5ection of tberapeuticz anb Pbarmacologw.

fMay 14, 1929.1

DISCUSSION ON THE ACTION AND USE OF
EPHEDRINE.
Professor J. A. Gunn (President): Ephedrine is an alkaloid obtained from
a Chinese plant, Ma Huang, a species of Ephedra, preparations of which have been
used medicinally by the Chinese for four thousand years or more. Ma Huang bad
the reputation of being a diaphoretic, circulatory stimulant, and sedative in cough.
The alkaloid ephedrine was isolated in 1887 by Nagai, and its mydriatic action
described, but for a long time little attention was paid to it. In the last five years
or so it has roused much interest, partly from its close chemical and pharmacological
affinity to adrenaline. This chemical relationship is shown in the following structural
formulae:
HO OH H OH CH3
HO { - C-N NHCH3 >-C- -- NHCH3
H H H H
Adrenaline. Ephedrine.

Ephedrine therefore differs from adrenaline in the absence of the two -OH groups
from the catechol nucleus and in the replacement of one of the -H atoms in the side
chain of adrenaline by a methyl group. As a result of the latter change, ephedrine
possesses two asymmetric carbon atoms, whereas adrenaline possesses only one.
Consequently, while there are three possible isomers of adrenaline, viz., d- 1- and
d. 1- adrenaline, there are six possible isomers of ephedrine, viz., d-. 1-, and d. 1.
ephedrine, and d-, 1- and d.1- pseudo-ephedrine.
The plant contains mainly lhvo-ephedrine and it is the salts of this alkaloid
(hydrochloride or sulphate) which have been chiefly used. A synthetically
manufactured racemic ephedrine' has been put on the market under the name
"ephetonin."
Ephedrine possesses a much more stable molecule than adrenaline, with the
following important consequences. Ephedrine is much less liable than adrenaline
to chemical change as the result of exposure to light and air, and can be boiled
without undergoing decomposition. Ephedrine is less. affected by digestive process
and can produce systemic effects when given by mouth, whereas adrenaline has
little or no effect when thus administered. Owing to its greater stability, ephedrine
is less rapidly destroyed by the tissues and therefore its effects are more persistent.
On the other hand, ephedrine' is, weight for weight, far less active than adrenaline,
so that the average dose of the former requires to be probably at least fifty times
greater.
IThe pharmacological actions of ephedrine are qualitatively very similar to those
of adrenaline but apparently not identical. Thus, in addition to the sympatho-
vnimetic action of adrenaline, ephedrine displays also a direct stimulant action on
smooth muscle. The pressor action of ephedrine, for example, is not completely
abolished 'by ergotoxine. This direct action on muscle is more conspicuous in the
case of pseudo-ephedrine, the pressor effect of which is hardly influenced by a
previous injection of ergotoxine. Further, it.has been suggested that ephedrine and
pseudo-ephedrine stimulate, in certain doses, the parasympathetic system, and
certainly the qualitative effect of these alkaloids varies considerably with the dose
and the particular organ investigated. Pseudo-ephedrine seems to be roughly half
as active as ephedrine. With further researches the pharmacology of these alkaloids
AUG.-THERAP. 1
1370 Proceedings of the Royal Society of Medicine 10
will, no doubt, be more fully elucidated, but in the meantime it is obviously
important that, in clinical and other investigations, care should be taken to
determine and state the exact type of ephedrine employed and the exact dosage
given.
Ephedrine has been tried clinically in most of the diseases for which adrenaline
has proved useful. The few years since its introduction have not, of course,
afforded sufficient time for anything approaching the extensive experience that has
accumulated of the effects of adrenaline, so that the therapeutic uses of ephedrine
are still in the experimental stage.
For its vasoconstrictor action it has been found useful, both by local application
and by oral administration, for causing shrinkage of the nasal mucous membrane,
in coryza, hay fever, etc. For its pressor action, it has been used in conditions of
low blood-pressure, for example in the prevention of this condition in spinal
ane,sthesia. It has been tried in Addison's disease and Stokes-Adams' disease.
Special attention has been paid to its efficacy for the relief of asthma.
Without attempting to prejudge or even to enumerate its therapeutic uses, one
may say that on the whole the pharmacological evidence suggests that the value of
ephedrine, as compared with adrenaline, will be rather in the direction of producing
constrictor effects (e.g., on the blood-vessels) than dilator effects (e.g., on the
bronchi). Where, however, it can replace adrenaline, it has the merit of greater
stability and more prolonged action, and also the possibility of producing its effects
when given by mouth.
Disagreeable effects have been described from time to time, mostly due to over-
dosage. Among these may be mentioned: Nausea, headacbe, thirst, palpitation,
insomnia and profuse sweating. No fatal case of poisoning has occurred in man.
Several writers urge that ephedrine should be administered with extreme caution to
patients with cardiovascular disease.
With more extended clinical experience of its effects and more accurate
knowledge of suitable doses, it seems probable that ephedrine will be a definite
gain to therapeutics, though possibly within a more limited range than its present
trials have covered.
Mr. J. H. Thompson (Department of Physiology, Middlesex Hospital Medical
School) said: For some time past I have been investigating the action of ephedrine
upon the blood-pressure of normal healthy male subjects, using the Thompson sphyg-
manograph, an instrument for recording human blood-pressure continuously.! A few
of the subjectshave been found to be completely unresponsive to ephedrine, whatever
the mode of administration. These subjects appeared to be normal except for
definite evidence of a failure of full development of secondary male characteristics.
In the majority of cases rises of blood-pressure occurred. The latent period varied
according to the mode of administration. After subcutaneous and intramuscular
injections the latent period averaged about three minutes; after oral administration,
seven to ten minutes. A rather interesting fact about the blood-pressure during
this latent period is that it frequently falls. Occasionally I have noticed this
depression of blood-pressure to occur in subjects exhibiting no subsequent rise.
The effect, however, is transitory and immediately succeeded by a well-marked rise
of blood-pressure. The rise is much greater after injection than after oral medication.
The rise after oral administration is greater when the drug is given on an empty
stomach. Oral administration possesses the advantage of a more lasting effect.
The height of the rise varies with the samedose in different people. A rise of
30 mm. Hg with 0*5 gr. is quite usual.
Two important facts about the effect upon blood-pressure have emerged in this
investigation. The initial rise of blood-pressure is not maintained for more than a
J. H. Thompson, Brit. Med.Journ., 1929 (i), 649.
11 Section of Therapeutics an7d 1369
Pharmacology1
fewminutes, but is followed by further rises. Thus, a series of rises results froimi
one administration. If given by injection, the rises rapidly succeed each other and
are few in number. If orally administered, the period elapsing between the rises is
longer, and the series persists for an hour or more, even with small doses, though
each rise is smaller than the preceding. The use of an ordinary sphygmomanometer
with isolated readings thus accounts for the statement made that ephedrine main-
tains a high blood-pressure for long periods. It is interesting to note thaty very
often a m-rked " step " or " dip " in the rise can be found, such as occurs during
stimulation of the splanchnic nerve in the presence of an anaesthetic.
The second important fact is the after-fall. The fall which occurs between the
rises is often almost precipitous, especially after a repeated dose, but does not proceed
below the subject's normal blood-pressure. After the rises have ceased, however,
the blood-pressure fails considerably below normal and remains subnormal for
approximately an hour.
During the rises of blood-prcssure all subjects have expressed a feeling of xvell-
being. This euphoria has been a constant characteristic. After the rises have
ceased and while the after-fall is in being, subjects have complained of a feeling of
coldness, renal i)ain, hunger pains, and, occasionally, colic.
Mr. Frank Coke said that the advantages of the use of eplhedrine over that of
adrenaline in the treatment of the paroxysm of asthma were twofold: (1) It could
be given by the mouth, and (2) its effects were often of much longer duration than
those of adrenaline. It relieved the spasm and removed the turgescence of the nasal
nucous membrane, whether given by the mouth or by outward application.
Its disadvantages were the appearance of tremor, the palpitation, and the insomnia
which it produced. In connexion with this last effect it had been used as an
antidote to scopolamine or morphine.
Occasionally very severe after-effects followed the use of ephedrine. One of his
(the speaker's) patients-a typical case of the aspirin-sensitive type of asthma, with
the usual frightful paroxysms of asthma each night, common to these people-heard
of ephedrine, and took half a grain on three successive nights. She received great
benefit from the drug the first two nights. On the third night she fainted. Pale
and sweating, she continued more or less unconscious for some hours, and was not
normal again for a week. Bloedorn and Dickens.had described a similar case.
Althauser and Schumacher gave this drug hypodermically; in one case the patient
immediately complained of intense, agonizing pain in the head.
He (Mr. Coke) was, however, aware of the same effect occurring after the
injection of adrenaline, when, presumably, the dose had reached the blood-stream
immediately through a small venule.
An alarming sequel to a dose of ephedrine nmight be that the patient would find
himself unable to micturate. A kind of retention was produced. There seemed to
he an entire absence of feelings of desire or compulsion to micturate, and when the
attempt was made the result was ineffective. He (the speaker) had known these
alarming symptoms to follow quite small doses, and the possibility of such results
should be widely emphasized.
Dr. John Freeman said that he had begun to use ephedrine for asthmatic cases
thrT years ago, but after a time he had given it up. It seemed to do good at first,
but in a definitely less degree if persisted in. He took it up again recently on
lhearing good effects attributed'to it, but the results in his hands were still as before.
He had tried alternating ephddrine with normal saline, unknown to the patient, and
she had been unable to tell'ihe difference.
Dr. John H. Hannan:(Middlesex Hospital Medical School) said: I propose to
confine my remarks to the use of ephedrine in the practice of obstetrics and,
AUG.-THERAiP. 2 A
 1370 Proceedings of the Royal Society of Medicine 12
gynmcology, in which the pressor effect of this substance is indicated as a therapeutic
measure.
Obstetric Shock and Collapse.-These emergencies frequently occur in obstetric
practice, and are almost invariably associated with considerable loss of blood and
fall of blood-pressure.
In private obstetric practice the facilities of a hospital are not available. Some
teop( riry and easily-administered measure is required which will enable the
accoucheur to control the collapse sufficiently long for him to prepare and Administer
the saline solution. In this connexion I have found ephedrine of considerable
assistance, and have, after stopping the source of the haemorrhage, administered
1 gr. of ephedrine in 8 c.c. of normal saline, intravenously, in addition to the more
commonly employed miieasures for combating the fall in blood-pressure, such as
elevating the foot of the bed.
On two occasions only I have adimiinistered 2 gr. of ephedrine.
Obstetric Shock in the Newborn.-This condition, better known as the white
asphyxia of the newborn, is a condition which, in the past, has been overtreated.
Artificial respiration and other violent methods of treatment have done much to.
extinguish the small spark of life remaining in these babies. The best treatment,
after ensuring that the airway is clear, is to leave the infant alone and to keep
it warm. Sometimes, however, the death of the baby seems certain, and no
respirations or heart beat can be detected. In such cases one feels that something.
might be done, and I have, on two occasions, given an intracardiac injection of 1 gr.
of ephedrine. In one of these cases the baby immediately recovered and is alive and
well to-day.
Gynsecological Practice.-Here the emergencies of shock and collapse occur as a
rule in the operating theatre, where we can rapidly prepare and administer saline
transfusions. Ephedrine is therefore not indicated to the same extent as in,
obstetrical practice.
Controlled observations during these emergencies are very difficult, and one must
be largely guided by observations of cases treated with ephedrine as compared
with a series of untreated cases. On this test I am satisfied that ephedrine is of
use as a remedial measure in operative shock and collapse.
Prophylactically ephedrine is of value, and I have as a routine ineasure-
given one gr. of ephedrine orally, one to two hours before any operative pro-
cedure when shock was anticipated.
Ephedrine at the Menopause.-I have published evidence during the last few
years that wornen and female animals at the menopause show a condition of
increased sensitiveness to adrenaline when this substance is administered
subcutaneously, or intravenously, or is instilled into the conjunctival sac. I have,.
therefore, investigated the effects of ephedrine at the menopause with a view to.
treating cases of menopausal hypotension with this substance. I have found, much
to my surprise, an increased tolerance to ephedrine. Thus in three women one gr.
of ephedrine, given subcutaneously or intramuscularly, was without effect when
observed with Thompson's apparatus. Furthermore, regular oral doses of Ai gr. of
ephedrine, three times daily, for as long as six weeks, did not appreciably affect
the blood-pressure or cause any ill-effect. One interesting phenomenon has
occurred in nineteen women during the oral administration of ephedrine, namely a
feeling of well-being which might be classified as a euphoria, and which persisted
as long as one hour after taking the ephedrine. In the laboratory series.
receiving subcutaneous and intramuscular injections, euphoria was noticed only
when a rise of blood-pressure occurred and did not take place in menopausal cases in
-the absence of a rise of blood-pressure. These results confirm the findings of
Dr. Thompson.
13 Section oJ Therapeutics and Pharmacology 1371
I have had injections of ephedrine myself in doses of from half to 1 gr., and
experienced euphoria.
Poisonous symptoms only occurred in three instances in these series; some
bladder irritation was complained of by one woman and a tendency to perspire by
two. In no instance were the symptoms sufficiently severe to justify a reduction in
the dosage of ephedrine.
Dr. George Graham said he had found that if people required a great deal of
adrenaline, ephedrine had no effect on them. In the case of two medical colleagues
he had seen good effects from the use of ephedrine in hay-fever, the dose taken being
1 gr. twice a day, and he considered that ephedrine had a future;
Dr. E. P. Poulton said that an Austrian physician, who, as soon as he had
arrived in this country, had had an attack of asthma so bad that it had prostrated
him, had found that ephedrine was the only treatment which benefited him.'
: Lcneet, 1929, ccxvi, 1037.