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are derived."

When oxidized, amy 1 alcohol is converted into valerianic acid
(CH3)2CH.CH2COOH
which maj'' be recognized by its odor.

TESTS

1. To test ordinary alcohol for fusel oil constituents: Mix
10 cc. of alcohol with 5 cc. of water and 1 cc. of glycerine and
allow the mixture to evaporate spontaneously from a piece of
filter paper. No odor should be perceptible when the last traces
of alcohol leave the paper. Compare this with a similar solution
to which 1 cc. of amyl alcohol has been added.

2. Warm 1 cc. of amyl alcohol with 2 cc. of concentrated
H2SO4. A rose red color is produced.

3. Heat 1 cc. of amyl alcohol with 1 cc. H2SO4 and a little
sodium acetate. Amyl acetate is produced which has a strong
smell of pears and is* known as pear oil.

4. Heat 1 cc. of amyl alcohol with 1 cc. ' H2SO4 and a
small crystal of potassium bichromate; valerianic aldehyde

/^

CH3(CH2)3C>^ is formed. This has a peculiar characteristic

H
odor.



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28 CHEMICAL PHABMACOLOGT

Valeric or valerianic acid (CH8(CH2)8COOH) is the acid cor-
responding to amyl alcohol, judt as acetic is the acid of ethyl
alcohol. There are four possible isomerides of valeric acid.
The normal valeric acid is N. propyl-acetic acid CH8CH2CH2.
CH2.COOH.

Valerian, which is used in medicine in (cases of hj steria and
other functional nervous trouble contains valerianic acid as the
active or odoriferous principle. The action in these cases is
psychic, and due to the impression made by the odor.

DIHYDRIC ALCOHOLS

These are of no pharmacologic interest except in illustrating
the influence of the change of the molecule on its physical and
physiological actions. The only dihydric alcohol that is used
at all is glycol or ethylene glycol,

CH2OH

I
CH2OH

Do not confuse this* with glycocoU (p. 67). The two hydrox-
yls here render the substance more soluble in water and less
soluble in other liquids, hence lessen the physiological activity
(See Meyer and Overton theory of narcosis). The introduction
of OH groups in this series also increases the sweetness of the
substance. Glycerine contains three OH groups and glucose five,
and they are sweeter in about this proportion. This is still more
strongly emphasized under trihydric or triatomic alcohol-
glycerine.

Glycerine, which contains three hydroxyl .groups is still less
active, and glucose, which is an hexatomic alcohol, is not toxic.
In fact, sugars are classified as foods rather than drugs.

Ethylene glycol is a thick, colorless, syrupy liquid with a
sweet taste (Greek, "glykys" meaning, sweet, and "ol,"
alcohol). It boils at 197.5° and mixes with water and alcohol
in all proportions. It was formerly recommended in the treat-
ment of tuberculosis, but is now considered worthless for this
purpose.

Glycol is formed when choUne is heated:



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GLYCOL 29

CHa CH2.CH2OH CHav

CH3— N— OH > CH3— ^N + GH2OH

CH3 CHa^ CH2OH

Choline Tri-methylamine. Glycol

Nitric acid oxidizes glycol to oxalic acid :

CH2OH CHO CHO COOH

I - I - I - I

CH2OH CH2OH CHO COOH

Glycol glycolaldehyde glyoxal oxalic acid

These products are formed when glycol is oxidieed in the body.
Oxalic acid is also formed from cellulose on treatment with caustic
potash, but it is doubtful if any such action occurs in the animal
body.

Glycolaldehyde is one of the products of the oxidation of
dextrose with alkalies and is thought by some to be formed in
the oxidation of sugars in the body.

TRIHYDRIC ALCOHOLS

Of trihydric or triatomic alcohols, glycerine only is important.
It is used extensively in medicine.

CH2OH

I .

CHOH

I
CH2OH

It has a strong avidity for water, and because of this when applied
to mucous membranes it is irritating. All ordinary fats are
esters of glycerine and a fatty acid. Glycerine is sweeter than
gilycol and is the only trihydric alcohol found in nature.

Chemical Tests

1. Test the solubility of glycerine in water, alcohol, and ether.
The increase in hydroxyl groups, as a rule, decreases the solu-
bility in ether, and increases the solubility in water. Compare
this with other alcohols.



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30 CHEMICAL PHARMACOLOGY

2. Taste alcohol, glycol, glycerine, and glucose. The hexoses
are alcoholic compounds. Increasing the hydroxyl groups is in
some way connected with the sweet taste, though not absolutely
essential to the taste, for benzosulphinidum, lead acetate, etc.
which have no (OH) groups may be five hundred times sweeter
than sugar (see p. 210).

•3. Heat a few drops of glycerine with a small crystal of KHSO4
over a free flame. It is dehydrated with the formation of acro-
lein ("Acer,** acrid, and "oleum," oil).

C3H6(OH)3 = C3H4O + 2H2O or C3H5(OH)3 = CH2 : CH.CHO

+ 2H2O

Glycerine is .used to a considerable degree in medicine. It
was formerly recommended in the treatment of diabetes, as a
sweetening agent to replace sugar^ It has been found, however,
to be of little use in these cases. In larger doses (5-20 cc.) it
is a laxative, but may produce gastro-enteritis. It is used in
suppositories as rectal enemata in cases of constipation; as a
vehicle or solvent for many drugs, and especially in the glycerites
of tannic acid, starch, and boroglycerine. It has some power as
a germicide, and is used to preserve vaccine lymph. The use of
it in skin diseases combined with substances Uke benzoin, for
chapped hands, Ups, or other parts is common. It has many
other uses in medicine.

HIGHER ALCOHOLS

Cetyl alcohol, CieHsaOH, is found in spermaceti, and myricyl
alcohol, C30H61OH, in waxes. These alcohols in waxes corre-
spond to the glycerine of ordinary fats; this is the main differ-
ence between the fats and waxes (g.v.). In waxes the fatty acid
also is higher in the series (niore C atoms) than the palmitic,
stearic or oleic acids of the ordinary fats.

SULPHUR ALCOHOLS OR MERCAPTANS

The sulphur alcohols correspond to the ordinary alcohols in
which (S) takes the place of (O). Ethyl mercaptan is formed
from ethyl chloride and potassium sulphydrate in alcohol solu-
tion: CsHbCI + KSH = C2H6SH + KCl

The sulphur confers greater chemical reactivity and also greater



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GENERAL ACTION OF ALCOHOLS 31

pharmacological activity on the alcohols. While the OH in
ordinary alcohols is replaceable only with Na, or K, the mercap-
tans react also with heavy metals. The name comes from their
reaction with mercury (mercurium captans) :

2C2H5.SH + HgO = (C2H5S)2.Hg + H2O
The sulphur alcohols are not used directly in medicine, but are
used in the manufacture of some medicinal agents. Ethyl mer-
captan is important because it was the first discovered mercaptan,
and because it forms the basis for the manufacture of the sul-
phone group of hypnotics, of which sulphonal or sulphonmethane
is the most important.

THE PHARMACOLOGY OB THE ALCOHOLS IN RELATION TO
THEIR CHEMISTRY

The relative inertness of the paraffins is markedly activated
by the introduction of the OH groups. The monhydric alco-
hols are pronounced narcotics, which action, seems to depend
on the hydrocarbon radical. Thus, CH4 is inert, CH3OH, nar-
cotic. Further oxidation destroys the CH3 groups, and the nar-
cotic action is lost. Ethane CH3CH3 is inert, ethyl alcohol
CH3CH2OH is narcotic, while if both CH3 groups in ethane are
oxidized giving glycol, CH2OHCH2OH, it is inactive. All
hydrocarbons are relatively inert except those that are volatile
liquids and have a solvent action.

Propyl Jalcohol, CH3CH2CH2OH, is more toxic than ethyl,
but when two more OH groups are substituted for H, as in
glycerol, CH2OH.CH.OHCH2OH, it loses its soporific and toxic
action. In large doses it may produce restlessness, tremors, and
even tetanus. These actions, however, are less than those of
propyl alcohol, and are apparently more on the motor than on
the sensory side of the nervous system.

As the number of carbon atoms in alcohols increases, the toxic-
ity increases. The six carbon alcohols or aldehydes correspond-
ing to the hexanes are highly toxic, while the corresponding
sugars are foods. Thus, normal hexane CH3CH2CH2CH2CH3
is actively intoxicant, producing, excitement followed by deep
anesthesia when inhaled. Glucose, CH2OH (CH0H)4CH0, has
no toxic properties in any amount. Secondary alcohols are
more toxic than primary, and tertiary more than secondary.



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32 CHEMICAL PHABMACOLOGY

The action of the alkyl radical of the alcohol is especially
noticeable in the tertiary alcohols where it is found that the
larger the alkyl radical attached to the carbon carrying the
hydroxyl, the more pronounced is the action, e.g.,

4 grams of tri-methyl carbinol (tertiary butyl alcohol)

(CH3)8COH, or
2 grams of dimethyl ethyl carbinol (CH8)2<v

■^OH, or
C2H6
1 gram of tri-ethyl carbinol (C2H6)8COH have about the
same sleep-producing power. A similar characteristic has been
observed in other compounds.
CH2OH
Glycol, I the dihydric primary alcohol, is inert, but if

CH2OH
alkyl groups are introduced, in place of the hydrogen attached
to the carbon, substances known as pinacones are formed (Gr.
pinax, pinak tablet). It has been foimd that 10 grams of methyl
pinacone

(CH8)2COH ^ ^ . .K 1 • (C2H6)2COH

(CH3)2COH "^ ^-^ ^^^^ "^ ''^^^ P^^^^"^^' •(C2H.)2COH

have about the same sleep-producing or depressing action.

These examples show clearly the pharmacological action of
alkyl radicals, which are hypnotics or depressants of the central
nervous system, and the greater the molecular weight the greater
the depression produced.

IV. ANESTHETICS, NARCOTICS, SOPORIFICS,
HYPNOTICS

The alkyl radicles are nerve depressants, and affect the cere-
brum especially. According to the degree of depression pro-
duced, several terms are used to define the condition.

Hypnotics, soporifics or somnifacients are used to produce
sleep. Alcohol, ether, or chloroform, in the proper dose may be
used, but more often milder bodies such as chloral, paraldehyde,
the sulphones, veronal, or similar drugs are used.

Narcotics produce a condition of narcosis or coma. The
depressant action is more profound than the hypnotic state and



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ANESTHESIA



33



may be produced by larger amounts of the same drugs. In
addition to the aliphatic narcotics mentioned, urethane and
morphine readily produce narcosis. The aliphatic anesthetics
most used are ether, ethyl chloride, and chloroform. Nitrous
oxide, although not an aliphatic preparation is usually studied
with them. The action of each of these is practically the same
as alcohol, but the stages of the action are more prolonged in
alcohol intoxication. Some stages in general anesthesia pro-
duced by ether or chloroform ^may be so fleeting that they are
difficult to observe.

Four distinct stages may be observed following the administra-
tion of the aliphatic narcotics and hypnotics.

Dixon gives the stages with the symptoms of ether anesthesia
as follows:



Stage I.



Disorganized

consciousness

and

analgesia



Stage 2.



Excitement
and

Unconscious-
ness



Irritant action of the vapour on the nasal and

bronchial mucous membrane.
Reflex effects — coughing, salivation, respiratory,

cardiac.
Disturbances of judgment.
Loss of memory and self-control.
Emotional tendencies.
Distiu-bances of special senses.
Analgesia.
Vertigo and ataxia.

Quickened pulse and rise in blood-pressure.
Increased respiration.
Dilated pupils.

Coughing, retching, vomiting.

Delirium varying from shouting to inarticulate

muttering.
Tonic, and clonic muscular spasm.
Reflexes diminished.
Unconsciousness.

Respiration irregular from the struggling.
Pulse accelerated and pupil dilated, both from

excitement.



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34



CHEMICAL PHABMACOLOGY



Stage 3.



Surgical
Anesthesia



Stage 4.



Leading to
Bulbar para-
lysis



Muscular relaxation.

Loss of reflexes.

Breathing regular, often "snoring."

Decrease of respiratory exchange.

Fall of temperature.

Fall of blood pressure.

Pupil small; does not react to light.

Loss of bladder and rectal reflexes.

Paralysis of vaso-motor centre (great fall of

blood-pressure).
Paralysis of respiratory centre.
Widely dilated pupils.
Great depression of cardiac muscle.



The amount of chloroform in the blood during light anesthesia
is 25 to 35 mgs. per 100 cc. If the concentration is raised to 40-70
mgs. per 100 cc. respiration fails. Diuing Ught ether anesthesia
there are 100-110 mgs. per 100 cc, and 130 to 140 mgs. in deep
anesthesia. 160 to 170 mgs. per 100 cc. causes failure of respira-
tion. In deep alcoholic coma in man Sweisheimer found that
the blood contained 2.25 parts per 1000 cc. Grehant found that
6 parts alcohol per 1000 cc. blood was invariably fatal to
animals.

Whether the heart or respiration stops first depends on the
method of administration. Large concentrations especially of
chlorine containing anesthetics, if too quickly administered,
paralyze the heart before respiration. When present in the
respired air, in the per cent, given, Cushny tabulates the differ-
ences between ether and chloroform as follows:

Chloroform Ether

0.5-0.7 per cent. 1.5-2.5 per cent. Insufficient to cause anes-
thesia.

1.0 per cent. 3-3.5 per cent. Causes anesthesia on pro-

longed inhalation.

2.0 per cent. 6.0 per cent. Arrests respiration after

sometime.



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ANESTHETICS



35



The amount of anesthetic in 100 cc. of the blood shows the same
proportion and is as follows:



Chloroform
25-35 mgs.
40r-70 mgs.



Ether
100-140 mgs.
160-170 mgs.



Anesthesia
Respiratory arrest.



According to the concentration of chloroform in the respired air,
Rosenfeld gives the following series of experiments to show the
effects:

Relationship Between the Percentaob op Chloroform -in the Re-
spired Air and the Depth and Rapidity op the Anesthesia (Rosenfeld,

Spenzer)
(From Meyer & Qottlieb)



Chloroform


Time necessary


Depth of




percentage in


to induce


anesthesia or


Remarks


respired air


anesthesia


narcosis




0.54-O.69


2hrs.


No narcosis


Somnolence only.


0.96-1.01


30-40 min.


Complete


Blood-pressure at first nor-
mal then gradual fall for
4 hrs. Respiration nor-
mal.


1.16-1.22


30min.


Complete


Cessation of resphation at
end of 2 hrs.


1.41-1.47


37 min.


Deep


As above after 1 hr.


1.63-1.66


12 min.


Deep


As above after 30 min.


Ether








percentage in








respired air








1.5


2hrs.


Hardly any


Slight somnolence only.


2.5




Very incom-
plete


Reflexes maintained.


3,2-3.6


25 min.


Complete


Respiration and cardiac
function remained good
for hours.


4.45


15 min.


Complete


Respiration slow and regu-
lar; pulse accelerated.


6.0






Respiration ceased in 8-
10 minutes.



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36 CHBMICAL PHABMACOLOGY

THEORIES REGARDING THE CAUSATION OF ANESTHESIA

Both chemical and physical theories have been advanced
to explain the action of ether and chloroform in producing
anesthesia.

1. The Meyer-Overton Theory. — Meyer and Overton think
that anesthesia is due to the solvent action of the anesthetic on
the lipoids ot the central nervous system. The anesthetics are
also somewhat soluble in water, and the anesthetic value depends
on the distribution, coefficient, i.e. the ratio of the solubility
in fats (S/F) to the solubility in water (S/W). The most power-
ful anesthetics are very soluble in fats and but little soluble in
water. Meyer studied many aliphatic narcotics and arranged
them in the order of their potency. These are expressed in the
fractions of normal solutions, that will produce the first definite
physiological effect, which he calls the liminal value.

Liminal value in Distribution SP

terms of normal r«^«:«;*«* ow

solution Coefficient SW

Trional 0.0018 4.46

Tetronal 0.0013 4.04

Sulphonal O.OOB 1 . 11

Butylchloral hydrate 0.002 1.59

Bromal hydrate 0.002 0.66

Chloral hydrate 0.02 0.22

Ethyl methane 0.04 0. 14

Methyl methane 0.4 0.04

Monacetin 0.05 0.06

Diacetin 0.015 0.23

Triacetin 0.01 0.3

Chloralamide 0.04

Chlorhydrin 0.04

Dichlorhydrin 0.002

While this theory is attractive, it merely explains how the
drug gets to the place of action, and Cushny has pointed out
that some benzene derivatives are good lipoid solvents and have a
high distribution coefficient, yet are without narcotic action.
Again cells rich in lipoid substances are not always attacked in
relation to this substance. The peripheral nerves are much less



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ANESTHESIA 37

influenced than the central nervous system. Baumann and Kast
give the following table to show that narcotic action depends
on the presence of ethyl radicals. -

Action Distribution
Coefficient

Dimethyl-sulpho-methane very sUght . 106

Dimethyl-sulpho-ethane sUght .151

Sulphonal (Diethyl sulphone dimethyl methane) marked 1 . 115
Trional (Diethyl sulphone methyl ethyl methane)

more marked 4.46
, Tetronal (Diethyl sulphone diethyl methane) more marked 4 . 04

2. The Theory of Moore and Roaf. — They believe that the
action of the anesthetic is due to a loose combination of the anes-
thetic with the cell proteins. A certain concentration of the
anesthetic in the blood is necessary to maintain the combination.
Lipoids may aid in keeping the necessary concentration of the
anesthetic around the living protein, and to this extent the
Meyer-Overton theory may hold.

3. Verwom's Theory. — He accepts the Meyer-Overton theory
to some extent, but believes that the fundamental action is the
prevention of oxidation by the cell. In the last step anesthesia
is an asphyxiation. Due to the presence of the anesthetic the
nerve cells cannot utilize the oxygen that may be present.

Many other theories have been presented but none are Entirely
satisfactory. In this connection it should be mentioned that
physiologists have been unable to present a satisfactory theory
to explain natural sleep.

The Hyderabad Commission — 1889 and 1890

Because of the difficulty of handling ether in hot climates
such as India, the Nizam of Hyderabad caused an investigation
to be made of the relative values of ether and, chloroform as
anesthetics, especially with reference to the action on the heart.
The commission concluded after numerous experiments that
the only means by which the heart's safety is jeopardized is
through paralysis of respiration. Accordingly respiration always
stops first. This report is both right and wrong. According to



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38



CHEMICAL PHABMACOLOOY



the conditions of their experiments, where the anesthetic in
the respired air is dilute and gradually increased, respiration
stops first. If, however, the concentration in the respired air
is too great at the beginning, or is quickly increased, the heart
may stop first due to direct action on and paralysis of the heart
muscle. It is quite possible, therefore, to have either respiration
or heart stop first, or both at the same time^ Consequently,
therefore, in giving an anesthetic, it is necessary to watch both
heart and respiration.

The relative toxicity of ether and chloroform on the heart
was found by perfusing the isolated heart through the coronary
vessels. To stop the heart's action 0.015 per cent, chloroform
or 0.4 per cent, of ether was required. This indicates that
chloroform is about 25 times as toxic as ether. On the respira-
tory center chloroform is about 4 times as toxic as ether.

Ether and chloroform are excreted mainly by the lungs. Ether
is excreted only in this way. Small amounts of chloroform have
been found in the urine and milk, but the statement that some
carbon monoxide is formed from chloroform in the body is
erroneous. Chloroform may be detected in the breath for 24
hours after narcosis. Nicloux gives the following figures to show
the disappearance from the blood.



Chloroform Content of Blood after Termination of Anesthesia



Time elapsed since termination of anesthesia


Per cent, of chloro-
form in blood




Exp. 1


Exp. 2


minutes


0.054

0.0255

0.0205

0.018

0.0135


0.0595


6 minutes




16 minutes




30 minutes


0.023


1 hour


0.018


3 hours


0.0075


7 hours


0.0015







Ether is eliminated somewhat more rapidly, which explains
the more rapid recovery from ether narcosis.



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ETHER ANESTHESIA 39

Ether Content of Blood afteb Tbbmination op Anesthesia



-


Per cent, of ether
in blood




Exp. 1


Exp. 2


minutes


0.115
0.071
0.063
0.052
0.025


0.159


3 minutes


0.108


5 minutes.


0.080


15 minutes


0.058


1 hour


0.021


2 hours


0.004







ETHER OR ETHYL OXIDE



Ether is prepared by mixing alcohol and sulphuric acid and
distilling. The following formula indicates the reaction.



C2H&



C2H5OH + Ss04 = ' %S04 + H2O
W H ^



H



C2HBOH + C2H5^ = }0 + H2SO4

Ether used for anesthesia is chemically pure ethyl ether.

CHEMICAL TESTS

1. Specific gravity 0.713 to 0.716 at 25^C. Boils at 35*^0.
which is below body temperature (37°C.)

To show inflammabiUty of ether apply a flame to 1 cc. of it in
a small dish. Repeat this with chloroform.

2. Shake ether with an equal volume of CS2. The mixture
becomes turbid if the ether contains water, not otherwise. Ether
will dissolve about 10 per cent, water. Anilin violet colors ether
which is adulterated with alcohol, but does not the pure ether.

3. Shaken with 3^0 volume of 5 per cent. KOH, no color
should be developed in either Uquid in the absence of aldehyde.

4. Ether is miscible with alcohol, benzine, chloroform, benzene,
fixed and volatile oils, and lipoids in all proportions. Test the



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40 CHEMICAL PHABMACOLOGY

solubility of oils, fats, lanolin, and other lipoids in ether. C/. the
Overton-Meyer theory of Narcosis, p. 36.

5. Na will not act on dry ether due to the absence of hydroxyl.

6. Strong acids decompose ether with the formation of ethereal
salts. The action of H2SO4 on alcohol is much more complete.
Similarly in the body, ether is excreted unchanged, while alcohol
is almost completely oxidized.

The replacement of the hydrogen hydroxyl in alcohol results
in marked physical and chemical changes. C2H6OC2H6 is much
more volatile than CsHbOH. The more volatile a substance the
more quickly it penetrates, consequently it acts more quickly
when takei^ into the body.

In the body, alcohol is rapidly and almost completely oxidized.
Ether is not oxidized in the body, but is a catalytic poison, i.e.,
it causes a marked reaction by action in the body without itself
undergoing any change. When oxidized outside the body it
yields the same products as alcohol. Ethers of the marsh-gas
series are always more active than the corresponding alcohol.

CH2OH
Glycerine — CHOH is inert, but when converted into glycerine

CH2OH
ether
CH2— O— CH2
CH — 0— CH
CH2— 0— CH2

it becomes narcotic. The narcotic action of the alkyl radical
is manifested in other compounds. Phenol CeHgOH which is
antiseptic and stimulating to the motor side of the cord loses its
antiseptic and stimulating action when converted into phene-

tol, C6HB.O.C2HB.

NH3, which is stimulating, loses its convulsant action as the
hydrogen atoms are replaced by alkyls and the quaternary
ammonium bases have a curara-like action.

Urea also becomes depressant when alkyl groups are sub-

NH2 " .N(C2H5)2

stituted for H, as when CO^^ becomes C0<^

^NH2 ^NH(C2H6)

These examples again show the depressant and hypnotic action
of the alkyl groups.



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HYPNOTICS 41

ETHYL CHLORIDE

Ethyl chloride, C2H5CI, is prepared bypassing HCl gas through
alcohol in which anhydrous ZnCl2 is dissolved, the ZnCU acting
as a catalytic and dehydrating agent. At ordinary temperatures
it is a gas whi<;h boils at 12.5*H;5. It is freed from HCl by passing
through water.

This compound, like chloroform, illustrates the influence of
introducing CI into the molecule. It is twice as soluble in water
as in the blood, and is sometimes used as a general anesthetic,
especially in nose and throat work. It has a greater paralytic
action on the heart muscle than ether, but much less than chloro-
form. All anesthetics containing chlorine act strongly on the
heart, as depressants.

Its main use is as a local anesthetic, the action being due to its
rapid evaporation. Freezing with any other agent would have



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