General anesthetics

Friday, March 20, 2 015

12:35 PM

A general anaesthetic ( or anesthetic) is a drug that brings about a reversible loss of

consciousness.
Early general anesthetic -- 1842 when Crawford Long for the first time administered
diethyl ether to a patient and performed a pain- less operation.
Early general anesthetic, N20, used in 1845.
it's not ideal because it's minimum alveolar concentration (MAC) is greater than
100%
MAC - minimum alveolar concentration (experessed as volume % of 1atm)
that is required to produce immobility in 50% of middle-age humans
only useful for procedures where full surgical anesthesia isn't required or
in combo use w\ other volatile anesthetics
The stages of anesthesia are characterized by degrees of neuronal depression
1. analgesia: reduced sensation to pain
2. delirium: depression of inhibitory neurons
a. leads to increased excitement, involuntary muscle movement, increased
heart rate, respiration, and blood pressure
3. surgical anesthesia: characterized by regular breathing, a loss of reflexes, and
roving eyeball movements
4. respiratory paralysis: overdose level characterized by respiratory and circulatory
failure
The ideal anesthetic state includes:
1. loss of all sensations
2. analgesia
3. muscle relaxation
characterized by:
1. rapid and pleasant induction and withdrawal
2. relaxation of skeletal muscles
3. adequate oxygen supply in mixture
4. wide margin of safety
5. absence of adverse effect
6. nonflammable
7. chemically compatible\stable w\ anesthetic devices
8. inexpensive

3. adequate oxygen supply in mixture

4. wide margin of safety
5. absence of adverse effect
6. nonflammable
7. chemically compatible\stable w\ anesthetic devices
8. inexpensive
There's currently no one agent that is "ideal"
Inhalation anesthetics include halogenated hydrocarbon and ethers
1. diethyl ether was one of the first anesthetics.
significant analgesic and neuromuscular relaxing effects
flammable
slow induction rates results in sinificant time progressing through the
delirium stage
2. short chain hydrocarbons
a. potency is proportional to chain length
b. flammable
c. CV toxicity
3. choroform
a. analgesic and neuromuscular relaxer
b. carcinogen
c. when the hydrocarbon backbone is halogenated, the potency is increased
and flammability is decreased
4. fluorinated hydrocarbons

a.

IV anesthetics
Types:
a. GABA agonists
b. Opioid agonists
c. Ultrahort-acting barbiturates
1. propofol, a 1-2% eulsion with soybean oil or glycerol
a. poorly water soluble
b. rapid induction and recovery
i. hypnosis is acheieved in 1 minute and lasts for ~ 5 minutes
ii. used for outpatient surgeries
2. ketamine:
a. potent, rapid onset of anesthesia

a. poorly water soluble

b. rapid induction and recovery
i. hypnosis is acheieved in 1 minute and lasts for ~ 5 minutes
ii. used for outpatient surgeries
2. ketamine:
a. potent, rapid onset of anesthesia
b. short duration: 10-25 minutes
c. recovery from anesthesia entails illusions and delirium
d. disturbing dreams and hallucinations can occur up to 24 hours after
administration
3. thiopental - multi-substitued thio-barbiturate
a. rapid unconsciousness
b. rapid, pleasant induction
c. used for initial induction while anesthesia is maintained

General anesthethics tend to belie the normal receptor-ligand concept by Paul Ehrlich.
Their molecular structure vary so much that there is no obvious SAR.
- Most general anesthetics have low affinity so the high concentrations needed
for efficacy lend to diverse side effects.
It is thought that they act through non- specific perturbation of lipid membrane of
CNS neurons
Evidence\Theories for general aesthetic MOA
1. Lipid solubility-anesthetic potency correlation (the Meyer- Overton correlation)

It is thought that they act through non- specific perturbation of lipid membrane of
CNS neurons
Evidence\Theories for general aesthetic MOA
1. Lipid solubility-anesthetic potency correlation (the Meyer- Overton correlation)

a.

i. Y axis should be minimum alveolar concentration

ii. The lesser the MAC the greater the potency
1) Halothane has a MAC of slightly less than 1 while Nitrous
oxide has a MAC of around 105
iii. The drug potency increases and the dose required to produce
anaesthesia reduces as the oil:gas solubility increases.
b. In 1847, V on Bibra and Harless suggested that general anesthetics may act
by dissolving in the fatty fraction of brain cells and removing fatty
constitutient from them, thus changing activity of brain cells and inducing
anesthesia.
c. 1899 - Meyer: anesthetic potency is proportional to the drug's lipophilicity
i. Potency = 1 / molar concentration to induce anesthesia in tadpoles
ii. Potency is compared to oil/water partition coefficient
iii. Linear relationship b\w potency and partition coefficient for
anesthetic moleulces
iv. EC50 for anesthetics was independent of the administration rate,
i.e., gas or aquaous phase
2. Outdated lipid hypotheses of general anesthetic action
a. Lipid bilayer expansion hypothesis of anesthetic effect

iii.

Linear relationship b\w potency and partition coefficient for

anesthetic moleulces
iv. EC50 for anesthetics was independent of the administration rate,
i.e., gas or aquaous phase
2. Outdated lipid hypotheses of general anesthetic action
a. Lipid bilayer expansion hypothesis of anesthetic effect
i. Bulky and hydrophobic anaesthetic molecules accumulate inside the
neuronal cell membrane causing its distortion and expansion
(thickening) due to volume displacement. Membrane thickening
reversibly alters function of membrane ion channels thus provid-
ing anaesthetic effect. Actual chemical structure of the anaes- thetic
agent per se was not important, but its molecular volume plays the
major role: the more space within membrane is occu- pied by
anaesthetic - the greater is the anaesthetic effect.
ii. This theory existed for over 60 years and was supported by
experimental fact that increases in atmospheric pressure reverse
anaesthetic effect ( pressure reversal effect).
b. Other anesthetic action theories involved phsyiochemical properties
i. changes in phase separation
ii. changes in bilayer thickness
iii. changes in order parameters
iv. changes in curvature elasticity
c. lateral phase separation theory: anaesthetics exert their action by
fluidizing nerve membranes to a point when phase separations in the
critical lipid regions disappear
i. Makes membranes less able to facilitate the conformational
changes in proteins
3. The outdated lipid theories suffer from 4 weaknesess.
a. The stereoisomers of anesthetic drugs have very different potencies while
their oil/gas partition coefficients are similar
b. Some higlhy lipophillic drugs that were expected to act as anesthetics
exert convulsive effect ( termed nonimmobilizers)
i. Suppression of movement is due to localization of action in the
spinal cord and is characteristic of a true anesthetic
c. A small increase in body temp affects membrane density and fluidity as
much as general anesthetics but doesn't exhibit any similar therapeutic
effect
d. Increasing the chain length in a homologous series of straight-chain
alcohols or alkanes increases their lipid solubility, but their anesthetic
potency stops increasing beyond a certain cutoff length.
i. anaesthetics exert their effect not by acting globally on membrane
lipids but rather by binding directly to hydrophobic pockets of well-
defined volumes in proteins. As the alkyl chain grows, the
anaesthetic fills more of the hydrophobic pocket and binds with

alcohols or alkanes increases their lipid solubility, but their anesthetic

potency stops increasing beyond a certain cutoff length.
i. anaesthetics exert their effect not by acting globally on membrane
lipids but rather by binding directly to hydrophobic pockets of well-
defined volumes in proteins. As the alkyl chain grows, the
anaesthetic fills more of the hydrophobic pocket and binds with
greater affinity. When the molecule is too large to be entirely
accommodated by the hydrophobic pocket, the binding affinity no
longer in- creases with increasing chain length. Thus the volume of
the n-alkanol chain at the cutoff length provides an esti- mate of the
binding site volume.
ii. Interpretation of the cutoff effect in the frame of the "lipid
hypothesis"
1) A) Short hydrocarbon chains are relatively rigid in terms of
con- formational enthropy and are close to alkanol hydroxyl
group ( buoy) tethered to the interface. This makes short
chain alka- nols efficient mediators that redistribute lateral
stress from mem- brane interior to its interface. B) This ability
decreases in the row of n-alkanols since longer chains are
more flexible and are not so tightly tethered to the hydroxyl
group. C) Polyhydroxyalkanes 1,6,11,16-hexadecanetetraol
and 2,7,12,17-octadecanetetraol exhibit significant
anaesthetic potency as was predicted by cut- off effect
because the length of the hydrocarbon chain between
hydroxyl groups is smaller than the cutoff.

2)

4. The modern version of lipid hypothesis states that anaesthetic effect happens if
solubilization of general anaesthetic in the bilayer causes a redistribution of
membrane lateral pressures.

a.

a.

b. Most membrane proteins especially ion channels are sensitive to changes

in this lateral pressure distribution profile.
c. This mechanism is nonspecific because the potency of the anesthetic is
determined not by its actual chemical structure, but by the positional and
orientational distribution of its segments and bonds within the bilayer.
General anaesthesia likely involves inhibition of the opening of the ion
channel in a postsynaptic ligand-gated membrane protein by the
following mechanism:
i. A channel tries to open in response to a nerve impulse.
1) This increases the cross-sectional area of the protein near the
aqueous interface than in the middle of the bilayer
ii. The anesthetic-inuced increase in lateral pressure near the interface
shifts the protein conformational equilibrium back to the closed
state since channel opening will require graeter work against the
higher pressure
According to the modern lipid hypothesis anaesthetics do not act
directly on their membrane protein tar`gets, but rather perturb
specialized lipid matrices at the protein-lipid interface, which act as
mediators. This is a new kind of transduction mechanism, different
from the usual key-lock interaction of ligand and receptor, where
the anaesthetic (ligand) affects the function of membrane proteins
by binding to the specific site on the protein.