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Hugh McGuigan.

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produce most violent toxic symptoms, when taken even in
small amounts, in some persons who are said to have an idiosyn-
crasy for those particular substances.

Classificatioiis. — Drugs may be classified as:
1. Inorganic or mineral

Animal
Vegetable

or as was done by chemists about the middle of the 17th Century,
as animal, vegetable, and mineral.

1



2. Organic



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Z CHEMICAL PHARMACOLOGY

'liWhen it was/fiscOvered that certain compounds are found in
botli animals, aijd .plants, the distinction between animal and
.,^eg^ti;5fe/jchipii\i^ry* disappeared and to .include both the broader
term '* organic'' was substituted. It was believed then that
*Wital force" was necessary for the formation of organic com-
pounds, and that these could not be produced by the chemist.
In 1828, however, Wohler prepared the organic substance,
"urea'' from the so-called inorganic compound, ammonium
isocyanate:

NH4 CNO = C(\

Ammonium isocyanate urea

Since this discovery a sharp distinction between organic and
inorganic compounds cannot be made. Yet, the term "organic"
has survived, and includes not only those substances formed in
plants and animals, but also most carbon compounds. Many
synthetic drugs which contain carbon, are in reality no more
organic than calcium carbonate, but are included in organic
chemistry because of relationship, or of historical interest.

The term vital force or vital activity is still used by physiolo-
gists and pharmacologists especially in discussing absorption and
secretion. It means simply that the known physics and chemis-
try is inadequate to explain all the phenomena, and that the
explanation of some life processes is still unknown.

In addition to carbon, the chemistry of drugs includes other
important elements. Twelve elements are necessary for life
and are consequently found in varying amounts, in all organic
matter. These elements are: C, H, N, O, S, P, Na, Mg, Ca, Fe,
CI, and K. If any of these elements be extracted from living
matter, death results.

If the amount of each element in a substance is determined,
we say that the analysis is ultimate. The elements however do
not exist in a free state in plants or animals, but are combined to
form fats, proteins, carbohydrates, volatile oils, gums, gum resins,
alkaloids, glucosides, salts, etc. These, when they are definite
chemical compounds, are called proximate principles, and the
determination of the amount of these substances is proximate
analysis.



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PROXIMATE PRINCIPLES d

Proximate princiiples because of their reaction are divided into
acid, neutral, and basic principles. The following scheme is
illustrative:

Organic Drugs
Animal Vegetable

\' /

Proximate Principles

. i



1. Proteins

2. Lipoids or ether extracts.



3. Carbohydrates.



Fats

oils

cholesterines

waxes

Celluloses

dextrin

gums

sugars

pectins

starches

glycogen

4. Alkaloids

5. Glucosides — which include saponins and sapotoxins.

6. Volatile, ethereal, or essential oils.

! Camphor
menthol
thymol
oleoresins

8. Resins gum resins

balsams

9. Organic acids.



10. Coloring matter or pigments.



Chlorophyll

carotin

xanthophyll



11. Ash or inorganic residue which remains when drugs or
plants are ignited to constant weight at red heat.

While according to their reaction these bodies are acid, basic,
or neutral; the term "neutral principle'' is often used in a different



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4 CHEMICAL PHABMACOLOGT

sense. It is applied especially to those neutral physiologically
active bodies that do not belong to a more definite chemical
class; e,g. picrotoxin is a neutral principle and is known only \^y
that term. Glucosides are also neutral, but are rarely referred
to as such, because the term, "glucoside" is more specific than
"neutral principle.'' An alkaloidal salt may be neutral in reac-
tion but is never referred to as a neutral principle, but is always
classified with alkaloids.

Proximate principles, when acted upon by bacteria, yeasts,
enzymes, heat or chemical agents, give rise to pure chemicals of
simpler composition such as paraffins, alcohols, ethers, acids,
etc., and these form the basis of organic chemistry. Many of
these chemicals are used in medicine, and a knowledge of the
structure of the simple organic bodies is essential for a study of
the more complicated proximate principles, and for the study
of pharmacology. Pharmacology in the last analysis is ap-
plied organic chemistry, or the chemistry and reactions of living
matter, as modified by changes in environment. The cause of
these changes whether due to noxious gases, decomposition
products of foods, impurities in water, bacterial toxins or
other injurious or modifying agent in the widest sense comes
under the term "drug.'' However, the study of pharmacology
is usually limited to those drugs that are used in therapeutics,
or that are especially valuable in investigative work.

THE COMPOSITION OF DRUGS
CARBON

Carbon in the elemental condition, and in the form of CO, CO2
and the carbonates is included in inorganic chemistry. All other
carbon compounds are, for convenience, classified under organic
chemistry.

The word, "carbon" is derived from the Latin, "carbo,"
meaning coal, and the ordinary test for carbon is the carbonizing
action or the becoming coal-like on burning. If we partially burn
a piece of wood, paper, or almost any organic substance it chars.
There is a similar action, if we add strong sulphuric to it. The
acid extracts the water part of the molecule leaving carbon
partially free, or charred. If enough oxygen is present in the



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CABBON O

molecule, or if burning continues, the carbon is completely oxi-
dized and disappears as a gas, CO or CO2, but always as CO2 if
enough oxygen be present. Most carbon compounds when
taken into the body are oxidized in a similar way, but the oxi-
dative potential of the body is not suflSciently high to oxidize
elementary carbon, nor even such compounds as cellulose.

Not all organic compounds carbonize on heating. If oxalic
acid, COOH. COOH, be heated, it breaks down into CO2, CO and
H2O without charring. The reason being that it contains enough
oxygen in the molecule, to completely oxidize the carbon present.
The form in which carbon occurs in the molecule is also an im-
portant factor in determining whether or not it will carbonize on
heating. When present in the form of carboxyl, as it is in the
case of oxalic acid, it is already oxidized and in a bound or

/^

gaseous form — C<^ so that carbonization is impossible

^OH
since it is abeady past that state. It may break either as

//^

H — Cr — > H2O -h CO in which case, the water is split

^OH
directly from the molecule; or in oxalic acid it may break into
CO2 and H2O, the H in the acid being oxidized to water by the
oxygen of the air;

COOH

I

COOH-hO = 2CO2 + H2O

There is a general tendency of organic acids, especially when
heated under the influence of strong dehydrating agents, to
break up, giving off CO2 or CO from the carboxyl group: e.gr.

Formic acid HCOOH + H2SO4 = CO + H2O

Malonic acid heated to 140^ COOH
yields acetic acid and CO2 |

CH2 = CH3COOH + CO2

I
COOH



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6 CHEMICAL PHARMACOLOGY

In case of aliphatic compounds, the tendency to yield CO2 is
greater where two carboxyl groups are attached to one carbon
atom.

COOH



'OH



Gallic acid when heated
yields pyrogallic acid and
OH carbon dioxide OH



OH OH



+ CO2



OH



For these reasons carbonization is not a general test for organic
substances. The formation of CO2 is a more definite test.

The presence of carbon can be shown in those cases that do
not char, if the gas evolved on heating be collected in NaOH or
Ca(0H)2; this results in the formation of a carbonate

2NaOH + CO2 = NaaCOs + H2O
or Ca(0H)2 + CO2 = CaCOa + H2O

The presence of CO2 in the respired air can be shown this way.
The formation of a carbonate is a general proof of the presence
of carbon whether or not there be carbonization.

Carbon, prepared by heating bone — ^bone charcoal, or wood —
wood charcoal, in absence of air or oxygen, is used in medicine in
some cases of stomach disease, and in other cases, as an absorbent
of gases. It will also absorb toxins as in diphtheria, and has
been sometimes applied locally for this purpose. It is used in
chemical analysis as a clarifying agent to absorb colors. When
carbon is wet its value as an absorbent for gases is greatly les-
sened, for this reason, its value when given to absorb gases in
the stomach is questionable.

Carbon dioxide in the body is the specific stimulus of the respi-
ratory centre. It is generated by the oxidation of the carbon of
the food. The fate of carbon and hydrogen is very important
since in the body the oxidation of the carbon and hydrogen of
the food is the exclusive source of heat and therefore of b6dy
temperature. The calorific value of foods in the body is the same
as they yield in the calorimeter, but in the body oxidation pro-



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HYDROGEN AND NITROGEN 7

ceeds at about 40°C. while in the calorimeter high temperatures
are necessary to complete the oxidation.

Test for Hydrogen

The presence of carbon and hydrogen together in drugs or
organic compounds can be shown by heating the dried material
with desiccated copper oxide in a glass tube. The copper oxide
is reduced in the presence of organic matter and the free O
oxidizes the C and H to CO2 and H2O. The CO2 is detected in
the usual way with lime water. The water formed will condense
in the cold part of the tube in which the substance is heated.
The formation of water is proof of the presence of hydrogen.
If desired, the water so formed may be collected in sulphuric
acid and weighed as is done in ultimate analysis. Hydrogen in
the free form is not used in medicine.

NITROGEN

Nitrogen as a free gas is characterized by its chemical inertness.
A burning splinter immersed in a vessel containing nitrogen
gas is immediately extinguished. Animals and plants die if
confined in an atmosphere of nitrogen. For this reason, it was
formerly called Azote (against life). It is a constant constituent
of all plants and in combination is an indispensible food. It is
also essential in the air as a diluent of oxygen, since life in pure
oxygen is impossible. Because of its inertness, the gas has been
used in therapeutics, in the pleural cavity, to collapse one lung
in case of tuberculosis of that organ; the idea being to rest the
lung by collapse and so permit healing, also by preventing move-
ment, to lessen the tendency to spread the diseased condition.
Nitrogen in plants exists mainly in the form of:

1. Proteins 9. Some glucosides

2. Amino acids 10. Mixed compounds, etc.

3. Amines

4. Alkaloids

5. Phosphatides

6. Nitrates

7. Cyanides

8. Ammonia



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8 CHEinCAL PHABMACOLOGT

To determine whether or not, a drug or any organic matter
contains nitrogen, the following tests may be used:

Test for Nitrogen

1. In many cases, when an organic substance is burned, an
odor like burnt feathers is given oflf; this is characteristic of the
presence of N.

2. Lassaigne's test: Organic bodies always contain carbon,
therefore if a small amount of the substance be heated in a dry
test tube to redness, with Na, or K, and the test tube be im-
mediately plunged into water in a beaker, the C and N, if present,
will combine with the Na, or K to form KCN or NaCN, which
may be detected by treating with a mixture of ferric and ferrous
salts, Prussian blue being formed.

Freshly prepared ferrous sulphate with a drop or two of ferric
chloride added, is a suitable reagent. During the operation some
ferrous hydrate is converted into ferric hydrate, which when
acidified with HCl is converted into ferric chloride. The reac-
tions may be illustrated as follows:

1. 2C + 2N + 2K -^ 2KCN

2. 6KCN + FeS04 -► K4Fe(CN)« + K2SO4

3. FeaCle + FeS04 + 8NaOH -► Fe2(0H)« + Fe(0H)2 +

6NaCl + Na2S04

4. 2Fe2(OH)« + 3K4Fe(CN)« + 12HCl-^Fe4{(Fe)(CN)«}s +

12KC1 + I2H2O
Or

1. FeS04 + 2K0H = Fe(0H)2 + K2SO4

2. Fe(0H)2 + 2KCN = Fe(CN)2 + 2K0H

3. Fe(CN)2 + 4KCN = K4Fe(CN)«

4. 2Fe2Cl6 + 3K4(Fe(CN)6) = Fe4{Fe (CN)6}8 + 12KC1

If the blue or green color does not quickly develop, a drop of ferric
chloride should be added. It often happens that not enough
Prussian blue is formed to give the blue color. The formation
of a green solution is sufficient proof.

Nessler's Test. — Nessler's reagent produces a brown precipitate
of NHg2l. H2O in solutions containing ammonia. If only a trace
of ammonia be present a yellow or reddish yellow color is pro-
duced. This reaction is used to determine ammonia in water.



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NITROGEN TS3STS 9



3. Kjeldahl's Test for Nitrogen. — ^Also the estimation of the
amount of nitrogen. This test consists essentially in boiling the
organic substance with strong H2SO4 which destroys the organic
matter and converts the nitrogen into (NH4)2S04; this is then
tested for NH3 which if present, proves the presence of nitrogen.
The method here described is the most used one for determination
of the amount of nitrogen and protein material in drugs, foods,
and other products. It is carried out as follows:

Place 1 to 5 grams of the dry material, accurately weighed in
a Kjeldahl flask of about 500 cc. capacity. Add 30 cc.
H2SO4 cone, and about 0.5 gram mercuric oxide, or pure mercury.
The mercury acts as a catalytic agent and hastens oxidation.
Boil over a free flame until the solution is a pale straw color, white
or clear water color. Sometimes the substance, on boiling,
bumps; to prevent this, kaolin, zinc or other finely divided inert
material is added, which prevents bumping by stirring the mix-
ture so that the heat is uniformly distributed and no point of the
glass becomes heated to a much greater extent than the rest.
Many substanjces foam so much on heating that parafl^ or some
other substance is added to lessen this. After the substance
has boiled until it is milky or water color, the flask is removed
and about 0.5 gram of KMn04 added, to complete the oxidation.
The nitrogen is now in the form of (NH4)2S04, which has been
proved by isolation and analysis of the crystals. An excess of
strong NaOH added to this solution liberates NH3, which may be
distilled and caught in a solution of acid of a known strength and
titrated, e.g., (NH4)2S04 + 2NaOH = Na2S04 + 2NH4OH.
If we collect this, say in 50 cc. of N/10 H2SO4 we know how much
NHa is present by titrating the excess of the acid with N/10
NaOH. 1 cc. of N/10 H2SO4 = .0017 grams NHs or .0014
grams N. For example: one grani of a substance treated as
above, with H2SO4 was made strongly alkaline and distilled into
50 cc. N/10 H2SO4. When this distillate was titrated with N/10
NaOH it was found that it took 20 cc. NaOH to neutralize.
Therefore, the nitrogen in one gram of the substance is equiva-
lent to 50 cc. N/10 - 20 cc. N/10 = 30 cc. N/10 acid. Since
1 cc. N/10 acid = .0014 grams N, 30 cc. = 0.042 grams N or
the amount in one gram of the substance and the percentage
is 100 times 0.042 = 4.2 per cent.



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10 CHEMICAL PHARMACOLOGY

Since protein contains on the average of 16 per cent. N, it is
customary to multiply the amount of N by 6.25 to obtain the
per cent, of protein (6.25 times 16 per cent. = 100 per cent.).
All protein, however, does not contain exactly 16 per cent, nitro-
gen, so that in some cases the factor 6.25 is not exact.

Various non-essential details in the method are used in some
cases, such as the .addition of potassium sulphate to raise the
boiling point and the addition of other catalytic agents.

OXYGEN

Oxygen. — In addition to carbon, hydrogen and nitrogen most
organic compounds also contain oxygen. Because these elements
occur so universally in organic matter, they have been called or-
ganogens. This term has also been used to include the other
essential ingredients of plants. The well known chemical prop-
erties of oxygen in the gaseous form cannot be demonstrated in
organic bodies. There is no simple practical method for its
direct determination. Its quantity is usually calculated in
analyses by the difference between 100 per cent, and the sum of the
percentage of the other elements present, after the other elements
have been determined. Ever since the importance of oxygen
became known, attempts have been made to use it in failing respi-
ration. As a rule, however, it is of little value, because in most
cases the asphyxiation that suggests its use, is really due to a
failure of the heart. Again the hemoglobin of the blood, which
is the oxygen carrier to the tissues, is in most cases saturated,
so that the administration of pure oxygen can aid but little. In
cases of severe hemorrhages or of poisoning carbon monoxide,
nitrites, chlorates, nitrobenzol, etc. which destroy the oxygen
carrying power of the blood, it has been shown that when pure
oxygen is administered the oxygen content of the red cells and
serum is increased somewhat, and this slight increase may be
very beneficial. If the gas be administered under tension there
may be suflScient oxygen increase in the blood to cause convul-
sions in animals. Hilarity and other nervous influences have
been observed in man. There is some increase in metabolism
but not sufficient to be of benefit in any given case.

Ash. — If an organic substance contains C, H, N, and only,
it will leave no residue or ash on burning. Plant drugs leave



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ASH 1 1

an ash which contains varying amounts of Na, K, Mg, Ca, CI, P,
S, Si and Fe, as necessary ingredients. Depending on the soil
on which they were grown, plants may also contain As, Ba, Mn,
I, Zn or any other element, not as essential, but as accidental
elements.

Before testing for these elements, it is necessary to reduce the
plant or drug to an ash. The organic matter must be completely
destroyed because the inorganic elements ^react only as ions and
ionization is prevented and masked by organic matter.

To aid in the "ashing'' some oxidizing agent which can be
driven oflf by heat may be used, e.g., H2O2 — HNO3, etc. or, in
case we do not wish to test for K, or CI, KCIO3 may be used. A
small amount of any of these agents aids oxidation and the reduc-
tion of the substance to a white or grey white ash. The ash of
plants is rarely pure white because of the presence of iron, and
other elements. After the ash has been prepared, it is dissolved
usually in dilute HCl and tests for the elements made with the
solution. The following scheme will show how to prepare the
ash of plants for analysis.

Weigh out 5 grams of the root, leaves, or whatever is to be
determined, and place in a platinum or porcelain crucible or
dish. Heat it gradually on a thin sheet of asbestos over a Bun-
sen burner. In order to avoid loss by volatilization, tilt the
dish or crucible, and at the beginning keep it covered. The
material first chars, then glows beginning at the top and gradu-
ally extending to the bottom. Carefully regulate the heat to a
dull redness (about 700°C.). If heated higher than this, there
is a loss of alkali chlorides by volatilization and the phosphates
fuse about the particles of carbon, so that this cannot be oxidized
completely. A muffle furnace may be used to complete the oxida-
tion. Finally, when the ashing is complete, weigh and calculate
the amount.

In an actual determination, several weighings are made, and
the substances heated between these weighings, until the weight
keeps constant. We know then that oxidation is complete.

The ash of plants contains considerable carbon dioxide, which
may be found with sodium, potash, or any of the other elements,
in the form of a carbonate and imparts to the ash an alkaline
reaction. The use of plant ash in earlier times for the formation



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12 .CHEBHCAL PHARMACOLOGY

of soap, is due to this fact. In the anal3rsis of an ash, therefore,
we determine the amount of COi, sand, silica, Fe, Al, Ca, Mg,
and acid radicals, SOs, P2O6, etc. These are in very smdl
amounts and while absolutely essential to the life of the plant,
and in the main, essential ingredients of foods, they are not
present in suflScient amount to be important as drugs.

n. PARAFFINS

The paraflSns are prepared from crude petroleum or rock oil
(petros-rock) which in turn is the result of the decomposition of
organic matter. Because of their inertness the name paraffin has
been applied (parum-small, affinis-affinity). The series is known
by a number of names:

1. Fatty or aliphatic because the best known fats belong
chemically to it (aliphos, fat).

2. The limit series because the valences of the carbon atoms are
saturated to the limit.

3. It is called the chain series or acyclic because the carbon
atoms are supposed to be arranged in the form of a chain



in contra-distinction to the ring, or benzene series.

4. Since methane, CH4, is the first member, it is also known
as the methane series. Because methane is found in nature in
marshes, the term marsh gas series is also used. Members of
from 1 to 60 carbon atoms are known.

All hydrocarbon compounds are grouped under three heads,
namely:

1. Fatty or acyclic, or chain-like carbon derivatives.

2. Carbocyclic, or aromatic compounds.

3. Heterocyclic compounds.

Properties of the Hydrocarbons of the Paraffin Series.
Those containing from 1 to 4 carbon atoms are gases; from 6 to 16
liquids; and those containing more than 16 carbon atoms are
solids. This statement refers to ordinary temperatures and



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PARAFFINS . 13

pressures. All of them may be converted into gas, or all into
solids, if the temperatures and pressure conditions are controlled.

The paraffins are saturated, therefore, they do not absorb
bromine or hydrogen and are not absorbed by sulphuric acid.
They are insoluble in water; the lower and intermediate members
are readily soluble in alcohol and ether. They are noted for
their chemical and pharmacologic inertness. Their action
in the body is mainly physical. However, such light distillates
as naphtha and benzine, are excellent solvents for fats, oils,
lipoids, resins, and their volatility aids absorption. These light
distillates often produce toxic effects that can be ascribed to
their action on the nervous system, probably due to a solvent
action on lipoids. Following their administration, headache,
nausea, giddiness, unconsciousness, muscular tremors, convulsions,
cyanosis and death, have been observed.

The irritant effect of the lighter members may also produce
gastritis and gastro-enteritis. When the boiling point reaches
that of kerosene, the toxicity is greatly diminished. Gastro-
enteritis and narcotic effects similar to alcohol have been ob-
served after kerosene, but no deaths have been reported, although
cases are reported where as much as a liter was swallowed. Liquid
petrolatum has an emollient effect. The solids are inert.

A few hydrocarbons, benzine, gasoline, kerosene, vaseline,
liquid petrolatum, and solid paraffin are used in medicine.
One should carefully distinguish between benzine, and benzene.
Benzine is a light paraffin, a mixture of C6H14 and C7 Hi«, while
benzene or benzol, CeHe, is an aromatic compound. It (benzol)
has recently had considerable vogue in the treatment of leukae-
mia. Small amounts of it (1 cc. dose) reduce the number of
white cells in the blood, but its continued use is fatal. Kerosene
is used especially in dispensary practice to rid the hair of nits
and lice.

The hydrocarbons above mentioned differ mainly in their
physical properties, but there is some chemical basis for this dif-
ference. The source of all these is crude petroleum.

CRUDE PETROLEUM

This is a most important source of the paraffin hydrocarbons.
When distilled at varying temperatures, the different fractions



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14 CHEMICAL PHARMACOLOGY



have a varying and mixed composition, but are approximately as
follows:

Distillation at temperature of: Gives as a resulting substance:






Gases, which may be liquified




under pressure, CH4 to C4H:o


18^


Rhigolene, C6H12— :CeHi4


50^ and 60°


Petroleum ether, or naphtha,




CeHn C7H16


70° and 90°


Benzine, a mixture of CeHu




and CtHu


90° and 120°


^ Ligroin, C7H16 and CgHig


120° and 150°


Petroleum benzine, CgHig —



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