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1. A marked depression of the central nervous system, com-
mencing above and descending. The perception to pain and the
sensitivity of the respiratory center, seem more depressed than
other functions.

2. Depression of the blood pressure and slowing of the heart
due to an action on the medullary centers.

3. A decrease in the peristalsis of the alimentary canal, pre-
ceded in some animals by stimulation.

4. A marked constriction of the pupil, due apparently to the
removal of a central action. The constriction disappears in the
paralytic stage, and in some animals in which morphine causes
stimulation or excitement rather than depression (cat, horse
and others) the pupil is dilated at all stages.

5. The cord is stimulated with all these drugs, and the reflexes
exaggerated. Morphine applied directly to the cord will cause
convulsions, and some of the morphine alkaloids stimulate only.
Dixon (Manual of Pharmacology, 1906, p. 137) because of these
differences arranges the morphine alkaloids as follows with the
percent of these alkaloids in opium

Morphine (most narcotic) 10. per cent.

Papaverine ■ 1.0 per cent.

Codeine 0.5 per cent.

Narcotine 6.0 per cent.

Thebaine 0.3 per cent.

Laudanine (most convulsant) trace

Apomorphine. — When morphine is heated in a sealed tube with
strong HCl at 140°C. it loses a molecule of water and apomor-
phine is formed. This change it has also been asserted, occurs
when morphine salts or their solutions are exposed to light, but
no proof of this has been advanced.

Solutions of apomorphine have a green color and the entire
physiological action of morphine is changed by the loSs of water
from the morphine molecule.

Apocodeine. — C18H19O2N has been prepared by the action of
zinc chloride solution on codeine hydrochloride. It is supposed to
bear the same relation to codeine that apomorphine does to



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280 CHEMICAL PHARBiACOLOGY

morphine. Dott (Pharm. Journal, 1891, III, XXI, 878, 916,
955, 996) claims that it is not a pure compound, but a mixture
of chlorocodeine apomorphine, amorphous bases, and codeine
(Knorr and Raabe, ibid., 1908, 41, 3050).
The chief actions of these apo-compounds are:

1. Apomorphine causes vomiting by a strong stimulation of
the vomiting center, and

2. Also stimiilates: the secretory centers for saliva, perspira-
tion, etc. It has a paralytic action on skeletal and heart muscle.

3. Apocodeine paralyzes all ganglion cells, and is toxic to all
forms of motor nerve endings.

'The Fate of These Alkaloids in the Body

Morphine is partly oxidized and a part is unchanged and ex-
creted by the alimentary tract. This is a different method of
excretion from most alkaloids which are excreted in the urine.
Faust foimd that 70 per cent, of that administered to a non-
immunized animal was excreted, but when tolerance is established
the oxidizing power of the tissues is increased. The excretion
into the alimentary tract begins soon after administration, as
shown by the fact that morphine has been foimd in the vomitus
soon after hypodermic administration. Codeine is excreted
much in the same way as morphine but tolerance is harder to
establish and more is excreted unoxidized. When injected
intravenously Marquis found 15 per cent, of the morphine de-
posited in the liver in 15 minutes and some retained in the central
nervous system. A slight amount is excreted in the urine in
combination with glycuronic acid. Morphine resists putrefac-
tion and has been found in putrefying material after 15 months.

Tests

Apomorphine.. — The solutions have a green color.

1. To a dilute solution add a few drops of HCl or H2SO4, then
neutralize with Na2C08 and add a drop of an alcoholic solution
of iodine. The emerald green color which is produced becomes
violet when shaken with ether.

2. Dissolve a trace of apomorphine hydrochloride in water and
shake. A green color appears. Add a trace of ferrous sulphate
and shake. The solution gradually turns blue and finally black.



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APOMORPHINE 281

On the addition of alcohol the blue color returns (different from
codeine and morphine).

3. Dissolve a trace of apomorphine in concentrated H2SO4 and
add a drop of concentrated HNO3; a violet color changing quickly
to red and yellowish red is formed.

4. Physiologic test: 0.01 gram apomorphine hydrochloride
hypodermically in a dog causes vomiting in a few minutes.

Codeine. — 1. To a little of the dry alkaloid in a crucible add a
few drops of concentrated H2SO4 and heat. A greenish color
which changes to violet-red results. Morphine gives none, or
only a sKghtly yellow color, except when heated, then it is brown.
HNO3 changes the reddish violet color of codeine to yellow and
purple.

2 Codeine with H2SO4 heated, with a drop of nitric acid added,
gives a blood red color.

3. Codeine with H2SO4 gives no color; add a drop of formalin
and a violet color is produced. Morphine gives an intense purple.

4. Codeine with H2SO4 with a trace of ferric chloride added
gives a violet blue color.

Tests for Morphine

1. 1 gram of morphine is soluble in 3340 cc. of water, 210 of
alcohol, 6260 of ether, or 1220 of chloroforift.

2. A satiu^ated aqueous solution of morphine is alkaline to
litmus.

3. Concentrated sulphuric acid produces either no color or
only a red or yellow tint when added to a morphine solution.
On heating a brown color is developed. Concentrated sulphuric
acid containing 0.1 per cent, formalin gives a piu^ple color.

4. Concentrated nitric acid with morphine produces an orange
red color fading to yellow.

6. Ferric chloride added to a neutral solution of morphine,
made by adding dilute H2SO4 to morphine, produces a blue
color. "

6. Iodic acid test: When morphine in dilute sulphuric, is
shaken with, a few drops of iodic acid and chloroform, iodine is
liberated and dissolves in the chloroform producing a violet color.
Other reducing substances may give this test.

7. Prussian blue test: When morphine is added to a dilute



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282 CHEMICAL PHARMACOLOGY

mixture of ferric chloride and potassium f erricyanide, a deep blue
color appears. When considerable morphine is added a precipi-
tate may be produced.

8. When morphine is added to silver nitrate with an excess of
ammonium hydroxide a gray precipitate of metaUic silver is
formed.

Thebaine. — 1. Thebaine gives a blood red coloration which
gradually becomes yellowish red with concentrated sulphuric
acid.

2. With nitric acid thebaine gives a yellow color.

3. Chlorine water dissolves thebaine. If ammonia be added
to the solution it becomes red-brown.

Papaverine occurs in opium to the extent of 0.5-1 per cent.

H H

H3CO— C C CH

I II I

H3CO— C C N

H I
CH2
I

HC CH

I II

HC CO.CH3

I

OCHs
Papaverine

It crystallizes in colorless poisons which melt at 147**C. It is
insoluble in water, soluble in ether 1 to 260 and freely soluble in
chloroform. Ether partially extracts it from tartaric acid solu-
tion, and completely extracts it from alkaline solutions. Chloro-
form extracts it easily from either acid or alkaline reaction.



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CAFFEINE 283

Tests

1. When pure, cold sulphuric acid does not color papaverine,
it becomes violet when heated. Impure solutions may be violet
without heating.

2. Concentrated nitric acid dissolves papaverine with a dark
red color.

3. Papaverine ' gives a purple color, changing to black and
green, when dissolved in sulphuric acid containing iodic acid.

4. With iodine in alcohol, papaverine yields a characteristic
crystalline periodide.

THE CAFFEINE GROUP

Caffeine and related drugs are important from the standpoints
of biochemistry, pharmacology, and as foods. They occur
especially in tea, coffee, cocoa, kola, gurana mat^ and in numerous
other plants in small amounts. The most important drugs of
this group are:

Purine, or the nucleus of the group.

Caffeine, or 1.3.7 — trimethyl xanthine.

Theobromine, 3.7 — dimethyl xanthine.

Theophylline, 1.3 — dimethyl xanthine.

Xanthine, 2.6— dioxy purine.

Hypoxanthine 6— oxy purine.

Guanine 2 — amino. 6 oxy purine.

Adenine 6 amino purine.

Uric acid 8 — hydroxy xanthine, or 2, 6, 8 trioxy purine.

1 N = 6 CH

I I 7

2 CH 6 C NH. 8

II II >H

3 N 4: C N ^

Purine 9
The word purine is a portmanteau word, a combination of
purum uricum.
N(CH3)— CQ NH CO

II II

CO C— NCCHa). CO C N(CH3)v

I .11 >H i II )CH

N(CH3)— C N^ NCCHa)— N ^

Caffeine Theobromine

Digitized by CjOOQ IC



284



CH— N— CO

I I
CO C— NH



CHEIUCAL PHABMACOLOGY

NH— CO



CH,— N— C-



-N'



CO C— NH.



CH



\



Theophylline
NH— CO



HC C— NHv

II II >

N— C— N^

Hypoxanthine
N=C— NHj



CH



HC .C— NH

^ II II
N— C— N

Adenine



>



, .. ^CH

NH— C— N^
Xanthine

NH— CO

I I •
HjN— C C— NH.

II II >H
N— C— N^

Guanine

NH— CO

I I

CO C— NH



CH



NH— C— NH

Uric Acid



>



CO



Piinne or the nucleus of the group is of interest only in showing
the chemical relationship of the whole group to uric acid. Purine
has been prepared from uric acid, and this in turn from simpler
well known compounds. The sodium salt of uric acid when
treated with phosphorus oxychloride, yields hydroxy di chlor
purine.

N=C— CI



C1.C C— NH



N— C— N



>



C.OH



When this is acted on by phosphorus trichloride, it gives trichlor-
purine

.N=C.C1



C1.C C— NH.



N— C— N



\



aci



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CAFFEINE GROUP



285



and when this is treated with hydriodic acid, diodo-purine is

N=-C.I

I I
I.C C— NHv

II II >H

formed, which when reduced by zinc dust and water gives purine
(p. 283).

According to Fischer purine may occur in the body, but can-
not be detected on accoimt of its ease of decomposition in the
body.

The establishment of the formulsB of uric acid and related
substances has been a slow growth. The suggestions for the
synthesis came principally from a study of the products of
hydrolysis of uric acid. Among these products were urea, para-
banic acid, alloxan, allantoine, etc., depending on the oxidatizing
agent. After niunerous attempts, the following steps were
successful in establishing the synthesis . and formula of these
bodies.

(I)



N;



Hi



HOI CO NH— C



H



,/



.0



C = O + CHj = CO CHj + H,0
H



N;



Nh



iHOjCO NH— CO



(II)



urea + malonic acid = malonyl urea or barbituric acid.



NH— C^ HONiO

I I , \ :::..

C=OCiHa +



NH— C^

I I

C CrN.OH



NH— CO NH— CO

Barbituric acid + Nitrous acid = iso-nitroso-malonyl urea



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286



CHEMICAL PHARMACOLOGY



(III) Reduction of iso-nitroso NH-
malonyl urea gives: |

C



I

CHNHj



NH CO

amino barituric acid



(IV)



NH-



y/



o



NH-



C H NH2 + KCNO + HCl = C



I
CHNHCO



NH-



-C = O



amino barbituric acid



NH C = ONHj

pseudo uric acid



(V) Pseudo uric acid loses water on treatment with dilute
mineral acids and gives uric acid.



NH-



./



,0



NH-



C = O CHNH



-</



O



^C =



c=o



C NH



NH-



>



CO + H2O



C = iOHI N



pseudo uric acid



NH C-NH

uric acid or 2.6.8. trioxy
purine

By reduction, the purin base has been prepared from uric acid,
as shown above.

Caffeine occurs especially in tea and coffee and similar stimu-
lant food' stuffs, in the following amounts:

Tea 1-4.8 per cent. Kola nuts 2.5-3.6 per cent.

Coffee.... 1-1 . 5 per cent. Mate 1 . 2-2 . per cent.

Gurana 3.0-5 per cent

It occurs partly free and partly combined as caffeine chlorogenate.
Caffeine has also been prepared synthetically by the action of



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CAFFEINE GROUP 287

methyliodide on theophylline. It Crystallizes in slender silky
needles which melt at 234°. It is soluble in water 1 : 46, alco-
hol 1 : 66, and in chloroform 1 : 8. Its solubility in water is
increased by heat, citric acid, benzoates and salicylates, bromides,
antipyrine and a number of other substances. Combinations,
such as caffeine sodiosalicylate and caffeine sodiobenzoate, pre-
pared by mixing caffeine with such solutions and evaporating the
mixture, are used in medicine. The object is to increase solu-
bility and to make the preparations available for hypodermic use.

Theobromine is^ the chief alkaloid of cocoa beans and is found
in small quantities in Kola nuts and leaves and in tea leaves. It
has also been synthesized. Caffeine may be separated fairly
well from theobromine by extraction with cold benzine in which
theobromine is insoluble.

Hypoxanthine, and guanine (6 oxy 2 amino purine) occur to-
gether in a number of plants, especially, curcubita pepo, hordeum
sativum. Hypoxanthine occurs free to some extent in animal
tissues, especially muscles, more is found in the combined state.

Xanthine is found in tea leaves, and the juice of beet root;
theobroniine, in theobroma cocoa; caffeine, in tea and coffee.
Uric acid is not found in plants. The murexide test makes the
recognition. of the purine base an easy matter, but the identifi-
cation of the individual members is a difficult task. Hypoxan-
thine and xanthine when administered to man increase the uric
acid to about 55 per cent, of the theoretical amount.

Guanine is uually prepared from guano — hence the name. It
occurs commonly in animal organisms and has been found in
small quantities in yeast, sugar cane, and beet root. It has also
been synthesized. Its main interest in pharmacology is its re-
lation to the more important caffeine drugs. In the urine of
pigs xanthine, hypoxanthine, with smaller amounts of adenine
and guanine preponderate in amount over uric acid. The tissues
of these animals are deficient in guanase, and the pig sometimes
suffers from ''guanine gout''. Nitrous acid converts guanine
into xanthine. This may also be accomplished by boiling it with
hydrochloric acid.

Adenine occurs in beet root, yeast, tea, and other plants and in
the animal organism especially in the pancreas. Adenase converts
it into hypoxanthine C6H3N4NH2 + H2O = CsHgNgO -|- NH3.



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288 CHEBaCAL PHARMACOLOGY

Murezide Test

Put 3 or 4 milligrams of caffeine in a white evaporating
dish. Add a few cc. of saturated chlorine or bromine water and
evaporate to dryness on a water bath. To the yellow residue
add a drop of NH4OH. A bright purple color is produced. Nitric
acid may be used to oxidize the caffeine instead of the chlorine
water, but it is not so efficient. HCl with a crystal of KCIO3 may
also be used. This decomposes the purine bases to alloxan
which, on reduction yields alloxantine:

CO NH NH CO CO NH

I II I /OH HOv| I

C = CO CO C^ ^C CO

till II

CO NH NH CO CO NH

Alloxan Alloxantine.

Alloxantine in presence of ammonia forms ammonium pur-
purate or murexide. — NH4.C8H4N6O6 + HjO

NH C^ CO NH

I

c=o

I

NH C = CO NH

Purpuric acid

2. Caffeine is also precipitated by the alkaloid reagents.
These tests are not characteristic.

3. The melting point is 235-237**. It is soluble in 46 parts
of water, 5.5 of chloroform, and in 530 parts of ether.

Action of Caffeine Compounds

Caffeine is used mainly as (1) a diuretic, and (2) as a stimulant
to respiration and circulation, (3) for its infUiences on muscle,
and (4) for its action on the nervous system. Theophylline has
less action than caffeine on the central nervous system and heart
but is a stronger diuretic, this diuretic action is said not to last
as. long as that produced by theobromine, which is a less powerful
diuretic. Theobromine also acts less on the central nervous




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CAFFEINE 289

system than caffeine. The other compounds have varying
actions, but these are not important in medicine.

1. The Diuretic Action of Caffeine. — Caffeine compoimds are
the diuretic drugs par excellence. Many laboratory exercises on
this point fail because they do not consider the fundamentals of
urine secretion or the condition in which caffeine acts best as a
diuretic. First, the kidneys cannot secrete water unless water
is present. While the blood normally contains over 90 per cent,
water, this water is apparently in combination with colloid mate-
rial and only free water can be secreted. In those clinical cases
where caffeine compounds act to the best advantage, the tissue^
are water logged either because of inadequacy on the part of the
heart, or change in the proteins, or salt retention. Caffeine
under these conditions causes a diuresis either by causing a
greater elimination of the free water or by liberating some x)f the
combined water. In normal animals the change caused by
caffeine on diuresis is so small that, as a class experiment, it is
unsatisfactory. Only as much water as is taken in can be poured
out, and in normal conditions this pouring out or urination pro-
ceeds at a constant rate and is hastened but little by diuretics.
To make a laboratory experiment show the real action of caffeine
on the kidneys, the animal should be given a large volume of
.liquid a short time before the caffeine is administered.

The action of caffeine is direct on the kidney because:

1. There are no secreting nerves to the kidney. Diuresis
occiu^ after section of all nerves and on the isolated kidney, and
after degeneration of th« nerves.

2. The fluids in the tissues are not changed.

3. The kidney increases in volume, when secreting:

(a) The action therefore is local but may be either on the ves-
sels — a circulatory action, or

(b) It may be an action on the secreting cell. Opinion at
present favors a direct action on the secreting cell:

4. Rost^ has found that the flow of urine is increased only
when considerable caffeine passes into the urine.

5. Richards and Plant^have shown that diuresis may occur with
caffeine even when there is no change in kidney volume.

1 Schmidebergs Archiv., 1895, vol. 36.
* Jour, of Pharmacology, 1915, p. 485.
19



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290 CHEMICAL PHARMACOLOGY

Fate of Caffeine in the Body .

In the body caffeine loses its methyl groups — first becoming
dimethyl — then monomethyl xanthine. Then xanthine is formed
and this may be broken down into urea. Of the monomethyl
xanthines, 7 monomethyl is formed in greatest quantity. Of the
dimethyl xanthines, paraxanthine — 1, 7 dimethylxanthine is found.
Both of these may be found in the urine after the ingestion of
caffeine. While this is true for man there is some difference in
the order in which the methyl groups are lost, in different
animals. In the dog all three dimethylxanthines appear in the
urine after larger doses of caffeine, although theophyUine 1.3
dimethylxanthine predominates; -while in the rabbit under the
same conditions and in man, paraxanthine or 1.7 dimethylxanthine
predominates. The monomethyl xanthines are also excreted in
different proportions in the various species of animal, but in man
and the rabbit heteroxanthine — 7 methyl xanthine prevails.

Only about 10 per cent, of the ingested caffeine appears in
the urine in the form of the above decomposition products. The
rest is oxidized in the body to urea and other end products, car-
bon dioxide and water. After the ingestion of 1 to 1.5 grams
caffeine daily uric acid elimination is increased (Benedict). This
is apparently due to a conversion of caffeine to uric acid, though
it might also be due to a stimulation of the kidney to secrete the
normal uric acid of the blood.

The tolerance that is acquired from the prolonged uses of tea
and coffee, is in great part due to the body acquiring the abiUty
to oxidize these alkaloids more rapidly than at the beginning.
This is not the only explanation, however, for large quantities
may still be obtained from the tissues.

Purin metabolism is especially interesting in relation to gout,
in which an apparent deficiency of the oxidation of uric acid or
an increased formation, or a change in combination exists. It
has been found that when dogs, pigs or rabbits are fed nucleic
acid, 90-95 per cent, of it can be recovered as allantoine, 3 to 6
per cent, as uric acid and 1 to 2 per cent, as purin bases. It
may be that in perverted metabolism more than the usual amount
of purin bases is converted into uric acid. There is no increase
in the uric acid content of the blood after the ingestion of foods



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CAFFEINE 291

rich in purines except in cases of renal insufficiency, for this
reason gout is looked upon as a beginning nephritis (Denis).

In normal cases the oxidation of purin bases takes place a^
follows — hypoxanthine — ^ xanthine — > uric acid — > allantoine. It
has been taught that allantoine was oxidized to CO2 and urea,
but at present it is beheved by many that allantoine is the end
product of purine oxidation. The human organism cannot oxi-
dize allantoine, since allantoine injected hypodermically in man
has been completely recovered.

It has been also found that 60 to 90 per cent, of uric acid ad-
ministered hypodermically can be recovered in the urine. Some
have found as much as 99 per cent, of that administered. Uric
acid is oxidized with much greater difficulty in man than in
monkeys, dogs, cats, rabbits or pigs. In fact no adequate evi-
dence exists that the tissues of man can oxidize uric acid. Urea
is formed from uric acid in vitro by a variety of oxidizing agents
and allantoine is hydrolysed by boiUng water into allanturic acid
and urea, so that its resistance to oxidation in the body is difficult
to understand.



Economic Use of Caffeine

Owing to the daily use of caffeine compounds in the form of
tea and coffee, frequent cases of chronic poisoning are seen.
The symptoms, mainly those of dyspepsia, are: epigastric
uneasiness, depression, succeeded by nervousness, restlessness
and excitement, tremors, disturbed sleep, anorexia, headache,
vertigo, confusion, palpitation, constipation and hysterical dis-
turbances. These symptoms are reUeved by the gradual re-
moval of the drug. No acute fatal case of caffeine poisoning is
recorded and the fatal dose is not known, but it is over 10 grams.
To avoid the symptoms of chronic poisoning and to allow the
use of tea and coffee in susceptible individuals, numerous at-
tempts to remove the caffeine from tea and coffee have been
made. Some manufacturers have placed the blame for the
nervous symptoms on the volatile oil content — the so-called
cafifeol — but this is insufficient to cause the symptoms, and the
caffeine content is quite sufficient to explain all the untoward
symptoms.



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292 CHEMICAL PHARMACOLOGY

TO ILLUSTRATE IN GENERAL THE ISOLATION OF

ALKALOIDS

POWER AND CHESTNUPS METHOD OF ASSAYING CAFFEINE IN
VEGETABLE MATERIAL'

Ten grams of the finely ground material, previously moistened
with a Uttle alcohol, are extracted for about 8 hours in a Soxhlet
apparatus with hot alcohol. The alcohoUc extract is then added
to a suspension of 10 grams of heavy magnesiiun oxide in 100 cc. of
water, contained in a porcelain dish, the flask being rinsed with
a Uttle hot water, and this liquid added to the mixture. The
mixture is allowed to evaporate slowly on a steam-bath or water-
bath, with frequent stirring, until all the alcohol is removed and
a nearly dry, powdery mass is obtained. This is mixed with
sufficient hot water to enable it to be brought on a filter, which
preferably should be smooth, and, after thoroughly cleaning the
dish by means of a glass rod, to which a piece of rubber tubing
is attached, the contents of the filter are washed with successive
portions of hot water until about 250 cc. of filtrate is obtained.
To the filtrate, contained in a flask of one-htey capacity, is added
10 cc. of a 10 per cent, solution of sulfuric acid, which causes the
liquid to become much lighter in color, and with some kinds of
material, such as Ilex leaves, a considerable precipitate is pro-
duced. In some cases, as with tea and guarana, it was foimd
necessary to use 20 cc. of the above-mentioned acid in order to
prevent the formation of an emulsion on subsequently extracting
with chloroform. After the addition of the acid, a small fimnel
is placed in the neck of the flask, and the Uquid, which is at first
gently heated until any frothing ceases, is kept in a state of
active ebullition for half an hour. This treatment is for the
purpose of hydrolyzing any saponin that may be present. After
being allowed to cool, the Uquid is passed through a double



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