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Hugh McGuigan.

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in potassium f erro cyanide which does not ionize but remains as a
salt is without action.

Diffusion. — When two or more gases are brought together with
no physical barrier to separate them, they soon form a homogene-
eous mixture; e.g., when gas is liberated in a room, it soon spreads
throughout the whole space and mixes uniformly with the oxygen
and nitrogen of the air. This process of mixing is called diffusion.

Osmosis. —If two miscible liquids are placed in the same vessel,
in a short time they will diffuse or mix imiformly just as gases.
This process is due to the movement of the molecules and is slower
in liquids than in gases. If the liquids are separated by a mem-
brane and the diffusion occims through the membrane, the proc-
ess is known as osmosis. Not only water but salts and crystal-
loids generally will pass through the membrane. Colloids diffuse
through a membrane very slowly.

If the process of osmosis is used to separate one substance from
another, as in the separation of crystalline substances from
colloids, the process is known as dialysis.

GAS PRESSURE IN RELATION TO OSMOTIC PRESSURE

It has been proved that the osmotic pressure, or osmotic
suction, of a crystalloid is the same as would be exerted by the
same number of particles of a gas if it were confined in the same
space. To illustrate; if a gram molecular weight of any gas
oxygen H2 = 2 grams O2 = 32 grams N2 = 28 grams is confined
in a liter volume at 0** (zero) centigrade, it will exert a pressure
of 22|32 atmospheres, or the converse of this a gram molecular



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376 CHEMICAL PHARMACOLOGY

weight of any ga^ at ordinary pressures occupies a volume of
22.32 litres. This is in accordance with the gas law; Pressure
times volume = pressure times Volume, or Pv — pV.

Crystalline substances do not pass into the gaseous state
without decomppsition, but when in solution they exert the same
pressure as they would if they were in a gaseous state in the same
volume. For instance, the gram molecular weight of cane sugar,
C12H22O11, is 342 grams. If this amount of cane sugar is dis-
solved in water and made up to 1 litre, it will exert a pressure of
22.32 atmospheres. An ion exerts the same influence as a
molecule, consequently, if a substance which contains two ions in
the molecule is completely ionized, the pressure will be doubled,

as in a very dilute solution of sodium chloride. In the case of

+ ■»• -

sodium sulfate, which ionizes into Na — Na — SO4, complete
ionization would make the pressure three times the molecular

pressure. In sodium phosphate, Na2H PO4, in complete ioniza-

+ + +

tion Na — Na — H — PO4 the complete pressure would be four

times the molecular. Calculation of osmotic pressure of solutions
that do not ionize is an easy task. All that is necessary is
to know the molecular weight of the substance and the concentra-
tion. For example:

I. To calculate the osmotic pressure of 5 per cent, cane sugar
solution. 342 grams in 1 liter or 34.2 per cent. = 22.32 atmos-

* 5

pheres. 5 per cent. = vr^^ times 22.32 atmospheres.

II. 5 per cent, solution of NaCl — assuming no ionization —

58.5 grams in 1 liter or 5.85 per cent. = 22.32 atmospheres

5
5 per cent. = -^^^ times 22.32 atmospheres.

If there is a certain percentage of ionization however the osmotic
pressure will be increased accordingly.

DIFFICULTIES IN DETERMINING OSMOTIC PRESSURE

The pressure exerted by a molecular solution is so enormous
that it is hard to get a semi-permeable membrane that will stand
the strain. Before the theoretic level is reached, most mem-
branes rupture. The nearest approach to a semi-permeable



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SALT ACTION 377

membrane that would stand the strain was devised by Pfeffer.
He used a porous clay cell and filled it with a solution of copper
sulfate and set it in a solution of potassium ferro cyanide. As
the two solutions permeated the porous clay they met and formed
a precipitate of copper ferro cyanide, which functions as a semi-
permeable membrane. Most animal membranes and collodion
tubes are only partially semi-permeable. Salts will pass in both
directions and while they answer for the ordinary purposes of
dialysis they cannot be used to determine or measure the extent of
osmotic pressure. In biological work the osmotic pressure is
not determined directly, but indirectly, from the freezing point.

RELATION OF OSMOTIC PRESSURE TO THE BOILING POINT AND
FREEZING POINT OF SOLUTIONS

The rise in the boiling point of a water solution of a substance,
provided the substance does not change on heating, bears a
direct relation to the number of molecules or ions in the solution.
An. ion exerts the same influence as a molecule. Since most
biological fluids contain proteins, and change in physical proper-
ties on heating, the boiling point method cannot be used.

Freezing Point Method. — This method is available in biological
work. It is simple and convenient. Each mol-ion added to a
liter of water depresses the freezing point 1.85°C. This depres-
sion of the freezing point is designated by A. Solutions with the
same freezing point have the same osmotic pressure. * To calculate
the freezing point of a pure substance in water, we must know its
formula and the per cent, of the solution. For example; to calcu-
late the freezing point of 1 per cent. NaCl. A molecular solution
of sodium chloride is 58.5 grams to the liter, or 5.85 per cent.
This depresses the freezing point 1.85°C. 1 per cent, solution

depresses it -^o-? of 1.85° C. or. 316°C. This assumes no ioniza-
tion. In actual work it is found that A = 0.589 which shows a
high per cent, of ionization. The freezing point of a 1 per cent,
solution of cane sugar, since a molecular solution of sugar — 342
grams in the liter or 34.2 per cent, is 144-2 of 1.86°C. or -0.054°C.
To Calculate the Osmotic Pressure from the Freezing Point.
The osmotic pressure of a molecular solution is 22.32 atmospheres
or 16,986 millimeters of mercury. This height of mercury is



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378 CHEMICAL PHARMACOLOGY

equivalent to a temperature reduction of 1.86°C. The osmotic
pressure of 1 per cent, cane sugar is therefore 16,986 : 1.86 : .054 :

0.054
X.or^'gg times 16,986 = 493 millimetres of mercury.

SALTS IN THE BODY

Certain salts are necessary for life, but the amount of these is
small (see p. 2). They exist in the body mainly as ions. The
freezing point of mammalian blood is .526; (varies from .480 to

.605) ; hence the osmotic pressure is y-^ times 22.3 atmosphere

or about 7.25 atmospheres. This is due almost entirely to
salts, sugar and urea. The proteins contribute but a small part
to the total osmotic pressure.

The average freezing point of serum is -0.6°C. 0.95 per cent.
NaCl has this same freezing point and is, therefore, iso-osmotic

or isotonic. The osmotic pressure calculated from this is t^X

22.32 = 7.24 atmospheres.

Calculated on the percentage basis and assuming no ionization,
a molecular solution of NaCl = 58.5 grams in a litre or 5.85
per cent. = 22.32 atmospheres. .95 per cent. NaCl should equal

95
^^ of 22.32 atmospheres = 3.62 atmospheres. Assuming no

ionization, the osmotic pressure here is just one half of that found
by direct determination, hence normal saline must be completely
ionized.

The action of sodium chloride when injected into the circulation
is not noticeable on the blood pressure or circulation. A solution
of KCl of the same osmotic pressure causes a pronounced depres-
sion of the heart. Since CI, as judged from the action of NaCl,
has no action, the action obtained from KCl must be due to the
K ion. This illustrates the difference between salt action and
ion action. Isotonic saUne solutions can exert no salt action,
and if an action results, it must be an ion action. Both ions
usually have some action, but in most salts one of the ions is
much more powerful pharmacologically than the other. K in
the KCl is the important ion, but in the case of KCN the CN
ion is so much more toxic than the K that the action of KCN is



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TOXICOLOGY 379

attributed almost entirely to the CN ion. Some drugs are not at
all dissociated in the body and therefore the only action they
exert is the molecular or salt action. Ether, sugar and alcohol are
not ionized. They exert only a salt action. Some of these,
however, may be broken down in the body and their cleavage
products may form ionizable compounds. Alcohol and sugar
yield CO2. This may react with the fixed bases of the body to
form carbonates, Na2C03, etc. The carbonates may be hydro-
lyzed to form NaOH which ionizes into Na + OH. While
alcohol contains the group OH, it does not ionize and it exerts
only a molecular action unless broken down.

SALT ACTION IN PHARMACOLOGY

Salts have the same importance in pharmacology as in physiol-
ogy, but in addition, many salts used as drugs owe most of their
action to osmosis, dialysis, and diffusion. This is especially
true of the cathartic salts. Because these are not absorbed from
the gut, the physical properties above enumerated suffice to
explain their action. In most cases when salt is administered
some is absorbed, and may either be excreted into the gut again
or by the kidneys. When excreted by the kidneys, salts exert
osmotic effects on the convoluted tubules. Some are reabsorbed
from the tubules, others such as sodium sulphate, are but little
reabsorbed and hence act as better diuretics than the chloride.
The diuretic action of these salts can be seen best when they are
injected into the circulation. Other instances of the osmotic
effects of salt might be cited, but none more impressive.

XXXVI. TOXICOLOGY
THE ISOLATION OF POISONS

For analytical purposes, poisons may be divided into groups
as follows:

Group I. — Volatile poisons which distil with steam from acid
solution without decomposition, and can be detected in the
distillate. They are arranged in the order of their boiling point —
which is about the order in which they would appear in the
distillate:



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380



CHEMICAL PHARMACOLOGY



Chloral hydrate 97°

Iodoform — m.p IIO**

Benzaldehyde 179°

Phenol ...180°

Aniline 183°

Creosote 200°+

Nitrobenzene 208°



Yellow phosphorus

Hydrocyanic acid 26°

Carbon disulphide 46°

Acetone.., 57°

Chloroform 61°

Methyl alcohol 67.4°

Ethyl alcohol 78°

Group II, — Non-volatile organic substances which can be ex-
tracted from extraneous matter with hot alcohol, after acidifica-
tion with tartaric acid. The principal members of this group
are:

The alkaloids, neutral principles, some glucosides and bitters,
synthetic organic drugs such as the sulphone hypnotics, the
antipyretics, phenacetine, acetanilide, antipyrine, pyramidone,
etc. After separating protein, fats, gums, resins, etc. that may
be mixed with these drugs in cases of poisoning, non-volatile
poisons may be subdivided into groups based on analytical
methods. One of the methods is the Stas-Otto process which
consists in extracting the Uquid in a separatory funnel with
immiscible solvents. Those extracted with ether when the
solution is acid are :

A. Acetanilide Colchicine Picrotoxin
Antipyrine Picric acid Salicylic acid
Caffeine Phenacetin Veronal

B. Those extracted with ether when the solution is made
alkaline with sodium hydroxide:

Aniline Codeine Pilocarpine

Antipyrine Coniine Pyramidone

Atropine Hydrastine • Quinine

Brucine Narcotine Scopolamine

Caffeine Nicotine Strychnine

Cocaine Physostigmine Veratrine

C. Those extracted with ether, in a solution made alkaline with
ammonia. The solution from the sodium hydroxide extract, is
first made slightly acid, and then ^IkaUne with ammonia. Ether
will extract from this alkaline solution apomorphine and traces
of morphine.



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TOXICOLOGY 381

D. Those extracted by chloroform. After the ether extract
from the ammoniacal solution has been removed, chloroform
will extract the following, if present:

Antipyrine
Caffeine
Morphine
Narceine

Group III. Metallic Poisons. — These may be found in the
residue after the extraction of the organic poisons, or an original
portion may be used to test for them. Before testing for these,
all organic matter must be destroyed. The most important
metallic poisons are:

Antimony Cadmium

Arsenic Chromium

Barium Lead

Bismuth Mercury
Tin

Group IV. — Poisons not in groups and for which special direct
tests must be made — the most important are:
(o) The mineral acids— HNO3, HCl, H2SO4.
(6) Oxalic acid.

(c) AlkaUes— NH4OH, NaOH, KOH.

(d) Chlorates.

(e) Miscellaneous organic:



Cantharidin


Opium


Cytisine


Santonin


Digitalis — glucosides


Saponins




Solanin


Ergot principles


Sulphonal


Pilocarpine


Trional


Ptomaines


Toxalbumins —




Abrin




Crotin




Curcin




Ricin




Robin



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382 CHEMICAL PHARMACOLOGY

METHODS OF ISOLATING POISONS

The tests made with pure substances, give one but little
conception of toxicology. The isolation of poisons, from stomach
contents or from the liver, and the preparation of these for
testing is more important than the tests, and much more difficult.

THE ISOLATION OF VOLATILE POISONS

The volatile poisons include those that are volatile in steam in
acid solution. The acid usfed must be non-volatile, especially
suitable is tartaric, but dilute sulphuric or phosphoric may be
used. Note that this group does not contain the volatile alka-
loids — nicotine, coniine, sparteine. Because the solution is
acid, salts of the alkaloids are formed, and these are not volatile.
Before distilling, certain preliminary tests are made. These
may shorten or obviate the necessity of much work.

Preliminary Test for Phosphorus
Scherer's test.

This is founded on the fact that phosphorus in a solution of
silver nitrate, acidified with nitric aeid, forms silver phosphide
(AgaP).

The vapor of phosphorus will give this test with filter paper
moistened with the silver nitrate solution. Hydrogen sulphide
will also darken silver nitrate so a control test must be made along
with the preliminary test, as follows: (See Fig. 3.)

Place some of the solution to be tested in a distillation flask,
with a cork stopper. Moisten a strip of filter paper about
6-10 cm. along, and 1 cm. in width, with the silver nitrate solu^
tion, a,nd insert this in a V-shaped slit in one side of the cork,
moisten another, similar piece of paper, with lead acetate, and
place this in a slit in the other side of the cork. Be sure that the
papers do not touch each other. Place the cork in the flask,
and set the flask on a water bath at about 50°C.

It is advisable to protect the papers from light, since light
colors the silver to some degree.

Discussion of Results

(a) If the silver paper only is darkened phosphorus may be
present.



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TOXICOLOGY



383



(6) If both papers are darkened HoS is also present, and in
either case the test for phosphorus should be made. Any-
volatile organic reducing substance such as formaldehyde or
formic acid may also darken the papers.

(c) If neither paper is darkened, phosphorus is absent and
further tests for phosphorus need not be made. The preliminary
test is more important therefore ih establishing the absence of
P. than its presence.




Fig. 3. — (After Autenrieth- Warren.)



FiQ. 4.



Principal Test for Phosphorus

I. Mitscherlich's Test. — In examining animal material such as
stomach and contents, liver, spleen, kidney, etc. It is ground to
a fine pulp in a mortar, a little clean sand may be used, and
placed in a flask of suitable size, suflScient water is added to give
it a mash like consistence. The flesh present may be cut with
scissors to about the size of peas before grinding. If the pre-
liminary test does not rule out P. set up a distillation apparatus
as in Fig. 4.

The glass tube in this case should be about 130 cm. long, 45
high and about 8 mm. internal diameter. The lower end of the
tube from the condenser should dip one or two centimeters under
water in the flask C to collect any gases Hk6 HCN that may come
over in the distillate. If yellow phosphorus is present a character-



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384 CHEMICAL PHARMACOLOGY

istic phosphorescence appears in the tube — and may be seen
best in a dark room or when the distilling apparatus is covered
with a black cloth. The phosphorescence is due to oxidation of
the phosphonls. It may be prevented or masked by alcohol,
ether, formaldehyde, formic acid, chloroform, chloral hydrate,
benzin, petroleum, turpentine, ethereal oils, hydrogen peroxid,
mercuric chlorid, phenol, creosote, hydrogen sulphide, and putre-
factive products. When the presence of P. is established by the



FiQ. 5. — (After Kippenberger.)

phosphorescence, it is advisable to let the apparatus cool, and
change the distillation to the regular Liebig condenser, see Pig. 6.

In heating organic matter in a flask over a free flame, there is
danger of breaking the flask, consequently some advise the
heating on a water bath or on an oil bath. Again in heating the
flask in presence of oxygen some of the phosphorus may be
oxidized to P2O5 which is not volatile, and to prevent this some
advise distillation from an atmosphere of CO2, see Pig. 5.

To test for phosphorus in the distillate, add an excess of
chlorine water, or fuming nitric acid and evaporate to dryness



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TOXICOLOGY



385



on a water bath. This oxidizes the phosphorus to H3PO4.
Acidify with a few drops of HNOa and dissolve in 10 cc. water.
Use 5 cc. for each of the following tests.




Fig. 6. — (After Autenreith-Warren.)

I. Ammonium Molybdate Test. — Add 5 cc. of the solution to be
tested to 5 cc. ammonium molybdate solution and warm on a
water bath at 40°C. A yellow precipitate of ammonium phospho-
molybdate is formed.



Fig. 7. — (After Kippenberger.)

II. Ammonium Magnesium Phosphate Test. — Add an equal
volume of magnesia mixture to 5 cc. phosphate solution. Be sure
the solution is slightly alkaline. Ammonium magnesium phos-
phate is precipitated (NH4) Mg.PO4.6H2O.

The precipitate is formed slowly and is facilitated by shaking.
Let stand over night if necessary.

26



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386 CHEMICAL PHARMACOLOGY

In an elementary course in toxicology where the object is
training in principles only, quantitative work is unnecessary,
yet in many cases quantitative work is of more value as an aid to
correlation and assimilation, than qualitative work.

The Mitscherlich-Scherer Method for the Qualitative and
Quantitative Estimation of Phosphorus. — A weighed portion of
the substance to be analyzed, hs placed in flask and acidified with
H2SO4, and a little ferrous sulphate added. This last is added to



Fig. 8. — (After Autenreith- Warren.)

prevent oxidation of the P. Before heating the air is expelled
from Ay by CO2, from the Kipp generator E. The CO2 is washed
with water in F. C contains water, and D contains a silver nitrate
solution. The stop-cock B permits the entrance of air, if desfred
to increase the phosphorescence. When this has been seen no
more air is admitted. The P collected in C is oxidized with bro-
mine water or HNO3, on a water bath and evaporated to dryness.
The P. is oxidized to phosphoric acid. This is precipitated with
magnesium mixture, filtered, dried, ignited and weighed as
magnesium pyrophosphate, Mg2P207.



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TOXICOLOGY 387

The P. in the silver nitrate in D as AgaP is heated with nitric
acid which oxidizes the P. The silver nitrate is precipitated and
removed as AgCl by the addition of NaCl. This is filtered off,
and the filtrate treated as the contents of C and added to C.

This method will detect .00006 gram of yellow phosphorus.

Detection of Phosphorus in Oils

Straub's Test. — Copper sulphate in contact with phosphorus,
forms copper phosphide Cu3P2(?) and at the same time tends to
oxidize the phosphorus. Because of this copper sulphate is
used in the treatment of phosphorus poisoning.

Test.— In a test tube shake equal volumes of oil containing
phosphorus and 1 per cent, copper sulphate. A black emulsion
is formed, or a black ring at the junction of the liquids when the
emulsion settles.

ACETONE

Acetone is not an important poison. To test for its presence
in the distillate use tests, page 63.

ANILINE

For tests see page 113.

OIL OF BITTER ALMONDS OR BENZALDEHYDE

See pages 76 and 104. Pure benzaldehyde is not poisonous,
but it occurs in oil of bitter almonds in the form of the cyan-
hydrin of benzaldehyde

/H
CeHs - C— OH
\CN

This is readily hydrolyzed by KOH into -^ KCN + H2O +
CfiHsCHO. (Benzaldehyde.)

Test for KCN. — To 2 cc. oil of bitter almonds or the same
volume of the distillate add 10 cc. KOH 5 per cent., heat gently,
add a few drops of freshly prepared ferrous sulphate containing
a drop or two of ferric chloride. Prussian blue is formed. See
test for nitrogen, page 8. To test for benzaldehyde: add KOH
to the original solution. Extract with ether in a separatory fun-
nel, remove and evaporate the ether on a water bath at 40°C.



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388 CHEMICAL PHARMACOLOGY

If benzaldehyde is present it is deposited as globules. Heat
these globules with 10 cc. 5 per cent, potassium dichromate and
dilute sulphuric acid under a reflux condenser. The benzalde-
hyde is converted into benzoic acid. Cool the liquid* and again
extract with ether. Evaporate the ether. Benzoic acid remains,
its melting point is 120°-121®C. When dissolved in dilute
NaOH, ferric chloride produces a flesh colored precipitate.

CARBON BISULPHIDE

Carbon bisulphide distils slowly with steam and is found
but little in the first third of the distillate.

I. Lead Acetate Test. — CS2 is not precipitated by lead until
after decomposition. Add an equal volume of lead acetate to
CS2 shake — no reaction. Now add an excess of KOH and boil.
A black precipitate of Pb.S will appear {cf, H2S).

II. When an aqueous solution of carbon bisulphide is heated
with an alcoholic solution of NH4OH — ammonium sulphocyanate
is formed together with ammonium sulphide. Evaporate
nearly to dryness on water bath to expel (NH4)2S. Dissolve in
dilute HCl. When ferric chloride is added to this a deep red
color due to iron sulphocyanide appears. .05 gram of CS2
will give this test.

The reaction is:

1 4NH3 + CS2 - (NH4) CNS + (NH4)2S

2. FeCls + 3 (NH4) CNS = Fe (CNS)3 + 3NH4CI

III. Xanthogenate Test. — When CS2 is shaken with 3-4 times
its volume of saturated alcoholic KOH it gives potassium xantho-
genate as follows:

SK

CS2 + C2H5OK = C = S

\
OC2H5

This is a yellow compoimd, when this is acidified with acetic
acid and copper sulphate added, a black precipitate of cupric
xanthogenate is formed.



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TOXICOLOGT


389


SK S




/ /




2 C = S + CUSO4 = (S = C


Cu + K2SO4


\ \




C2H6 CjHj


i


The cupric xanthogenate then decomposes into cuprous


xanthogenate and ethyl xanthogen disulphide, as follows:




OCjHe OC2H,


OC2H5


%


/ /


/




s = c s = c s


= c




\ \


\




s s


&-Cu




\ +




2


Cu = S


S— Cu




/ /


/




s s = c s =


= C



/



\



s - c



\



\

OC2H6



\



\



OC2H6



OC2H6



Ethyl Cuprous

xanthogen + xanthogenate
disulphide



Cupric
xanthogenate

Chloroform: Tests see p. 42.
Introduce 5 cc. chloroform into flask a (Fig. 7) ; heat on a water
bath and blow current of air through the flask and through the
heated tube c. This decomposes the chloroform vapor with
formation of HCl, which can be demonstrated by collecting it in
the U tube d. which contains a one per cent, solution of AgNOa.

CHLORAL HYDRATE

Chloral hydrate distils very slowly with steam. The solution
should beidistilled for a long time and quite completely in order
to get most of it over. It is decomposed by distillation. For
tests, see page 60.

ETHYL ALCOHOL

This would be present in the same distillate as methyl alcohol.
It is quite impossible to separate them but tests for each may be
made. For tests see page 23.



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390 CHEMICAL PHARMACOLOGY

METHYL ALCOHOL

This would be all distilled over when one third of the original
volume is distilled. For tests see page 18.

IODOFORM

Iodoform distils readily with steam giving a milky distillate
which may be recognized by its odor. For tests and reactions



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