky C. elegans and volatile anesthetics WormBook.org

Unraveling the mystery of general anesthesia mechanism Genes and genesets that control the behavior of C. elegans in volatile anesthetics have beenidentified

Genetic data fail to identify a single protein or channel that is uniquelyresponsible for the effects of anesthetics!!

anesthetics anna final

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