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., 5075% 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 . values correspond well with the oil/gas partition coefficient, which is easier to determine experimentally.

These

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. 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

B. SOLUBILITY
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. 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

In

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.

TABLE OF POTENCIES OF GASES

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 ndecane 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 nalkanol with a given number of carbons is more potent than the nalkane 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. cyclopropane and ethylene were at one time routinely administered to patients and did have some favorable properties there were distinct disadvantages.

Although

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). partially fluorinated pentanes, hexanes, and heptanes did not produce anesthesia when administered alone at their vapor pressures

Most

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. 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.

Nevertheless,

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. 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

The

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 Methoxyflurane contain either (1) one hydrogen banned from with two halogens other than nephrotoxic effects fluorine or (2) two or more hydrogens with at least one bromine or one chlorine.

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)-1,1,1trifluoro-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-chloro1,1,1-trifluoroethane

HALOTHANE
It

is colorless and pleasant-smelling, but unstable in light. It is packaged in darkcolored bottles and contains 0.01% thymol as a stabilizing agent. use of inhaled anesthetics and halothane in particular can produce malignant hyperthermia (MH) in genetically susceptible individuals.

The

COMPARATIVE ASSESSMENT OF ENFLURANE (E), HALOTHANE (H), AND ISOFLURANE (I)

DESFLURANE
Desflurane

is a nonflammable, colorless, very volatile liquid packaged in ambercolored vials. It requires a vaporizer specifically designed for desflurane.

2-(difluoromethoxy)1,1,1,2-tetrafluoroethane

DESFLURANE
Not

recommended for induction anesthesia in children monoxide results from the degradation of desflurane by the strong base present in carbon dioxide absorbents (most likely when desiccation is present).

Carbon

SEVOFLURANE
Sevoflurane

is a fluorinated methyl isopropyl ether.

Sevoflurane

is nonpungent, has minimal odor

1,1,1,3,3,3-hexafluoro2(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. date, its high cost has hindered its acceptance in anesthesia practice

To