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Hugh McGuigan.

An introduction to chemical pharmacology: pharmacodynamics in relation to ... online

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electronegative colloids like kaolin, sulphur, charcoal, silk, cotton,
etc.

XXXI. THE REACTION OF LIVING MATTER

Living matter is alkaline in reaction, but becomes acid after
death. To determine the reaction during life therefore, it is
necessary to use an indicator that will act in the living body with-
out kiUing it. Such indicators are neutral red and cyanamine,
the former being an orange red color in alkaline reaction and
pink in acids. Cyanamine is red in alkaline and blue in acids.
Acid fuchsin does not stain alkaline protoplasm, but staiins it
red when the protein reacts acid. When the circulation stops,
protoplasm becomes acid. This may be shown in the following
experiment: Inject a frog with a solution of acid fuchsin. After
it has penetrated all the tissues, tie off the circulation of one leg,
and stimulate the muscles of this leg. On removal of the skin
from the muscles on the Ugated side, it will be found that they
have become red due to acid formation. It is known that lactic
acid develops during muscular contraction, in the absence of
sufficient oxygen.

In order to determine the reaction of tissues by the use of a
stain, several conditions must be fulfilled: (1) The stain must
penetrate the tissue fluids. (2) It must not kill the tissues,
since the reaction changes after death. (3) Since the tissues
have oxidation and reduction properties, the stain must not be
influenced by the oxidation and reduction processes of the body.

The alkaline reaction of the body is due to excess of OH
ions. Acid reaction is due to H ions. The concentration of



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REACTION OP LIVING MATTER 351

these ions present in the body fluids may be determined by a
number of methods.

1. The Colorimetric Method. — Solutions of acids of known
strength in which complete ionization has taken place, or where
the degree of ionization is known, in terms of a normal solution,
are colored by some indicators in intensity directly as the con-
centration of the ions. This being the case, one may determine
the hydrogen ion concentration of a solution by comparing it,
when treated with an indicator, with the color solutions produced
by the same indicator in solutions of known hydrogen ion con-
centration. This is most easily done by using tubes of the same
bore, and containing the same amount of fluid as the control
and the same amount of indicator by using a series of tubes of
known but varying PH concentrations as controls the unknown
concentration can be found by matching its color with a control
tube. Such control tubes sealed and with different PH values can
be obtained, sealed from Hynson Westcott and Co., Baltimore.

2. Electro Potential Method or Gas Chain Method.— When
a metal is dipped in a solution of one of its salts an electromotive
force is set up at the surface of contact. The voltage developed
depends on the strength of the salt solution. These electrode
potentials are susceptible of direct measurement, consequently,
two solutions of different concentration having the same ions in
common have different electrical potentials. When such solu-
tions are connected by a conductor, a current flows from the
stronger toward the weaker. The strength of this current
depends upon the relative concentration of the two solutions.
In the case of an acid it is in direct ratio of the hydrogen ions.
It has been foimd that a ten fold difference in the ionic concen-
tration of solutions with common ions is equal to a voltage of 58
millivolts. Since the logarithm of 10 is 1, the factor obtained by
dividing the voltage by .058 will give the logarithm of the dilu-
tion. -To determine the hydrogen ion concentration of blood or
other fluid by this method therefore the difference in the concen-
tration of a known solution as compared with the concentration
of, H ions in the blood may be represented by the formula;

e = K log Cone. Hi/Conc. H2

Where e = the difference in the potential determined by



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352 CHEMICAL PHARBfACOLOGY

measurement. K = .058 volts when common logarithms are

E.M.F.
used, consequently — qko— is equal the number of ten-fold

dilutions or PH.

In an actual determination of PH there are many technical
difficulties to be observed and overcome. While every ten-fold
dilution makes a difference in potential of 58 millivolts an actual
determination if made in a chain consisting of —

H|HC1 n/10|HCl n/100|H would show only 0.019 volts.
This is due to a contact potential at the junction of the acid
solutions developed by the difference in speed of H. and CI ions
and which acts in opposition to the electrode potentials. To
obviate this error, a neutral conducting solution is placed between
the acid solutions. Such a solution is KCl. The ions of this
solution have about the same speed, but in opposite directions,
consequently neutralize the effect of each other. When such
a chain is connected we get a voltage of 0.058 at 20°C.

HiHCl n/10|KCl|HCl n/100|H

Again in actual practice instead of using two hydrogen electrodes,
as in the above, a standard calomel electrode is used for the known
solution. The normal calomel electrode has a voltage of 280
millivolts above the normal hydrogen electrode. Consequently
the electromotive force E, developed by this when assembled
with an unknown hydrogen cell (C) would be:

E = 0.280 - .058 log C or
E - 0.280 . ^ . 1 ^
0.058 =-logC = log^ = PH.

If a normal tenth normal calomel electrode be used it has a volt-
age of .337 above the normal hydrogen electrode, consequently
0.337 is used instead of 0.280 in the above formula.

METHOD OF EXPRESSING HYDROGEN ION CONCENTRATION

The hydrogen ion concentration of body fluids is very close
to that of water. It would be cumbersome to express frequently
a dilution of one molecule of dissociated H. in ten million Utres of
water by 0.000.000.1. In biologic work we have to deal mainly
with such dilutions. The adoption of a more convenient method
of expression is therefore advisable.



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HYDROGEN ION CONCENTRATION 353

Since the ionization constant of water is H times OH = 10~"^*
or H = 10-^ and OH = 10""^, and since the factor 10~"" is always
constant, when H increases, OH decreases.

Thus if H = 10-S OH = 10-l^ and theoretically if H = 10®
OH = 10-" =1 gram molecule OH in 10.000.000.000.000 Utres.
The older methods of expressing H ion concentration retained the
constant 10"^ and until recently the acidity or alkalinity of body
fluids was expressed:

2 times 10-^

1 times 10-^

or 0. 5 times 10~"^ etc.

Following the suggestion of Sorensen it is customary to express
the reaction by the reciprocal or colog'arithm of the number.
In reality this is the logarithm of the dilution in terms of normal
solution. Thus potential of H when H = 10"^ is expressed
PH = 7, and H = 10-^^ PH = 10. This method of expression
is brief but confusing until one gets accustomed to translating the
numbers, and knowing that the greater the value of PH the lesser
the acidity, and thinking in terms of logarithms and remembering
that PHi PH2 PH3 etc. differ by powers of 10.
Thus:

PHi = n/10 acid or PH = 1

PH2 = n/100 acid PH = 2

PH3 = n/1000 acid PH = 3

PHe = n/1,000,000 acid PH = 6
PHg = n/1,000,000 alkali PH = 8
• PBu = n/1000 alkali PH = 11

PH12 = n/100 alkali PH = 12

PH13 = n/10 alkali PH = 13

PH,4 = n/1 alkali PH = 14

Since the numbers refer to negative logarithms the higher the
number the fewer H ions in a given volume, while the OH ions
increase. This is quite comprehensible when we recall that H
times OH is always 14 or 10"". If PH is 14, it follows that OH
must be O and if PHi is N/10 acid P(OH)i must be N/10 alkali.
Some confusion may also raise in translating such expressions
as PH = 2 X 10-^ into the more modern figures. One readily
sees that in terms of normal solution 2 X 10"^ is twice as strong



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354



CHEMICAL PHARMACOLOGY



as 10-« but that PH = 5.70 (Log. 2 = - 0.3 hence 6-0.3 =

5.70) = n/500.000, is not so obvious.

Similarily:

0.35 X 10-' = n/28. 580.000 or PH = 7.45
0.91X10-1= PH = 1.04

0.98 X 10-« = PH = 3.01

Since normal metabolism and therefore, normal health, depend
on the maintenance of the normal alkalinity, pharmacology is
concerned with the regulating mechanisms and the changes in
the alkalinity that may be produced by -drugs.

REGULATING MECHANISM

The blood always contains a mixture of CO2, NaHCOa, NaHj-
PO4 and NaoHP04. All of these dissociate so weakly and
normally occur in such quantities that the reaction is constantly
kept close to PH = 7.2. The normal ratio of NaH2P04 : Na2-
HPO4 is stated by Michaelis and Garmendia to be 1 :5.1
molecules. If these were the only salts present in a solution of
water in the proportion of Ice. n/10 NaH2P04 and 2.5 cc. n/10
NaiHP04 we would have a PH of 7.0. The carbonates modify
this to the PH found in the blood. While the salts which main-
tain the normal PH are fairly well known the reason why these
salts are found in the necessary concentrations is not known. It
should be emphasized that there is a wide margin of safety within
which they may vary without materially changing t^e PH. For
example if m/3 solutions of Na2HP04 and NaH2P04 are mixed in
the following amounts PH =

Na2HP04 NaH2P04 PH =



1 cc.


32 cc.


5.11


1


16


5.42


1




6.62


2




6.92


4




7.22


8




7.62


16




7.82


32




8.12



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BUFFER VALUE 355

The lungs and the kidneys play an important part in the regu-
lation of the H ion concentration, e.gr., CO2 is excreted by the
liings. It is continuously formed in digestion. Alkaline salts
are constantly taken in the foods, especially vegetable foods.
NH3 is formed from the digestion of proteins. Acid salts are
formed and these act as diuretics. Hence, under normal con-
ditions formation and excretion take place at such pace that the
body holds a reserve or potential alkalinity.

It is thus possible to give an account of the mechanism as it
exists or to state reactions as they probably occur. The basic
cause, or why, is still beyond the scope of science.

Under some conditions this mechanism fails and acidosis
develops. A knowledge of the normal mechanism enables us to
modify and treat the acidosis. The importance of this may be
reaUzed since it has been shown by Henderson and Palmer that
the acid formation in the human organism corresponds to be-
tween 600 and 700 cc. n/1 acid solution daily.

ACTUAL AND POTENTIAL ALKALINITY AND BUFFER VALUE

Sodium bicarbonate reacts slightly alkaline to litmus. This
alkaline reaction is explained by the fact that in water we have
H and OH ions. When NaHCOs is dissolved in water we also get
Na, H, OH and CO3 ions. Consequently there will be a shifting of

the balance. Since the constant of carbonic acid, — jj~c^ ^

very small and the constant of — ^ ^tt is large, the carbonic

acid will be suppressed and the constant of NaOH will tend to

be estabUshed. This full constant cannot be reached because

+ + —

the NaHCOs also has a constant xt rri- ^ = K and in

JNaJlOUs

this case only a certain number ofNa, + ions can remain in the ionic

state in the presence of NaHCOa. The whole solution, therefore,

strikes a balance at a strength which reacts slightly alkaline to

litmus. This balance point is known as the actual alkalinity of

the solution. This is the PH of the solution as represented by

the colorimetric or gas; chain method.

If we titrate a solution of sodium bicarbonate with an acid,

the acid removes the OH ions, but when these are removed.



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356 CHEinCAL PHARMACOLOGY

others are formed from the bicarbonate which will keep forming
OH ions in the attempt to form the balance until the whole is
neutralized by the acid, in tte following way.

NaOH ^

Na times OH
This titratable alkalinity is known as the total or potential
alkalinity.

POTENTIAL ALKALINITY OF BLOOD

The weak alkaline' condition of the blood is guaranteed by a

mixture of H2CO3, NaHCOa, NaH2P04. These (buffers) are all

very weakly dissociating substances and may be considered in

the blood in a balanced State.

H2CO3 ^ ,NaH2P04 ^
= K and ^Kj^a ^rT = ^t



NaHCOs " """ N2H PO4
Where K and K2 are constants, and the sum of these constants
in terms of H ions is about PH 7.1 to 7.8

H2C0a T^
NaHCOs "
K acid be added to this directly or indirectly, as in cases of acido-
sis, it Uberates H2CO3. This will either break into CO2 and H2O,
and K kept constant; or it will tend to act with Na2C03 if such
be present and restore the constant in that way. If enough acid
be added or developed, the whole alkaU reserve may be exhausted.
The phosphates are balanced in the same way. According to
MichaeUs and Garmendia, the ratio of

Na H2PO4 1 Tv>r 1 1

N^ PO; = 51 ^^^"'^^"^-
Since the normal blood always contains CO2, NaHCOa and
Na2 HPO4 in this balanced state, the H ion concentration at any
one time cannot be determined by titration, because as fast as
the actual alkaUnity is removed, the potential alkalinity is con-
verted into actual. Consequently, the titration alkaUnity is the
siun of actual and potential.

This difference between the actual and total alkalinity of the
blood, is known as the "buffer" value, and NaHCOs and Na2-
HPO4 are the buffers, NaHC03 especially. The value of this
buffer is illustrated by comparing the effect of acid added to a
Uter of water, and to a liter of NaHCOa. The reaction of a solu-



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BUFFERS 357

tion of pure NaHCOs is veiy weakly alkaline. Water is neutral.
A drop of acid added to a liter of water will definitely acidify it.
When added to a solution of NaHCOs, however, it will not change
the actual alkaUnity, and will not exceed the acidity of CO2 until
all of the NaHCOs has been decomposed. The amount of acid
required to do this will deptod on the amount of the NaHCOs in
solution, in other words on the bufifer value of the solution. The
carbonates are the chief biologic buffers, and the constant in
blood plasma of

H^^Qa - 1/20
NaHCOs ~ ^Z"^"-

Now PH, or CH as it is sometimes given, is directly proportional

to this ratio. And any condition in which the ratio of these in

the plasma is greater than 3^0 ^aay be looked on as an acidosis.

Since CO2 is the principal reagent used by the organism to

regulate the reaction, it is evident that H ion concentration and

CO2 concentration run parallel. Hence knowing the one 'we can

calculate the other. Hasselbach (Biochemische Zeitschrift, 1912,

vol. 46, p. 403) thinks that the hydrogen ion concentration is the

real stimulus of the respiration rather than CO2. However,

while many accept the view that C02acts because of the hydrogen

ion concentration of its solutions, the question of a specific

action of molecular CO2 has not been satisfactorily answered.

ACIDOSIS

By acidosis is meant the poisoning of the organism with acids,
due directly to neutraUzation or depletion of the alkaline reserve
or potential alkalinity. A better term would be hypoalkalinity.
Acute poisoning by acids due to corrosion or local action of acids
does not come under the term acidosis. Most cases are due to
faulty metabolism, and in such cases oxybutyric acid, diacetic
acid, lactic acid and acetone are formed and may be found in the
urine. Acidosis occurs especially in diabetes when as much as
250 grams of acetone bodies may be produced in a day. The
normal excretion in adults is from 3 to 15 mflligrams per day.
Until quite recently (1907) diabetes was the only disease in which
acidosis was known to occur. We now know that it is present
also in certain nephritic cases, in cholera, in certain intoxications
in children, starvation, phosphorus poisoning, etc. It often



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358 CHEBHCAL PHARMACOLOGY

happens that these acetone bodies are present in the mine when
there is no symptoms of acidosis. The presence of acetone
bodies in the urine develops after the reserve alkalies or bnflFers
have been somewhat depleted. This form of acidosis is called
a ketosis or poisoning by ketone. No special names are given
to the other acidoses. This depletion may also be caused by the
introduction of weak acids into the body either by mouth or
parenterally, and this method of pioducing the symptoms is
largely responsible for the term acidosis.

The symptoms of acidosis are mainly those of asphyxia, labored
respiration, air hunger, cyanosis, coma, and convulsions. Death
is due to respiratory paralysis. These occur before the blood at^
tains an acid reaction. It requires three hundred times as much
acid to render blood acid, as it does to acidify water. This is
because of the potential alkalinity or buffer value, due to the
proteins, carbonates and phosphates in the blood which neutralize
acids. The treatment of acidosis is the administration of sodium
carbonate, and even in the last stages this is often effective.

In uremia and diabetes, the acidosis may reach a degree suflB-
cient to produce coma. Fasting, high fat diet, arsenical and
phosphorus poisoning, and heavy metals may cause an increase
in the H ion content of the blood, but not sufficient to produce
coma.

Why depletion of the alkaline reserve should cause death while
the blood is still alkaline is like many other whys — hard to answer.
We know, however, that certain conditions are necessary for life.
These are the presence of certain essential chemical elements and
in addition a balance of these elements. Loeb has shown that
the ova of fish living in sea water, die in an isotonic solution of
sodiiun chloride sooner than they do in distilled water. In this
case the poisonous action of the sodium can be neutralized by
traces of calcium. A similar, but perhaps more complex, reaction
occurs in the human body when the alkaline reserve is depleted,
i.e., after abnormal loss of the Na"*", K"^, Mg"^"^, and other
positive ions. When the balance is destroyed other elements
like potassium, or hydrogen act more as poisons.

Acidosis is a problem still under investigation and for a clear
statement of the problem, the student is referred to the little
book by Sellards, Harvard University Press — 1917.



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ACIDOSIS 359

THE DETERMINATION OF THE EXISTENCE OF ACIDOSIS

Formerly the presence of acetone bodies in the urine, was the
only diagnostic test used. This, however, is a relatively late
sign, and in order to be of much value an earlier indication. is
needed. It was thought, therefore, that in the development of
acidosis the blood would become less alkaline, and attempts were
made to titrate the blood with a standard acid. But while this
method is theoretically sound, it has been found unsatisfactory
for several reasons: (1) It is hard to remove the coloring matter
of the blood to allow a satisfactory titration; (2) large volumes
of blood are required; (3) the proteins of the blood interfere with
acid titration; and the "buflFers" in normal cases vary to a
greater degree than the possible range of a true acidosis. Acidosis
is a question of the tissues, hence the blood may not be a true
indication of the body state as a whole.

The methods now used to detect' acidosis are:

1. Increased tolerance to sodium bicarbonate.

2. Urinary changes:

(a) Increased acidity and acetone bodies. (6) Increase in
ammonia, (c) Changes in the fixed bases.

3. Lowered tension of carbon dioxide in the respired air.

4. Lowered carbon dioxide content of blood = lessened amount
of carbonate in the blood.

5. Lowered alkalinity of the blood = increased hydrogen ion
concentration.

. 1. Tolerance to Carbonate. — The normal individual cannot
take more than 5 grams of sodium bicarbonate a day without the
urine becoming alkaline. In case of acidosis the sodium bicar-
bonate is apparently depleted. The tissues absorb and retain
as much as 100 grams per day before the urine becomes alkaline.
It has been proven in these cases that the retention is not due
to defective kidney function.

2. Urinary Changes. — (a) Increased acidity and acetone
bodies. Acetone bodies indicate mainly disturbance of carbohy-
drate metabolism and may have no reference to acidosis. Again
acidosis may develop in diabetes without the presence of acetone
bodies in the urine.

(5) Increase in ammonia. When the fixed bases of the body



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360 CHEMICAL PHARMACOLOGY

are used to neutralize the acids formed in acidosis there is some
break-down of protein with the formation of ammonia to aid in
the neutralization and to make up the alkaline deficit. It was
therefore thought that the free ammonia excretion in the urine
would be a measure of the acidosis. But in primary disturbances
of protein metabolism the ammonia coefiicient may be high, and
it may be low ifi acidosis. This may be because ammonia in
some cases is converted into stable salts and in other cases urea
may be decomposed yielding ammonia.

(c) Change in the fixed bases of the urine, sodium, calcium,
magnesium and potassium are somewhat used to neutralize the
acids formed in acidosis. The excretion; of these, therefore, in
the urine may be increased. Since, however, it is the depletion
of these in the tissues that gives rise to the symptoms of acidosis,
their amount in the urine may be lower, at the height of the
attack. The determination of these bases, therefore, to be of
value must extend over a number of days. Since the determina-
tion is tedious and time consuming it is little used.

3. Lowered Tension of Carbon Dioxide in the Respired Air.
The normal venous blood carbon dioxide exists under a tension of
about 6 per cent. (42.6 mms. Hg.) practically 40-50 millimeters.
An extreme fall of the carbon dioxide is virtually pathognomic
of acidosis. In four cases of uremia Sellards found 10 to 24 mms.

The CO2 content of the alveolar air is practically the same as
that of the venous blood 37.6 mm.: 42.6 mm. Hg. and more
closely approaches the content of the arterial blood. For this
reason, analysis of the respired air has been used to aid in the
diagnosis. The principle is based on the fact that alkaline
solutions absorb CO2 in proportion to the strength of the solution.
The reaction does not go on to completion and is reversible.

2 NaHCOa T± NasCOa + H2O + CO2

or expressed in another form —

H CO
N~lTrA~ "^ ^ constant (about 1/20). (Isolated plasma only)

Since H2CO3— >H20 + CO2, and the CO2 readily penetrates the
alveolar tissue, a measure of the CO2 in the alveolar air, is prac-
tically a measure of the buffer value of the blood.

4. Carbon Dioxide Capacity of the Plasma (alkali reserve).
Method of Van Slyke and Cullen — Principle — The plasma from



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PHOSPHORUS 361

oxalated blood is shaken in a separatory funnel filled with a CO2-
air mixture approximating the composition of the alveolar air
which has a CO2 tension equivalent to that of arterial blood. In
this way the sample of blood plasma combines with as much
CO2 as it is able to hold under normal tension. A measured
quantity of this saturated plasma is then acidified within a
special pipette, and its CO2 is liberated by the production of a
partial vacuum. The Uberated CO2 is then measured under
atmospheric pressure and the volume corresponding to 100 cc.
of plasma calculated.

This method is the most useful clinically because of the ease
with which it can be carried out and because it directly measures
the alkali reserve of the blood under conditions simulating the
conditions in the body.

The H ion concentration of the blood varies so little that it
is of less value in the diagnosis of acidosis than the measurement
of the alkali reserve.^

XXXn. PHOSPHORUS

There are two forms of phosphorus, yellow and red or amor-
phous. The red form is not used in medicine, being inert. The
yellow is the medicinal variety and it is in the metallic state. It
appears as a translucent, nearly colorless soUd, of a waxy lustre,
with the consistency of beeswax.

Phosphorus is very slightly soluble in water, and its solubility
in alcohol is 1 :350; it is easily oxidized and burns when exposed to
the, air. On thi^ acount, it should be cut and handled imder water.

In the body it is rather insoluble, and is active only in the finely
divided metallic, state. A large mass may pass through the
body unchanged, but in the finely-divided state or in solution
in oil, it is readily absorbed and highly toxic, 0.05 to 0.1 gram has
proved fatal to man.

Phosphorus exists in the blood as such and its actions are due



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