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amount of the active principles, but also perhaps because fewer of the
contaminating substances are extracted from the leaves. Similar
advantages may be possessed by other extracts, for example, the
quite stable dialysate, as well as by the tincture, which is so often
preferred for long-continued use.
20



306 PHARMACOLOGY OF CIRCULATION

Digipuratum. During the preparation of digipuratum, an extract
of purified digitalis, the elimination of inactive contaminating sub-
stances is carried still further, for as much as 90 per cent, of the
solid constituents may be removed from alcoholic extracts of the
leaves without diminishing their physiological or therapeutic activity.
It would appear that this preparation is especially free from digitonin
and other saponin-like components of the crude drug, for it represents
in almost pure form the combinations of tannic acid and the active
glucosides. These are insoluble in the stomach, and therefore irritate
its mucous membrane but slightly, while, in the alkaline intestinal
contents, they are readily soluble, and therefore relatively easily
absorbed. According to some observers (Hopffner}, this preparation
disturbs the stomach less than all other digitalis preparations of equal
physiological activity.*

INTRAVENOUS ADMINISTRATION. When in critical cases it is im-
portant to obtain the effect of digitalis more rapidly than is possible
by oral administration, intravenous administration may, with great
advantage, be employed. The subcutaneous or intramuscular injection
of all active digitalis preparations is painful, and, if really effective
doses are thus administered, marked local irritation results, while the
subcutaneous injections of weaker preparations or of relatively high
dilutions possess no advantage over their administration by mouth
[except that at times the stomach rejects all medication administered
orally. In such cases the rectal administration of relatively large
doses in moderate dilution may be followed by gratifying results.
TR.].

After intravenous injection of suitable preparations of digitalis,
the effects on the circulation may manifest themselves within a few
minutes, and the favorable action is usually fully developed at the
end of an hour and often lasts for a long time [12 to 24 hours or
more. TR.]. Only pure substances readily soluble in water should
be used for this purpose. This method was first employed by Kott-
mann, who used digalen for this purpose, but, since its recommen-
dation by Frdnkel and Schwartz, strophanthin in dosage of 0.5-1.0

* [Inasmuch as both clinical experience and such laboratory investigations
as those of Hatcher have clearly demonstrated that the nausea and vomiting
produced by digitalis is usually the result of its action on the vomiting centres,
and as the desired effects on the circulation often manifest themselves only with
doses which also produce these undesirable effects, one must accept with extreme
caution the claims made for any preparation of digitalis or any of its group
that it does not cause gastric disturbances. Ordinarily this is equivalent to
stating that the preparation is more or less inert in other particulars. The
claimed superiority of digipuratum in this respect may appear to be justified
by clinical observation, but the translator has seen it cause typical digitalis
vomiting. If this drug is really less likely to upset the stomach when given in
therapeutic doses, it is perhaps due to the convenience with which sufficient
amounts may be given without causing the patient to swallow nauseous tasting
mixtures or draughts. TE.]



TREATMENT OF CIRCULATORY FAILURE 307

ing. has proved an important advance in therapeutics.* [Cushny and
Dock over ten years ago injected a dilute solution of digitalis into
the vein of a human patient, with temporary good results. Personal
communication to translator.]

BIBLIOGRAPHY

Boos: Archiv of Internal Medicine, 1911, No. 4.

Cloetta: Munchn. med. Woch., 1904, No. 33, p. 1466.

Deucher: Arch. f. klin. Med., 1896, vol. 62.

Focke: Arch. f. Pharm., 1903, vol. 241, p. 669.

Focke: Therap. d. Gegenwart, June, 1904.

^Frankel: Therap. d. Gegenwart, March, 1902.

"Frankel: Arch. f. exp. Path. u. Pharm., 1903, vol. 51, p. 84; 1907, vol. 57, p. 123.

"Friinkel: Ergebnisse d. inn. Med., 1908, vol. 1, p. 68.

Friinkel u. Schwartz: Arch. f. Path. u. Pharm., 1906, vol. 57.

Gottlieb u. Tambach: Munchn. med. Woch., 1911, No. 1.

Gottlieb u. Magnus: Arch. f. exp. Path. u. Pharm., 1901, vol. 47, p. 135.

Hopffner: Munchn. med. Woch., 1908, No. 34.

Kiliani: Munchn. med. Woch., 1907, No. 18.

Kochmann: Arch, intern, de Pharmacodyn. et de Therap., 1906, vol. 16, p. 221.

Kottmann: Ztschr. f. klin. Med., 1905, vol. 56.

Loewi : Wien. klin. Woch., 1906, No. 39.

Marx: Inaug. Diss., Strassburg, 1898.

Miiller, Leo: Miinchn. med. Woch., 1908, No. 51.

Schmiedeberg : Arch. f. exp. Path. u. Pharm., 1874, vol. 3, p. 16.

Zeltner: Munchn. med. Woch., 1900, No. 26.

Ziegenbein: Arch. f. Pharm., 1902, vol. 240, No. 6, p. 454.

TREATMENT OF CARDIAC AND VASCULAR DEPRESSION

By cardiac weakness is understood a disturbance of the circulation
which is characterized by weak, rapid, and often irregular pulse,
pallor, and sometimes cyanosis. Such conditions may develop in the
final stages of many kinds of poisoning as well as in the course of
various infectious diseases. In an earlier section (p. 290) it has been
stated that cardiac insufficiency, which is equally pronounced in both
right and left hearts, results only in a slowing up of the blood flow
without the occurrence of stasis. This would typify the conditions
in a case of uncomplicated depression, but, as a matter of fact,
except as a result of hemorrhage, cardiac weakness is never observed
except in combination with a more or less general vasoparesis, for not
only the toxins of infectious diseases, but also other cardiac depres-
sants, such as chloral hydrate, chloroform, arsenic, etc., affect both
e heart and the vasomotor centres [or the vessels themselves. TR.].




[It should be emphasized that strophanthin and ouabein are both enormously
ic substances. Since their introduction as drugs to be administered intra-
nously, clinicians have learned that their administration is not unattended
with danger. 0.3 mg. is ordinarily a sufficient initial dose and, in the translator's
opinion, 0.5 mg. is the largest amount that should be given as a first dose.
Further, all those who have used these drugs at all extensively insist on the
extreme danger of giving them to patients who have recently taken any con-
siderable amounts of digitalis or its congeners. Two days or so should be
allowed to elapse between the last considerable digitalis dosage given by mouth
and the intravenous administration of strophanthin or ouabein. TR.]



308 PHARMACOLOGY OF CIRCULATION

Consequently, the phenomena resulting from vasomotor depression
develop simultaneously with those resulting from cardiac insufficiency,
or precede or follow them. Moreover, even if the heart is not directly
affected by the toxic agents, vasomotor depression being the primary
condition, cardiac weakness develops secondarily, for, as stated in the
introductory portion of this chapter, the functions of the heart
and of the vessels reciprocally affect each other most markedly.

A vasoparesis in the splanchnic system produces the most severe
disturbances of the circulation. Under normal conditions the vessels
of the abdominal viscera are maintained in a state of moderate con-
traction by the constantly acting influence of the vasomotor centres.
If this influence be removed, the vessels dilate and become a reservoir
of such great capacity that its filling deprives the other vascular sys-
tems of most of their blood. At the start the organism compensates
for this by the constriction of the vessels in other systems, and
pallor, due to contraction of the vessels of the skin and muscles,
appears before the general blood-pressure has sunk appreciably. From
the teleological point of view, this regulating process appears useful,
as thus the blood flow through the heart and nervous system is main-
tained as long as possible, for when this fails the general blood-
pressure must sink so decidedly that the insufficient blood flow in
the nervous system causes faintness, while inadequate circulation
through the cardiac muscle impairs its functional power.

In man the symptoms of such collapse, due chiefly to vasoparesis,
closely resemble those resulting from cardiac weakness. In both
conditions the blood-pressure in the aorta falls, the pulse tension is
lowered, and the pulse becomes rapid and small. This acceleration
is due to the depression of the vagus tone, which, in turn, is a conse-
quence of the lowered blood-pressure. In cardiac failure the pulse
becomes feeble and small because the strength of the cardiac contrac-
tions is primarily depressed; in vasoparesis the same changes occur
because the heart contracts when insufficiently filled with blood. In
primary cardiac depression the heart pumps insufficiently because of
impairment of its power to contract, but in vascular paresis, even
though the cardiac muscle is capable of vigorous contractions, so little
blood is received by the heart that only insufficient amounts may be
pumped out into the aorta. In each case the effect on the flow of
blood throughout the body is the same. It is therefore clear that
cardiac weakness and vascular depression may not readily be differ-
entiated by their symptoms and that they usually exist coincidently.

Theoretically they differ from each other in that in conditions of vaso-
paresis the great veins of the systemic circulation are insufficiently filled, while
in primary cardiac failure the blood accumulates largely in the veins of both the
systemic and pulmonary circulations. It has, however, been stated previously
that cardiac weakness accompanied by a slowing up of the blood flow causes
merely an alteration in the blood distribution throughout the body and is very
different from those forms of cardiac insufficiency for which stasis is character-
istic. If in cases with disturbance of cardiac function stasis is not markedly



309

developed, there results merely a diminished flow of blood throughout the whole
circulation, a relatively insufficient filling of the arteries, and a fall in aortic
blood-pressure, just as is the case in conditions of vascular depression.

Circulatory failure resulting from vasoparesis occurs in the ad-
vanced stages of many toxic conditions, the vasomotor centres being
often markedly depressed by a number of narcotic poisons while the
heart is still beating well and the respiratory centre remains suffi-
ciently excitable to maintain life. Although formerly in such cases
of circulatory failure it was the custom to consider them as due to
cardiac weakness, Romberg and his coworkers have correctly insisted
that, in the course of infectious diseases, disturbances of the circu-
lation develop which closely resemble the picture seen in vasomotor
paresis. Using pneumococci and diphtheria bacilli, as well as pyocya-
neus cultures, they were able to show experimentally that, at any rate
during a long period during which the blood-pressure continued to fall,
this was chiefly due to a vasoparesis and not to any direct harmful
action on the heart (Romberg, Passler, Bruhns u. Mutter, Passler u.
Roily], and that the same holds true for experimentally induced
septic peritonitis (Romberg u. Heinecke).

In man also the collapse occurring in such conditions may in
most cases be attributed chiefly to the central vasodepressant action
of the bacterial toxins. However, Krehl claims that usually, when the
disease is at its height, the heart, too, has been harmfully affected, and
that this is not simply a secondary effect of the vasoparesis but a
direct effect resulting from the action of the toxins on the heart itself.
It has been proved, especially for experimental diphtheria intoxication,
that in the more advanced stages a progressive true cardiac depression
is superimposed on the depression of the vasoconstrictor centres
(Roily, Steyskal). Other poisons causing depression of the nerve-
centres produce the same effects, lessened reflexes, depression of the
vasomotor and respiratory centres, all occurring together in such
poisoning as that induced by chloral hydrate. In healthy animals
the heart is less affected by this drug than are the vital centres in
the medulla. The diseased heart, however, is much less resistant, so
that in chloral poisoning, if the heart be already diseased, death may
result from cessation of the heart's action before the respiration
fails completely. It would appear that diphtheria toxin may act
lilarly (Gottlieb}.

It was, therefore, of the highest clinical importance to obtain, by
investigation of cases of circulatory failure, new criteria for
letermining in the individual case whether the damage done to the
heart by the toxins of the infection or the vascular depression caused
by them is of greater moment, for the choice of the means used for
treating the condition must be made according to the conclusion
reached. "With these conditions and facts in mind, Passler, using
ifected animals, investigated the effect of various cardiac and vascu-



mfectei



310 PHARMACOLOGY OF CIRCULATION

lar drugs in the final stages of the toxaemia, and Schwartz did the
same for the earlier stages. It is clear, however, that the interpretation
of their experiments is attended by great difficulties, for, in the first
place, the pathological conditions on which the drugs acted were not
sufficiently understood, and, secondly, most drugs affecting the func-
tion of the heart also act on the vessels and vice versa.

IN CASES IN WHICH CARDIAC INSUFFICIENCY IS THE PREDOMINANT
FEATURE,

Digitalis is the first drug to be thought of, but the slow absorption
of digitalis makes it self-evident that in acute circulatory failure not
much can be expected from its oral administration. The intravenous
injection of strophanthin is, however, a feasible procedure from which
good results might be expected, as the injections are so promptly fol-
lowed by the full development of its actions, and, as a matter of fact,
it has been found clinically that an increase of the volume of the pulse
and a rise in blood-pressure often follow the intravenous injection of
0.5 mg. of strophanthin in the collapse of typhoid and that of other
conditions. [Crile's experiments with the intravenous injection of
digitalis in animals suffering from shock would indicate that in
collapse of this type strophanthin would be of no value, or would
act harmfully. TR.]

Camphor may also improve the action of the failing heart. It is
used for this indication in doses of 0.1-0.5 gm. dissolved in oil, or in
oil and ether, or in ether and alcohol; but, on account of its insolu-
bility, it is but slowly and uncertainly absorbed from the stomach.
By reason of its volatility and its solubility in the lipoids of the
tissues, amounts sufficient to produce effects on the circulation are
quite readily absorbed from the subcutaneous tissues [see p. 316 TR.] ,
"but its action is rather evanescent, for in the body it is transformed
into camphor-glycuronic acid (Schmeide'berg) .

Other Actions. In connection with the general systemic action of camphor
the stimulant action on the cerebral function should again be mentioned
(p. 24). In animals large doses cause clonic convulsions, but these have been
very rarely observed in man, as the margin between therapeutic and toxic doses
is so great. The respiratory and vasomotor centres are stimulated, and increased
blood flow in the skin causes, even after small doses, a subjective feeling of
warmth. Very large doses produce an antipyretic effect in fever. [Its local car-
minative action on the stomach, with the usual reflex effect, should also be
mentioned. Moderate antiseptic powers are also possessed by this drug. TB.]

BIBLIOGRAPHY

Gottlieb: Med. Klin., 1905, No. 25.

Hopffner: Deut. Arch. f. klin. Med., 1908, vol. 92, p. 485.

Krehl: Pathol. Physiol., Leipzig, 1907, 5th edition, p. 119.

Liebermeister: Medizin. Klinik, 1908, No. 8.

Ortner: Prag. Ztschr. f. Heilk., 1905, p. 183.

Passler: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 715.

Passler u. Roily: Deut. Arch. f. klin. Med., vol. 77, p. 96.

Roily: Arch. f. exp. Path. u. Pharm., 1899, vol. 42, p. 283.

Romberg u. Heinecke : Deut. Arch, f . klin. Med., 1901, vol. 69, p. 429.



TREATMENT OF CIRCULATORY FAILURE 311

Romberg, Passler, Bruhns u. Miiller: Deut. Arch. f. klin. Med., 1899, vol. 64, p. 652.
Schmiedeberg u. Hans Meyer: Ztschr. f. physiol. Chemie, 1879, vol. 3, p. 422.
Schwartz: Arch. f. exp. Path. u. Pharm., 1905, vol. 54, p. 135.
Steyskal: Ztschr. f. klin. Med., 1902, vol. 367; vol. 51, p. 129.

IN CONDITIONS OF UNCOMPLICATED VASCULAR DEPRESSION HO benefit

can be expected from, the administration of cardiac stimulants, for
such can result only if the tone of the splanchnic vessels be restored.
If this be done, the previously insufficient blood flow through the
vessels of the skin, muscles, and brain becomes sufficient (v. Basch,
Biedl), and, the heart again receiving sufficient amounts of blood,
the pressure in the aorta rises. It is thus that sensory reflexes and
centrally acting vasomotor stimulants for example, strychnine and
caffeine may favorably influence vascular paresis. On the other
hand, peripherally acting vasoconstricting drugs, such as epinephrin,
may similarly alter the general distribution of the blood in spite of
the existing depression of the vasomotor centres.

Sensory Stimuli. As a general rule, it may be stated that a very
strong sensory stimulation reflexly lowers the blood-pressure, while
weaker stimuli raise it. The effects resulting from the use of mus-
tard plasters and baths or of friction with skin irritants, etc., are best
explained as resulting from such reflex actions. By the use of the
plethysmograph it may be shown that the kidney volume diminishes
while the blood-vessels are more completely filled and the blood-
pressure rises under the influence of such sensory stimulation (Wer-
theimer, Roy} .

Strychnine is the best example of a central vasomotor stimulant,
its action on the circulation being a partial expression of its action on
the central nervous system. Therapeutically it is of importance that
the action on the vasomotor centres develops before the occurrence of
the convulsive symptoms. In this stage mild sensory stimuli, such
as blowing on the skin, reflexly cause a rise in blood-pressure in the
rabbit. However, a persistent rise in the blood-pressure occurs in nor-
mal animals only when the increased reflex excitability of the motor
centres of the cord is fairly evident (Denis). With depressed ex-
citability of the central nervous system, the danger of causing convul-
sions is much lessened, and it has been shown that strychnine may
improve the circulation in chloralized animals without necessarily
causing convulsions. These actions are the basis for the adminis-
ition of this drug in acute alcohol or chloral poisoning, as also in

ther conditions with similar disturbances of the circulation, a prac-
tice much more common in other countries than in Germany.* In

England and America a direct favorable action on the tone of the
heart muscle is attributed to strychnine, and recent experiments of
Cameron indicate that this is the case.

* [Many careful clinicians as a result of painstaking investigation of the
effects of strychnine under such conditions have lost their faith in this drug as
means of improving the circulation in infectious disease. TE.]




312 PHARMACOLOGY OF CIRCULATION

BIBLIOGRAPHY

v. Basch: Ber. d. Sachs. Akad. d. Wiss., 1875, vol. 27, p. 373.

Cameron, cited from Hirschf elder : Diseases of the Heart and Aorta, Philadelphia

and London, 1910, p. 181.

Denis: Arch. f. exp. Path. u. Pharm., 1885, vol. 20, p. 306.
Biedl u. Rainer: Pfliiger's Arch., 1900, vol. 79.
Roy and Sherrington: Journ. of Physiol., 1890, vol. 11, p. 85.
Wertheimer: Arch, de Physiol., 1893, No. 2.

Caffeine. The less dangerous caffeine resembles strychnine in its
action on the circulation, but never increases the blood-pressure to so
great an extent. In previous sections it has been shown that caffeine
also is a stimulant for the whole central nervous system (p. 25ff), its
vasomotor actions going hand in hand with the stimulation of the
respiratory centre and of the cerebral function. In this way is ex-
plained the fact that caffeine is one of the most useful analeptics
in cases where the circulatory failure results from depression of all
the functions of the central nervous system.

Experimentally it has been shown that the vasomotor excitability in dogs
poisoned by alcohol is increased under the influence of caffeine and that the
blood-pressure returns to a normal height after moderate doses (Binz). This
return of reflex excitability may also be well observed in chloralized rabbits,
Passler studied the actions of caffeine on the depressed circulation of infected
rabbits, and found that subcutaneous injections of caffeine-sodium salicylate
raised the lowered blood-pressure even in the final stages of pronounced vasomotor
depression. Under these conditions the reflex excitability of the vasomotor
centres was restored or improved, and this favorable action persisted for a con-
siderable time up to 1% hours.

In experiments on animals it may be shown that it is especially
moderate doses of caffeine which favorably influence the blood-pres-
sure, an increase of the dose causing further rise, and very large
doses or rapid intravenous injection being followed by a fall. This is
due to the depression of the functional power of the heart which
undoubtedly occurs after toxic doses of caffeine. The discussion of the
cardiac action of caffeine (see pp. 267-8) has made it evident that under
normal conditions it produces no favorable effects on the performance
of the heart, and that after large doses there is a diminution of the
amount of blood expelled by the heart in the unit of time. This should
soon result in a fall of the arterial pressure, but actually this remains
high, as a result of the opposing influence of the vasoconstriction
caused by the drug (Bock}. Thus, during the action of caffeine we
must assume that increased tone of the splanchnic vessels occurs
simultaneously with lessening of the heart's pumping capacity.

Further, as has been previously mentioned, caffeine exerts two
actions, each of which tends to affect the frequency of the pulse in
opposite directions. On the one hand, it stimulates the vagus centre
and slows the pulse (Wagner, Swirski, Bock}, and this effect appears
to be the predominant one resulting from therapeutic doses in man
(Riegel) [?TR.]. Following larger doses, on the other hand, the



TREATMENT OF CIRCULATORY FAILURE 313

pulse is always accelerated, as a result of stimulation of the accelerator
terminations in the heart. It is possible that this action on the
motor centres in the heart plays a more important role in patho-
logical conditions.* From what has been said, an increase in the
blood-pressure following the administration of caffeine is to be attrib-
uted to the vasoconstriction in the splanchnic system as well as to an
increased frequency of the pulse in the later stages of its action.

Therapeutically this power of bringing about an alteration in the
distribution of the blood is made use of in conditions of vascular
depression. It is possible, too, that this forcing of the blood out of
the visceral vessels, as well as direct stimulation of the cerebral func-
tion, accounts for the use of the various beverages containing caffeine.
The effect of caffeine in overcoming the feeling of fatigue after eating
may be due to the action of caffeine in preventing the hyperaemia of
the intestinal vessels which usually follows the ingestion of large
amounts of food, and thus preventing the relative anaemia of the
brain which accompanies hyperaemia of the portal system. The in-
creased blood supply to the skin expresses itself as a subjective feeling
of warmth following the drinking of beverages containing caffeine.

The indirect effect on the heart resulting from the rise in blood-
pressure due to central vasoconstrictor stimulation is of much im-
portance, for under the influence of caffeine the constriction of the
visceral vessels brings larger amounts of blood to the right heart,
and as a result an improvement of the cardiac function occurs. This



Online LibraryHans Horst MeyerPharmacology, clinical and experimental : a groundwork of medical treatment : being a textbook for students and physicians → online text (page 38 of 74)