INHALED ANESTHETHICS
INHALED
ANESTHETHICS
DEFINITION
A wide variety of gases and volatile
liquids can produce anesthesia.
chemical compound possessing
general anaesthetic properties that
can be delivered via inhalation.
IDEAL ANESTHETIC
Inexpensive
Potent
Pleasant to inhale
Minimally soluble in the blood and tissues
Stable on the shelf during administration
Lack of undesirable side effects or
toxicity
NO ANESTHETIC AGENT
CURRENTLY IN USE MEETS
ALL THESE REQUIREMENTS!
DYNAMIC EQUILIBRIA EXISTING
DURING THE STATE OF
AMNESIA
PROPERTIES
One of the troublesome properties of the
inhalational anesthetics is their low safety
margin.
The inhalational anesthetics have therapeutic
indices (LD50/ED50) that range from 2 to 4,
making these among the most dangerous drugs
in clinical use.
The toxicity of these drugs is largely a function
of their side effects, and each of the inhalational
anesthetics has a unique side-effect profile.
MEASUREMENT OF
ANESTHETIC ACTIVITY
Most measurements of inhaled anesthetic
potencies involve the abolishment of
movement (either induced or
reflexive/spontaneous) as an anesthetic end
point.
MEASUREMENT OF ANESTHETIC
ACTIVITY
Minimum alveolar concentration (MAC)
Solubility
Stability
A. MINIMUM ALVEOLAR
CONCENTRATION
The most common way to measure inhaled anesthetic potency is by recording the minimum alveolar concentration (MAC) needed to prevent movement to a painful stimulus.
The MAC concentrations are recorded at 1 atmosphere and reported as the mean concentration needed to abolish movement in 50% of subjects
A. MAC-AWAKE
Another term, the “MAC-Awake,” is used to
describe the concentration of anesthetic at
which appropriate responses to verbal
commands are lost in 50% of the patients
tested.
At this concentration, amnesia and a loss of
awareness are evident, and the patient is said
to be in a state of hypnosis.
The MAC-Awake occurs at concentrations
significantly lower (e.g., 50–75% lower) than
those required for surgical anesthesia.
MAC OF INHALED ANESTHETICS
B. SOLUBILITY
The solubility of an agent in the blood
usually is expressed as the blood/gas
partition coefficient, which is the ratio of
the concentration of anesthetic in blood
to that in the gas phase at equilibrium .
These values correspond well with the
oil/gas partition coefficient, which is
easier to determine experimentally.
B. SOLUBILITY
The partition coefficient is defined as the ratio of the amount of substance (e.g., inhalant) present in one phase (oil, blood etc.) compared with another (gas), the two phases being of equal volume and in equilibrium.
A blood: gas PC of 0.5 means that the concentration of inhalant in the blood is half that present in the alveolar gas when the partial pressure of the anesthetic is identical at both sites
A very potent anesthetic (e.g.,
methoxyflurane) has a low MAC value and a
high oil/gas PC, whereas a low potency
agent (e.g., N2O) has a high MAC and low
oil/gas PC.
In other words, an anesthetic with a high oil
solubility (i.e., high oil/gas PC) is effective at
a low alveolar concentration and has a high
potency
B. SOLUBILITY
C. STABILITY
The early inhaled anesthetics suffered from
stability problems, leading to explosions and
operating room fires.
Halogenation clearly stabilizes the inhaled
agent and all inhaled anesthetics used
today contain halogens
C. STABILITY OF SEVOFLURANE
The operating room fires involving sevoflurane all involved the recapture process and recirculating equipment.
Recirculating breathing apparatus were developed.
These breathing apparatus are designed to capture the expired gas, remove the carbon dioxide, and then allow the patient to inhale the anesthetic gas again.
STRUCTURE ACTIVITY
RELATIONSHIP OF
INHALED ANESTHETICS
While it is true that there is no single
pharmacophore for the inhaled
anesthetics, the chemical structure
is related to the activity of the drug
molecule.
MEYER-OVERTON THEORY
In the early 1900s Hans Meyer and Charles
Overton suggested that the potency of a
substance as an anesthetic was directly
related to its lipid solubility, or oil/gas
partition coefficient
Arguing against this theory, however, is the
finding that not all highly lipid-soluble
substances are capable of producing
anesthesia.
LIPID SOLUBILITY-ANAESTHETIC POTENCY
CORRELATION (THE MEYER-OVERTON
CORRELATION) FOR ANESTHETHICS
CHEMICAL STRUCTURES OF SOME
INHALED ANESTHETIC AGENTS
GASES INERT AND OTHERWISE
Of all the gases, the most potent
anesthetic is xenon, and potency
progressively decreases with decreasing
atomic weight
Helium and neon have no detectable
anesthetic effect at high pressures (~100
atm), and administration of these high
pressures may actually antagonize the
effects of conventional inhaled anesthetics
and initiate convulsions
GASES INERT AND OTHERWISE
Nitrous oxide potency (as determined by
MAC) varies more among species than
most other anesthetics, and more than a
twofold difference in nitrous oxide
requirement exists between humans and
rodents
GASES INERT AND OTHERWISE
Because noble gases may constitute the
centers of crystallized structures of water
molecules (hydrates), it was once proposed
that hydrates were important in the
production of anesthesia. However, such
crystal water formations cannot explain the
anesthetic properties of all of these gases.
In general, these gases do obey the Meyer–
Overton hypothesis.
TA
BL
E O
F P
OT
EN
CIE
S O
F
GA
SE
S
HYDROCARBONS
Unsubstituted Hydrocarbons
Normal Alkanes
Cycloalkanes
Unsaturated Compounds
Alkanols
Halogenated Alkanes
Partially Fluorinated Alkanes
Perfluorinated Alkanes
Chlorine, Bromine, and Iodine Substitutions
Halogenated Cycloalkanes
NORMAL ALKANES
In the anesthetic properties of the alkanes from
methane through octane , a tendency was found
for increasing chain length to be associated with
increased anesthetic potency.
In contrast, in 1971 Mullins reported that n-
decane had no anesthetic effect.
CYCLOALKANES
Cyclic hydrocarbons are more potent
anesthetics than their n-alkane analogs of
equal carbon numbers.
Example:
The MAC of cyclopropane in rats (~0.2 atm)
is about one fifth the MAC for n-propane
(0.94 atm), and the MAC of cyclopentane
(0.053 atm) is less than one half the MAC
for n-pentane (0.127 atm)
CYCLOALKANES
As with the n-alkanes, the anesthetic
potencies of the cycloalkanes tend to
increase with cyclooctane having no
anesthetic effect
UNSATURATED COMPOUNDS
Hydrocarbons containing double bonds
appear to have a relatively greater
anesthetic potency, although only limited
information is available.
Example:
Ethylene MAC is 0.67 atm in humans and
1.32 atm in rats, whereas the MAC for
ethane in rats is 1.59 atm.
ALKANOLS
A similar increase in potency with
increase in carbon length was seen in
the n-alkanol series. In addition, the n-
alkanol with a given number of
carbons is more potent than the n-
alkane with the same chain length
HALOGENATED ALKANES
The unsuitability of inhaled hydrocarbons for
clinical anesthesia provided the impetus to
search for hydrocarbon alkane derivatives
that might be more clinically useful.
Although cyclopropane and ethylene were
at one time routinely administered to
patients and did have some favorable
properties there were distinct
disadvantages.
HALOGENATED ALKANES
The approach taken to find a safer and more stable inhaled anesthetic was to develop fluorinated compounds, because it was known that the strong chemical bond between fluorine and carbon was nonreactive.
Higher atomic mass halogens increased potency compared to lower atomic mass halogens.
PARTIALLY FLUORINATED ALKANES
For the partially fluorinated ethanes,
propanes, and butanes, the highest potency
was seen when the terminal carbon
contained one hydrogen (CHF2(CF2)nCHF2).
Most partially fluorinated pentanes,
hexanes, and heptanes did not produce
anesthesia when administered alone at their
vapor pressures
PARTIALLY FLUORINATED ALKANES
Example:
For the methanes, CF2H2 is the most potent,
with a MAC of 0.72 atm (the MAC of CH4
[9.9 atm] being approximately tenfold
greater).
Of the ethanes, CF2HCF2H was the most
potent (MAC = 0.115 atm).
PERFLUORINATED ALKANES
Also known as
completely fluorinated
alkanes
For the n-alkane series,
fully saturating the
alkane with fluorine
abolished activity
except when n equaled
one.
CHLORINE, BROMINE, AND IODINE
SUBSTITUTIONS
Substitution of a chlorine or bromine into a
fluorohydrocarbon resulted in a more potent
anesthetic, and that bromine was several
times more potent than chlorine in
enhancing anesthetic potency.
CHLORINE, BROMINE, AND IODINE
SUBSTITUTIONS
Iodinated alkanes have also been
synthesized and tested for their anesthetic
potencies, but these iodinated agents tend
to be chemically unstable and promote
cardiac arrhythmias.
HALOGENATED CYCLOALKANES
It was recognized early that
completely halogenated
cycloalkanes were poor
anesthetics and that these
compounds were often
convulsants.
Hydrogen substitutions into
halogenated cyclobutane
derivatives may result in an
anesthetic HALOTHANE
ETHERS Influence of carbon chain length and bonding
Diethyl Ethers
Methyl Ethyl Ethers
Isopropyl Ethyl Ethers
Cyclic Ethers
Influence of chemical substitutions
Thioethers
Chlorine and Bromine Substitutions
Convulsant Ethers
Isomers
Structural
Optical (Stereoisiomers)
ETHERS
The introduction of halothane into clinical
practice in the 1950s made apparent the
advantages of a nonflammable inhaled
anesthetic.
Nevertheless, halothane was also recognized
to be imperfect because of its requirement for
additives for stability in storage, its ability to
react with soda lime and undergo metabolic
breakdown, and the propensity of alkanes to
cause cardiac arrhythmias.
DIETHYL ETHERS
Because diethylether had been in clinical use since the 1840s, it was reasonable to expect that halogenated derivatives of diethylether might provide safer and nonflammable inhaled anesthetics.
The halogenated diethylethers were found to be poor anesthetics (as assessed by qualitative screening studies of the righting reflex in mice) and tended to produce convulsive activity
DIETHYL ETHERS
Unsaturated
derivatives (vinyl
ethers) enhanced
anesthetic potency
but were also
associated with
irritation and
instability. Banned from market because
of toxic components produced
from metabolic breakdown!
METHYL ETHYL ETHERS
Examination of a large series of
halogenated methyl ethyl ethers
in the 1960s and 1970s led to
the conclusion that the
compounds having the most
favorable anesthetic properties
contain either (1) one hydrogen
with two halogens other than
fluorine or (2) two or more
hydrogens with at least one
bromine or one chlorine.
Methoxyflurane
banned from
nephrotoxic effects
ISOPROPYL ETHYL ETHERS
Sevoflurane
[CFH2OCH(CF3)2],
containing no
chlorine atoms, is
the only isopropyl
methyl ether in
current clinical use
CYCLIC ETHERS
Although certain
cyclic ethers might be
expected to be potent
anesthetics and be
reasonably stable,
none have been in
clinical use and only
limited quantitative
information is
available on
anesthetic potencies.
Dioxychlorane
More potent anesthetic
than isoflurane in dogs
THIOETHERS
Qualitative screening studies in mice
showed that thioethers tended to be more
potent than their oxygen analogues, but
would probably not be clinically useful
compounds because of their unpleasant
odor, greater toxicity, and limited volatility.
CHLORINE AND BROMINE SUBSTITUTION
Initial screening studies in
mice revealed that chlorine
or bromine substitution into
ethers enhances anesthetic
potency and that insertion of
bromine is more potent than
chlorine.
Same with halogenated
alkanes
STRUCTURAL ISOMERS
The best-known pair
of anesthetic ether
structural isomers is
isoflurane and
enflurane ,empirical
formula C3ClF5H2O,
because these
agents are in routine
clinical use.
OPTICAL (STEREOISOMERS)
Because optical isomers of volatile
anesthetics can be isolated only in limited
quantities at great expense, most
experiments with these agents have
involved in vitro systems
In the rat, complete MAC determinations
have been performed after obtaining
adequate quantities of the isoflurane
stereoisomers, and the (+) isomer (MAC =
1.06% atm) is 53% more potent than the (–)
isomer (MAC = 1.62% atm)
CONVULSANT ETHERS
As noted previously,
ethers containing
end-methyl groups
that are completely
halogenated often
are poor
anesthetics and are
commonly
associated with
convulsive activity.
Flurothyl or
Hexafluorodiethylether
Substitute for
electroconvulsive therapy
INHALED ANESTHETICS
MONOGRAPH
ISOFLURANE
Isoflurane is a
halogenated methyl ethyl
ether that has a pungent,
ethereal odor.
Together with enflurane
and halothane, it replaced
the flammable ethers used
in the pioneer days
of surgery.
2-chloro-2-
(difluoromethoxy)-1,1,1-
trifluoro-ethane
or
1-chloro-2,2,2-trifluoroethyl
difluoromethyl ether
ISOFLURANE
Isoflurane is always administered in conjunction
with air and/or pure oxygen. Often nitrous
oxide is also used.
It is usually used to maintain a state of general
anesthesia that has been induced with another
drug, such as thiopentone or propofol. It
vaporizes readily, but is a liquid at room
temperature. It is completely non-flammable.
ENFLURANE
Enflurane is a halogenated
methyl ethyl ether that has a
pungent, ethereal odor.
Enflurane also lowers the
threshold for seizures, and
should especially not be used
on people with epilepsy. 2-chloro-1-
(difluoromethoxy)-
1,1,2-trifluoro-ethane
HALOTHANE
Halothane is a
nonflammable,
nonpungent, volatile,
liquid, halogenated
(F, Cl, and Br) ethane
It is the only
inhalational anesthetic
agent containing
a bromine atom
2-Bromo-2-chloro-
1,1,1-trifluoroethane
HALOTHANE
It is colorless and pleasant-smelling, but
unstable in light. It is packaged in dark-
colored bottles and contains
0.01% thymol as a stabilizing agent.
The use of inhaled anesthetics and
halothane in particular can produce
malignant hyperthermia (MH) in genetically
susceptible individuals.
COMPARATIVE ASSESSMENT OF ENFLURANE
(E), HALOTHANE (H), AND ISOFLURANE (I)
DESFLURANE
Desflurane is a
nonflammable, colorless,
very volatile liquid
packaged in amber-
colored vials.
It requires a vaporizer
specifically designed for
desflurane. 2-(difluoromethoxy)-
1,1,1,2-tetrafluoro-
ethane
DESFLURANE Not recommended for induction anesthesia in
children
Carbon monoxide results from the degradation
of desflurane by the strong base present in
carbon dioxide absorbents (most likely when
desiccation is present).
SEVOFLURANE
Sevoflurane is a
fluorinated methyl
isopropyl ether.
Sevoflurane is
nonpungent, has
minimal odor 1,1,1,3,3,3-hexafluoro-
2-
(fluoromethoxy)propane
NITROUS OXIDE
Nitrous oxide is a gas at room temperature
and is supplied as a liquid under pressure in
metal cylinders.
Nitrous oxide is a “dissociative anesthetic”
and causes slight euphoria and
hallucinations.
The low potency of nitrous oxide (MAC
104%) precludes it from being used alone
for surgical anesthesia.
NITROUS OXIDE
To use it as the sole anesthetic agent the
patient would have to breathe in pure N2O to
the exclusion of oxygen. This situation would
obviously cause hypoxia and potentially lead to
death.
Nitrous oxide is a popular anesthetic in
dentistry were it is commonly referred to as
“laughing gas.” It is used in combination with
more potent anesthetics for surgical anesthesia
and remains a drug of recreational abuse.
XENON
Xenon is an inert gas that is nonexplosive,
nonpungent and odorless, and chemically
inert, as reflected by an absence of
metabolism and low toxicity.
To date, its high cost has hindered its
acceptance in anesthesia practice