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


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


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

inhaled anesthethics

Documents