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patient on a large piece of rubber sheeting, of which the edges are
raised over pillows or rolled-up sheets. Cold water is poured in
around the patient, ice added, and the patient's body soused with
the water by means of a large sponge.

In the cold-pack one or two sheets are wrung out of cold water
and wrapped around the patient, the first layer of sheet passing
beneath the arms and being tucked between the legs. The patient
lies on a blanket, in which he is then completely enveloped up to
the neck. After fifteen minutes these coverings are removed. If
desired, the sheets may again be wrung out of cold water and the
process renewed. When the drip-sheet is used as an antipyretic
measure the patient is wrapped in a sheet in the same manner as
above, but sits up and has cold water poured over him. These
methods of applying cold, whether followed by a good reaction
or by shivering, cause an increase in the viscosity of the blood
(Determann, Austrian).

ANTIPYRETIC DRUGS

The group known as antipyretics includes only those drugs
whose most pronounced property is to reduce the temperature
of fever. It does not include aconite, alcohol, digitalis, phenol,



462 PHARMACOLOGY AND THERAPEUTICS

and other drugs which possess the power to lower temperature in
fever, but have other important activities that lead us to class
them elsewhere. For convenience, the essential antipyretics may
be divided into three therapeutic groups, viz., the analgesics, the
antimalarials, and the antirheumatics.

THE ANALGESIC ANTIPYRETICS

The official ones are antipyrine, acetanilid, and acet-phenet-
idin. Some of the quinoline derivatives, among the so-called
coal-tar drugs, have been employed largely as antipyretics
(kairin, thallin, etc.), but have been discarded in favor of more
certain remedies.

Antipyrina, antipyrine, phenyl-dimethyl-pyrazolon,

NC C H 5
CH 3 N/\CO



CH 3 C



CH



is freely soluble in water and alcohol, and has a slightly bitter
taste. It is a body closely resembling the alkaloids, and is pre-
cipitated by tannic acid, alkalies, and some other alkaloidal pre-
cipitants. With calomel it forms a poisonous compound. With
spirit of nitrous ether or other nitrites it gives a deep-green color
(iso-nitroso-antipyrine) ; with ferric salts a deep red ; with chloral
hydrate, naphthol, phenol, and sodium salicylate it liquefies; with
caffeine, quinine, and some other alkaloids it forms soluble
double salts. Dose, 4 grains (0.25 gm.). For local application it
is employed in 5 to 25 per cent, aqueous solution. Close relatives
are pyramidon, dimethyl-dimethyl-amino-pyrazolon, and sali-
pyrine, antipyrine salicylate.

Acetanilidum, acetanilid, phen-acetamide, C 6 H 5 .NH.CH 3 CO,
has a slightly biting taste, ancl is soluble in 190 parts of water and
in 3.4 of alcohol. Its solubility in water is increased by acids and
decreased by alkalies. Dose, 4 grains (0.25 gm.).

Close relatives of acetanilid are exalginc, methyl-acetanilid,
and salophen, acetanilid-salicylic acid.

Acet-phenetidinum, C 6 H 4 .OCoH 5 .NH.CH3CO, more familarly
known under the proprietary name "phenacetin," is a derivative
of phenol. It is soluble in 1310 parts of water and 15 of alcohol,
and is almost tasteless. The chemic formula shows that phen-
acetin might properly be called oxyethyl-acetanilid, but it is not
a direct derivative of acetanilid, and may better be placed in a
separate group with other phenetidin compounds. It is not
readily soluble in water. Dose, 5 grains (0.3 gm.). The other



THE ANALGESIC ANTIPYRETICS 463

phenetidin compounds worthy of note are lactophenin, a lactic-
acid derivative; malakin, a salicylic-acid derivative; and apolysin
and citrophen, the mono- and tri-phenetidin citric acids.

Pharmacologic Action. These drugs all reduce temperature
in the same way, are all analgesic, are all nerve sedatives, and are
all antiseptic. This antiseptic action is mild, but is the same in
kind as that of the phenol group of antiseptics, to which they are
closely related chemically. Their antipyretic action is powerful,
as exhibited in the reduction of temperature in the infectious
fevers. Their analgesic action is chiefly shown in headache and
nerve and muscle pains.

Locally, antipyrine differs from the others in that a 10 to 25
per cent, solution applied to a mucous membrane acts mildly like
cocaine, inducing vasoconstriction with shrinkage of the mem-
brane and the checking of small hemorrhages, and lessening pain.
Acetanilid is slightly irritant locally, and phenacetin is bland.

The Antipyretic Effect.- It seems probable that in many cases
hyperthermy or fever is a protective reaction on the part of the
body, and in these cases moderate degrees of fever require no
antipyretic treatment. There are some cases, however, in which
even mild degrees of fever seem disadvantageous, and others in
which the protective fever reaction overshoots the mark and pro-
duces a high and dangerous body temperature, and it is in these
that antipyretic measures are indicated. Hektoen believes that
fever is an indication that foreign protein is being broken down.

In fever the temperature may be reduced either by lessened
production of heat or by increased output of heat, or by both.
The tendency of the body is to keep itself at a normal tempera-
ture. If the body is too warm, there is a dilatation of cutaneous
blood-vessels and an outpouring of sweat, so that the body will
undergo heat loss by (i) Radiation and convection of heat, more
heated blood from the interior being brought to the surface ; and
(2) the evaporation of sweat. At the same time there is a
tendency to lessened muscular activity with diminished heat
production. This combination of lessened heat production and
greater heat dissipation tends to bring the overheated body to a
normal temperature.

If, on the contrary, the body is too cool, there is stimulus to
greater muscular activity, the muscular act of shivering takes
place, sweating stops, and the cutaneous vessels are contracted.
So there are greater heat production and lessened heat dissipa-
tion, and the too cool body becomes warmed.

This heat production and heat-dissipation are, to a certain
extent, under the control of some central structures spoken of
collectively as the heat-regulating centers, the function of which



464 PHARMACOLOGY AND THERAPEUTICS

is to keep the body temperature normal. There are probably
thermogenic centers governing the production of heat, and
thermolytic centers governing the dissipation of heat, and it is
believed that they are situated in the corpus striatum and optic
thalamus. Barbour and Wing have shown that heat applied
directly in these regions results in body cooling, and cold results
in body warming. Any variations from the normal affect these
centers; and they at once send out impulses which influence the
mechanisms for the production or the dissipation of heat, as may
be needed.

In active muscular exercise much heat is produced; but
through the heat-regulating mechanism heat dissipation is in-
creased to correspond, so that the temperature scarcely rises, and
if it does, is soon restored to normal. The extra loss of heat
is brought about by dilatation of the cutaneous vessels and
sweating.

But in some of the infectious fevers that have been studied
the heat production has been found very little increased, and
the hyperthermy to be due to the failure of the heat-dissipating
mechanisms to do their work. For example, in one case of malaria
Liebermeister estimated the increase in heat production during
the hot stage to be 21 to 24 per cent., much less than the increase
during active exercise; but during the malarial chill, owing to the
muscular activity of vigorous shivering, the heat production rose
147 per cent. At the same time, owing to the constriction of the
cutaneous vessels, the mechanisms for heat dissipation were in
abeyance. It would seem in such cases that the fever results
from the failure of the heat-regulating centers to make the heat
loss keep pace with the heat production. Whether or not the
toxins of the disease affect the center directly is still a question.

A chill is considered to be the result of surface cooling from
constriction of the cutaneous arterioles, the skin being the site
of the nerve-endings through which temperature changes are
perceived. In a chill, shivering is the heat-producing response of
the regulators to the cold at the surface rather than to general
body temperature. The subsequent fever results from this
excessive heat production at a time when the skin vessels are still
constricted and sweating absent, i. c., when heat loss is at a
minimum.

In those of the infectious fevers which have been studied in
this regard there is a great increase in the nitrogen elimination
during the fever, but no material increase in the amount of fats
and carbohydrates oxidized, as shown by the elimination of CO 2 ;
therefore heat production is not greatly increased. Just the
opposite condition is found in active exercise, in which there is



THE ANALGESIC ANTIPYRETICS 465

great increase in the elimination of CO 2 and only a moderate
increase in the nitrogen of the urine.

Liebermeister has likened the heat-regulating centers to the
heat-regulator of a room. The heat regulator is set at a certain
temperature; if the room gets warmer, the mercury rises or a
metallic band expands, and by making an electric connection
operates on one or more dampers in the furnace so that the fire
burns less briskly, or shuts down the registers so that the room
receives less heat. If the temperature of the room falls below that
at which the regulator is set, the dampers or registers are opened
and more heat comes into the room. Now, to carry out the
analogy, the heat-regulating centers in the human body may be
thought of as being normally set for a temperature between 98
and 99 F. If the temperature goes up a degree or two, the centers
send out impulses which result either in a lessening of heat pro-
duction, i. e., by diminution in muscular and circulatory activity,
or an increase in heat loss, i. e., by dilatation of the cutaneous
vessels and sweating. On the contrary, if the temperature falls
a degree or two, the heat production may be increased by
muscular activity, shivering, etc., or the heat loss diminished by
contraction of the cutaneous vessels and the stoppage of sweating.

The temperature-regulating centers have little discriminating
po\ver, and a surface chill may induce the centers to constrict the
vessels and lessen heat loss, and at the same time to increase the
production of heat, so that fever may result. To what extent the
body reaction which results in fever is beneficial or harmful, we
are not yet able to state. Recently certain infections seem to have
been cured by the repeated artificial production of a chill with
high fever, as by the intravenous administration of foreign
protein, usually typhoid vaccine.

In some fevers the regulating centers may lose their control at
certain times of the day only. In tuberculosis there is a tendency
to afternoon fever, accompanied by headache, discomfort, and
weakness from failure of heat loss, while at night there may be an
overaction of the mechanism for cooling, with diminished metabo-
lism and the production of profuse sweat, the result being chilling
of the surface (cold night-sweats) and a fall of temperature
to subnormal. Frequently, in tuberculosis fever cases, the
morning temperature is normal and the patient feels at his best
at that time. But in tuberculosis the centers are incompetent, so
that a slight exertion tends to produce fever at any time.

In malaria there is a severe chill with contraction of the skin

vessels and the generation of much heat (by shivering). After a

time this results in great fever and discomfort, the contraction

of the skin vessels and the absence of sweating preventing heat

30



466 PHARMACOLOGY AND THERAPEUTICS

loss. But presently the centers gain control, and great activity
of the cooling mechanism follows. The result is dilatation of the
skin vessels and profuse sweating, with a fall in temperature
to normal or even subnormal, and the restoration of the patient's
comfort till the next chill comes on a day or two later.

In a continuous fever like typhoid, apparently the heat-
regulating centers are set at a high point, 102 F., 103 F., 104 F.
The centers are just as sensitive to changes as ordinarily, for
shivering follows a drop of 2 or 3 degrees in the temperature, and
sweating results from a rise of i or 2 degrees. But the tempera-
ture at which the centers tend to keep the body is not 98.6 F.,
but 102 F., 103 F., or 104 F., as the case may be.

But even in typhoid fever there is a tendency to a morning
remission of temperature, with rise to the highest point in the
afternoon or evening. And it would seem as if, preceding the rise
in temperature in these cases, the heat regulators are affected by
the poisons of the disease, so that they allow the temperature to
rise above normal; but that, at a certain point, the centers gather
themselves together and are able to assert themselves and regain
their control, and the temperature is brought backjx>ward normal.
This makes a daily rhythm.

Action of Drugs. A drug may tend to lessen the temperature
in fever by decreasing metabolism, as quinine, by lessening the
activity of the circulation, as veratrum, by dilating the cutaneous
vessels, as whisky, or by inducing perspiration, as solution of
ammonium acetate. But antipyrine, acetanilid, acet-phenetidin,
and their allies act centrally, and they result in a lowering of the
temperature in fever either by increasing the resistance of the
regulating centers to the disease poisons, or by lowering the degree
at which the heat-regulating centers are set (if we may use such an
analogy). Meyer regards them as mild narcotics to irritated
thermogenic centers. The effect of these drugs is not to any
extent to reduce heat production, for they do not diminish
metabolism, and acetanilid even increases metabolism. They
act by enabling the center to improve its control over the mechanisms
of heat dissipation, which are the ones at fault in the infectious
fevers.

That they act through the centers is shown by their failure to
affect the temperature in health, by their failure to reduce tem-
perature if the spinal cord is severed, and by the fact that there
is no attempt on the part of the body, as the temperature falls,
to manufacture more heat by shivering, etc., as occurs when the
temperature is reduced by external cold (cold baths, etc.). The
lowering of temperature by these drugs may be accompanied by
profuse sweating, but this is a result of the action upon the centers,




Fig. 58. Acetanilid, 0.4 mg. per kilo. Ventricle (upper tracing) shows increased
lonicity and diminished contractility (down-stroke, systole). Arterial pressure,
lower tracing, falls from 75 to 42 mm. The pulse-rate drops from 130 to 120.
(Tracing made by Dr. C. C. Lieb.)




Fig. 59. Urticarial eruption following antipyrinc (\V. S. Gottheil in Archives of

Diagnosis).



Fig. 60. Kxfoiiative dermatitis following the administration of large doses ot



antipvrme. JIair and nails shed (Schamberg).




THE ANALGESIC ANTIPYRETICS 467

and they are still antipyretic if the sweating is prevented by
atropine. Occasionally, as the result of their action, the centers
reassert themselves too strongly, overshoot the mark, and carry
the temperature away below the normal. In some cases this
results in collapse.

Schutze has shown that antipyrine does not prevent the forma-
tion of antitoxins in the body, so it does not interfere with the
natural forces of protection against disease, except as fever is
beneficial.

The other parts of the nervous system are also affected prac-
tically alike by these three drugs.

Cerebrum. This is somewhat depressed, all three remedies
being useful in overcoming nervous irritability and restlessness.
They have also a notable power in lessening pain, especially that
from neuralgia or neuritis, or a lesion of the central nervous
system. They are especially useful in headache. Head suggests
the hypothesis that the analgesia is the result of an action on
synapses in the pain-conveying tract in the thalamus adjacent to
the heat center. Stekel believes that the action in headache is
due to the regulation of the balance between heat production and
heat loss. In migrainal headache, for example, he noted that
there was diminished surface temperature, as noted in the axilla,
though normal rectal temperature, and that after small doses of
antipyrine the axillary temperature rose as much as one degree
with the disappearance of the headache. Martin, Grace, and
McGuire found a marked lowering of general electrocutaneous
sensitiveness within one hour of mouth doses of acet-phenetidin,
5 to 15 grains (0.3-1 gm.).

These remedies are not strongly hypnotic, and do not pro-
duce somnolence if the patient is up and about; yet if taken at
bedtime, they favor the onset and maintenance of normal sleep.
The cerebral cortex, then, is partly depressed ; yet even large doses
seem to have very little depressing effect on the intellectual
functions. This distinguishes them markedly from morphine,
the bromides, and other central depressants. Phenacetin, being
an ethyl compound, is more hypnotic than the others; antipyrine
is the least hypnotic. But antipyrine is said to be more depress-
ing to the motor areas, so that it has been used in epilepsy, chorea,
and whooping-cough with more or less benefit.

The centers of the medulla are scarcely, if at all, affected. In
poisoning, convulsions may occur, clue probably to stimulation
of the spinal cord centers, or perhaps to asphyxia.

Circulation. A number of cases of collapse following the use
of antipyrine, acet-phenetidin, and acetanilid have been reported,
so that these drugs have acquired a bad reputation as circulatory



468 PHARMACOLOGY AND THERAPEUTICS

depressants. In experimental work the heart muscle is directly
stimulated by ordinary doses, the beat being stronger and more
rapid. But from large doses the muscle is weakened, and the
beat may be slow and irregular, causing collapse. The skin
vessels are dilated in fever, apparently as a result of the action of
the heat-regulating centers.

The collapse action is most pronounced with acetanilid, and
when it occurs from moderate doses, would seem to be due to
idiosyncrasy. Nearly all the fatalities or cases of serious collapse
from these drugs have come from very large doses taken in the
form of proprietary headache and anti-pain remedies. Many of
these cases have occurred from preparations containing caffeine,
which is often added as a heart stimulant, and it has been shown
by Worth Hale that they are more dangerous with caffeine than
without, and less dangerous with sodium bicarbonate. Employed
in proper dosage, these drugs are practically as safe as any other
powerful depressants, but must be used with equal caution.



Acetanilid,
NaHCO, . . ,



Acetanilid. . |
Acetanilid,
caffeine,
NaHCO. . . |

Acetanilid,
caffeine . . . . I



Fig. 61. Toxicity of acetanilid increased strikingly by caffeine, decreased by
sodium bicarbonate. Experiments on mice by Worth Hale. The degree of
toxicity is represented by the length of the bars.

Metabolism. Antipyrine and acet-phenetidin have probably
no appreciable effect on the metabolism in health, as shown by the
elimination of N, the absorption of O 2 , and the elimination of
CO->. Acetanilid increases metabolism, as shown by an increase
in the urea and total nitrogen of the urine.

In fever, in association with the reduction of the temperature,
the metabolism is lessened.

Excretion is by the kidneys. Antipyrine appears n the urine
either unchanged or as oxyantipyrine in combination with glycu-
ronic and sulphuric acids. Acetanilid appears as para-amidophe-
nol. Acet-phenetidin appears as phenetidin compounds.

Untoward Effects. From idiosyncrasy, antipyrine not infre-
quently has produced a scarlatiniform rash with edema of the
face and fever; or urticaria, or a vesicular, bullous, or eczematous
eruption. The chief untoward effects from acetanilid and acet-
phenetidin are cyanosis and collapse; a petechial eruption has
been noted from acet-phenetidin.

Toxicology. Acute poisoning shows in affections of the alimcn-



THE' ANALGESIC ANTIPYRETICS 469

tary tract and nervous system. There are: burning and swelling
of the whole alimentary tract, with stomatitis, nausea, vomiting,
gastritis, perhaps enteritis, mental dulness, tremors, convulsions
(cerebral), and coma. Death results from failure of the respira-
tion. With acetanilid and acet-phenetidin cyanosis and collapse
may occur early. Toxic effects in a girl of twenty have been
reported from 10 grains of antipyrine. The treatment is by
demulcents for the gastro-intestinal tract, and, if necessary, meas-
ures to combat collapse.

A common result of poisoning by acetanilid and acet-phenet-
idin is a marked cyanosis, with which there may be more or less
dyspnea, rapid heart, and even collapse. There is some destruc-
tion of red cells, and some formation of methemoglobin by reduc-
tion, but the cyanosis seems to be out of proportion to the meth-
emoglobin formation and out of proportion to the patient's
symptoms. There is probably some other reduction compound
present in the blood, and Bachmann says that it is aniline. Ten
grains of acetanilid taken internally have produced cyanosis,
also acetanilid powder applied to ulcer of the leg. The author
saw one case from a phenacetin powder, probably 10 grains,
given by a pharmacist for headache.

Chronic Poisoning. Many nervous patients have the habit
of taking these drugs. The habit does not have a hold upon
them, like the morphine habit, and can be broken without any
systemic rebellion; yet it is a difficult habit to overcome, for the
symptoms are never startling, and the friends, not perceiving any
harm from the drug, note the apparent suffering when the drug is
stopped (headache, irritability, restlessness, sleeplessness). There
is a proneness to digestive disturbances, to neuroses, to neuralgic
pains, to various skin rashes, as erythema and eczema, or simple
itching without a rash, and to mild forms of neuritis. There may
be dyspnea on exertion, and other evidences of cardiac weakness.
Impotence has been reported. We have had under our care one
striking case of chronic poisoning with cyanosis which persisted
for weeks after the stoppage of the acetanilid. Many chemic
and spectroscopic tests of the blood revealed no foreign chem-
ical other than methemoglobin. Antipyrine does not have this
effect upon the blood.

Therapeutics. Antipyrine, in 10 to 25 per cent, solution, is
employed locally to stop nasal hemorrhage, and as an application
in the painful throat of tuberculous laryngitis. Systemically, it
has been used with moderate success as a motor depressant and
general sedative in cl/orca and whooping-cough. It has also some
employment in diabetes insipidus and diabetes meUitus. Its other
uses are those of acetanilid and acet-phenetidin.



470 PHARMACOLOGY AND THERAPEUTICS

All the drugs of the group are employed very largely for their
effects upon the nervous system and in fever. Their general
therapeutic powers are:

(a) To overcome fever. In the high temperature of influenza,
tonsillitis, etc., these drugs not merely reduce the temperature,
but also greatly promote the comfort of the patient by lessening
pain, if present, by lessening nervousness and headache, and by
promoting quiet and rest. There are cases of typhoid fever in
which these antipyretics have a decidedly better effect than the
cold bath, as when there are shivering and cyanosis during
the bath and for some time afterward, and discomfort both
physically from the cold and mentally from the dread of the next
bath. The drugs are much used where cold baths are not prac-
ticable, and their antipyretic and quieting effects usually last
from four to eight hours. In the afternoon fevers of tuberculosis,
also, they promote the comfort of the patient.

(b) To relieve pain in conditions without fever , as in dysmenor-
rhea and muscular rheumatism; headache, migraine, neuralgia,
sciatica, peripheral neuritis; the lightning pains of locomotor
ataxia, and the pain of an intracranial or spinal tumor. They
have little influence on pain from traumatism.

(c) To allay nervous excitability and promote sleep in conditions
without fever emotional shock, hysteria, and nervous conditions



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