Medicine Monographs
1 MEDICINE MONOGRAPHS are comprehensive
'! reviews that adequately discuss a disease, certain
aspects of a disease, or subjects that allow a better
|, comprehension of disease processes.
p;
if MEDICINE MONOGRAPHS will enable the teacher,
If the clinician, and the laboratory worker to have avatta-
I ble, in convenient and readable form, critical digests of
>the recent views on general medicine, neurology and
pediatrics.
MEDICINE MONOGRAPHS originally appeared
in MEDICINE, a quarterly periodical edited by
David L. Edsatt, Harvard Medical School; Associate
i Editor, Alan M. Chesney, Johns Hopkins Hospital.
t'
EPHEDRINE AND RELATED
SUBSTANCES
s
>* '
MEDICINE MONOGRAPHS
VOLUME XVII
EPHEDRINE
AND RELATED SUBSTANCES
BY
K. K. CHEN
Department of Pharmacology
Johis Hopktns University
AND
CARL F. SCHMIDT
Department of Pharmacology
University of Pennsylvania
BAILLliiRE, TINDALL AND COX
LONDON
THE WILLIAMS & WILKINS COMPANY
BALTIMORE
1930
ALL RIGHTS RESERVED, 1930
PRINTED IN AMERICA
EPHEDRINE AND RELATED SUBSTANCES
K. K. CHEN, EH.D., M.D., AND CARL F. SCHMIDT, M.D.
Departments of Pharmacology, Johns Hopkins University and University of Pennsylvania
CONTENTS
L Introduction 2
Historical 4
n. Pharmacognosy and chemistry 7
1. Botany 7
2. Properties of ephedrine 9
a. Isolation 9
b. Yield 9
c. Recent commercial development 11
d. Physical and chemical characteristics 12
e. Structure and isomerism 13
f . Other alkaloids occurring in Ma Huang 14
g. Synthesis of ephedrine 14
in. Pharmacological action 15
1. Action on lower forma of life 16
2. Actions on the circulation 17
a. Effect upon blood pressure 17
b. Action on heart 23
c. Action on blood vessels 29
3. Action on respiration 32
4. Action on smooth muscle 33
a. Pupil 33
b. Gastro-intestinal tract 35
c. Uterus 39
d. Urinary tract 39
e. Bronchi 40
5. Action on secretions 40
a. Saliva 40
b. Gastric secretion 41
c. Pancreatic secretion 41
d. Intestinal secretion 41
e. Bile 41
f. Sweat 41
g. Lymph 42
h. Urine 42
6. Action on blood 42
a. Blood cells 42
b. Blood chemistry 43
1
2 K. K. CHEN AND CARL P. SCHMIDT
7. Action on metabolism 44
a. Metabolic rate 44
b. Gaseous exchange 44
c. Body temperature 44
8. Action on central nervous system 45
9. Action on peripheral nerves and voluritary muscles 45
10. Mode of action 46
a. Circulatory responses 48
b. Effects upon smooth muscle 51
11. Absorption and excretion 59
12. Toxicity 59
a. Minimal lethal dose 59
b. Toxic symptomatology 61
c. Repeated administration 61
IV. Clinical applications 62
1. Methods of administration and dosage 62
2. Side effects 63
V. Therapeutic uses 65
1. In asthma 65
2. In hay fever 69
3. In bronchitis and emphysema 70
4. In whooping cough 70
5. In spinal anesthesia 71
6. In hypotension 72
7. In shock 74
8. In Adams-Stokes' syndrome 75
9. As a nasal astringent 76
10. As a mydriatic 77
11. As an antidote for narcotic drugs 79
12. In dermatology 80
a. In urticaria 80
b. In dermatitis medicamentosa 81
c. In leprosy 81
13. In dysmenorrhea 82
VI. Action of synthetic ephedrine and compounds optically isomeric with or related
to ephedrine 82
1. Synthetic or tW-ephedrine 82
2. Pseudoephedrine 4. 85
3. Other optical isomers of ephedrine 87
4. Compounds related to ephedrine 88
VTI. Summary 93
References 94
I. INTRODUCTION
The rise of ephedrine from obscurity to its present state of wide-
spread popularity, within less than five years, involves a variety of
features of unusual interest. Much of the initial enthusiasm for the
EPHEDRINE AND RELATED SUBSTANCES 3
drug was doubtless due to the somewhat dramatic circumstance that
the traditional faith of the Chinese in one of their ancient remedies
was about to be justified by Western science. While ephedrine has
recently found a real place in therapeutics, the drug was known to
experimenters and clinicians for some thirty years before its possi-
bilities were appreciated. The reason for this tardy recognition
was simply the failure of the original investigators to use any but toxic
doses in their animal experiments a circumstance which illustrates
the readiness with which an initial misconception may be propagated
and may influence the subsequent fate of a new remedy. The history
of ephedrine is therefore of more than usual interest.
Apart from the historical aspect, ephedrine has been the object of
a great deal of investigation on the part of laboratory workers and
clinicians. The result has been not only the discovery of unantici-
pated uses for the drug but of greater ultimate importance a
renewal of interest in the problem of the relation of chemical com-
position to physiological actions, and the direction of attention to the
incompleteness of our knowledge concerning the mode of action of
sympathomimetic drugs (i.e , those which produce effects similar to
the result of excitation of sympathetic innervations). It is now quite
certain that ephedrine, in spite of its present popularity, is far from
ideal in certain respects. In the search for other remedies of this sort
important progress has already been made, and undoubtedly much
more lies in the immediate future. For the benefit of those concerned in
such work, and of the clinicians in whose hands rests the final decision
concerning the validity of laboratory experimentation with agents of
possible therapeutic importance, a compilation of the literature
dealing with ephedrine should serve a useful purpose. For if ephedrine
is not the only agent of this sort to have been introduced into thera-
peutics since epinephrine was discovered, it has certainly been the
object of more investigation than any other. In spite of this, the
v literature is full of disagreements and unjustified assumptions with
Irespect to the fundamental features in the action of the drug, though
|the_ clinical results are quite uniform in indicating that it produces
'i effects that are of the same nature as those of ep^ejDhrine. It is
Inevitable that workers with other substances of tlnTsdrt will be con-
fronted with the same difficulties. These can be obviated, to some
4 K. K. CHEN AND CAUL F. SCHMIDT
extent at least, if it is generally realized that a drug can be sympa-
thomimetic, in the original sense of the term, without duplicating all
of the effects of epinephrine.
HISTORICAL
As is generally known, ephedrine is an alkaloidal active principle
obtained from a Chinese herb which, under the name of Ma Huang,
has been used by native physicians for some 5000 years. It was one
of the drugs which is said to have been tasted by the Emperor Shen
Nung, who placed it in the "medium class." It is mentioned in the
Pentsao Kang Mu, the Chinese dispensatory, written in 1596 by
Shih-Cheng Li. According to this authority Ma Huang is of value as
a circulatory stimulant, diaphoretic, antipyretic, sedative in cough,
and it is an ingredient of many famous prescriptions. An English
translation of the ancient Chinese records can be found in the paper
by Hagerty and Woo.
Plants similar to, if not identical with Ma Huang have been em-
ployed as medicines since remote antiquity in other parts of the world.
Thus, it is said (Berendes) that Greek physicians employed plants of
the same genus (Ephedra) as Ma Huang, and that the Hippuris of
Dioscorides (about 50 A.D.) was E. fragUis var. graeca. The top of
this plant was used as an astringent; taken with wine it was said to
produce diuresis and to cure dysentery, and both root and top were
reputed to be useful in the treatment of cough, orthopnea, and internal
rupture (Berendes).
In Russia Ephedras have been in medical use since olden times. In
the 19th century decoctions of E. wlgaris, together with milk and
butter, were recommended in the treatment of rheumatism and were
regarded as a specific remedy for syphilis and gout, the latter virtue
being attributed to the twigs and roots of the plant. The sap and
candied fruits were used in the treatment of respiratory disorders.
A peasant named Kusmitsch effected such marvelous cures with
decoctions of Ephedra that he won a wide reputation, and Bechtin
(1891) reported very striking results with decoctions of E. vulgaris in
patients with rheumatism. Sassetsky and Lewaschew, however, were
unable to confirm these results (Grahe).
In India the dried branches of E. pachydada, or E. intermedia,
EPEEDRINE AND BELATED SUBSTANCES 5
/ are thought to possess medicinal value, but they are chiefly used in
I religious (Parsi) ceremonials. It is also said that this plant, mixed
1 with milk and honey and allowed to ferment, was the "soma" of
the Vedas, which was used to induce an exhilarating intoxication.
'; , Incidentally, this appears to be the only instance of employment of an
\ Ephedra for the purpose of pleasurable intoxication, and it is possible
that the effects were due to alcohol in this case.
In America a number of Ephedra plants were used by the Indians
for various purposes. E. antisyphilitica, E. caUfornica, and E.
nevadensis were regarded as valuable in the treatment of syphilis and
gonorrhoea, and were used as local applications as well as by internal
administration. The Coahuila Indians made a cooling beverage
from E. nevadensis, and the Panamint Indians made bread from the
ground roasted seeds of the same plant. The Indians and Spaniards
used decoctions of E. catifomica as a tonic and blood purifier, and
E. trifurca was regarded as an excellent remedy for nephritis. In
Mexico, E. aspera is still used occasionally in the treatment of pneu-
monia, and in Zacatecas E. pedunculata is highly esteemed as a remedy
for pleurisy and pneumonia.
It appears, therefore, that the Epkedras have long been utilized as
empirical remedies hi many discontiguous parts of the world. On
the whole, they seem to have enjoyed a reputation for two different
sorts of usefulness first, in the treatment of venereal diseases, and
second, in treating disorders of the respiratory system.
The development of a useful modern drug out of these ancient
remedies has centered upon the Chinese plant Ma Huang and, as is
usually the case, has followed as a natural consequence of the isolation
of an active principle. Pioneer work along these lines was done
wholly by the Japanese, whose interest in Chinese drugs was naturally
greater than that of the Western world because most of their empirical
materia medica including Ma Huang was derived from the ancient
culture of China. An active principle was first isolated from Ma
Huang in 18&5 by G. Yamanashi, who obtained a crystalline though
impure substance. After his death the study was continued by Nagai,
with the assistance of Y. Hori, who obtained the alkaloid in pure form
(1887). The same compound was obtained in Germany by E. Merck
in 1888. The name ephedrine was first applied to this substance by
6 K. Z. CHEN AND CARL P. SCHMIDT
Nagai, though the name had already been coined in 1875 by Loew
for the tannin which he had prepared from E. antisypMHtica. The
name ephedrine is now used only in the sense in which Nagai em-
pjoyed it, viz., to designate an alkaloidal active principle of Ma
Huang and other Ephedras.
Nagai's ephedrine was subjected to physiological investigations by
Miura (1887). This study disclosed the toxic effects of large doses
upon the circulation and demonstrated the mydriatic action of the
drug. As a result it was introduced to Western medicine as a new
mydriatic, but its vogue was limited and brief. Apparently it was
not utilized for other purposes and was regarded as a very toxic sub-
stance. It is interesting to note that ephedrine, which has recently
attained popularity as a substitute for or adjuvant to epinephrine,
was available in pure form five years before the actions of suprarenal
extracts were first worked out completely and more than twelve years
before epinephrine, the active principle of suprarenal medulla, was
first isolated.
Subsequently interest in ephedrine was, for many years, almost
wholly limited to analyses of its chemical composition and to attempts
at synthesizing it (see below). Six years before our work was under-
taken the Japanese investigators Amatsu and Kubota (1917) demon-
strated the essentially sympathomimetic (epinephrine-like) effects of
ephedrine, and other workers Hirose, and To also contributed to
,the same conclusion. These publications attracted little attention in
America and Europe, but as a result of their work the Japanese became
so convinced of the value of ephedrine in the treatment of one condi-
tion that is relieved by epinephrine namely, asthma that an
fephedrine-containing preparation was put on the market in Mukden
[.under the name of Asthmatol. No publication was made of the
nfesults obtained with this product and when the question of the
therapeutic possibilities of ephedrine was reopened in 1923 this
development was unknown to the Western world (and to the authors).
It is proper, however, that the Japanese scientists should be given due
credit for having been the first to appreciate the usefulness of ephe-
drine for purposes other than ophthalmologic.
The work done by the authors upon this subject was the result of a
suggestion made by a Chinese druggist, in response to an inquiry
EPHEDBJNE AND RELATED SUBSTANCES 7
concerning native drugs which might be expected to possess real
actions. Among others, Ma Huang was mentioned, and a small
supply was obtained for future investigation. In the autumn of 1923
a decoction made from this material was injected into a vein of an
anesthetized dog remaining alive at the end of a student exercise.
The consequent circulatory effect was the one now familiar as that of
ephedrine, and attention was concentrated upon this promising drug.
A crystalline alkaloid was readily isolated from it, and further experi-
ments demonstrated that this was the active principle, that it possessed
epinephrine-like effects, that it was of comparatively low toxicity,
and that it was effectively absorbed from the gastro-intestinal tracts of
dogs and men. A search of the literature disclosed the identity of this
substance as ephedrine. Clinical trial of the drug was limited by the
small quantity of ephedrine available at the time. As soon as a
sufficient supply was prepared it was submitted to Dr. T. G. Miller,
of the University of Pennsylvania, and to Dr. L. G. Rowntree, of the
Mayo Clinic, for clinical experiments. The results being favorable,
ephedrine was made available to clinicians in general, as rapidly as
possible. In 1926 ephedrine was submitted to the Council of Pharmacy
and Chemistry of the American Medical Association, and was sub-
sequently approved by it. The drug is now prepared by a number of
manufacturers and is quite generally obtainable.
One of the interesting aspects of the usefulness of ephedrine, as
established by modern clinicians and experimenters, is that it justifies
the Chinese tradition concerning Ma Huang in many respects.
H. PHAKUACOGNOSY AND CHEMISTRY
1. Botany
Ephedrine occurs in certain plants of the genus Ephedra (family
Ephedraceae) which includes a large number of species (35, according
to Engler and Prantl, 1926 ; 45, according to the Index Kewensis, 1895-
1920). These are distributed throughout the temperate and sub-
tropical regions of Europe, Asia, and America. They are found hi an
area extending from the middle Amur region through central Asia,
including its deserts and covering China and Arabia, to the Mediter-
ranean and even to the Canary Islands (Engler and Prantl), as well as
8 K. K. CFTF.N AND CARL P. SCHMIDT
Siberia, Hungary, the Carpathian Mountains, the Western Alps, and
Western France. In the Americas they grow along the Rocky Moun-
tains as far south as New Mexico, from Bolivia to Patagonia, and from
Paraguay to the Atlantic Ocean.
Only a few of these Ephedras contain ephedrine. In China ephe-
drine-bearing plants are found in the Tai-hung Mountains, which are
the site of the Great Wall in Chihli Province. They also occur in
Shansi, Shensi, Kansu, Honan, and Hupeh Provinces (Read and
associates, 1928). They are also found in Northern Chosen (Korea)
and in Akita Prefecture in Japan. In India and Tibet they occur
along the Himalaya Mountains (Chopra and associates).
The actual identification of Ma Huang has been somewhat uncer-
tain. It was formerly classified as E. vulgaris var. helvetica (Nagai;
Botanical Nomenclature, etc.), but this name appears to be obsolete.
Cowdry (1922) identified Ma Huang as E. equisetina, and this is the
name recognized by the Council on Pharmacy and Chemistry of the
American Medical Association for the plant from which ephedrine is
obtained. Holmes (1926) suggested that Ma Huang is E. intermedia
var. tibetica, while Stapf (1927) gave a provisional new name of E.
simica to specimens submitted by Read and by Parke, Davis & Com-
pany. Liu and Read (1929) identified another species, E. distachya,
which is found in Western Chihli and is also known as Ma Huang.
This statement needs confirmation. At present it appears that Ma
Huang, from which most of the present supply of ephedrine is ob-
tained, is E. sinica or E. equisetina (Small and Short). It has been
shown recently by Chopra and his coworkers (1928), that ephe-
drine also occurs in the Indian species, E. vulgaris, E. pachyclada or
intermedia, and E. intermedia var. helvetica. Their results have been
confirmed by Read and Feng (1928).
These are the principal natural sources of ephedrine at present,
though ephedrine is also found in plants growing in Southern Europe,
in Northern China and in Japan. Other Ephedras have been examined
but they contained no alkaloid, or only the isomeric pseudoephedrine,
which is distinctly less useful than ephedrine. The American ^species
E. trifurca, E. nevadensis, E. calif arnica, and E. viridis were examined by
Nielson, McCausland, and Spruth, and found to contain no alkaloid.
Terry obtained the same negative result with E. nevadensis. Clark
1 1
EPEEDRINE AND BELATED SUBSTANCES'- ' ' 9
s^
and Groff reported the presence of pressor siibstan^es~"iineXEfacts
of jE. californica and E. nevadensis, though no try&tallinV.active
substance could be isolated. Their results were not substantiated by
De Eds and Butt or by Read and Feng. Black and Kelly found only
pseudoephedrine in E. alata, collected in Morocco. None of the
American Ephedras have been shown to contain ephedrine, and upon
transplanting the Swiss E. vulgaris (E. distachya), which is believed
to yield ephedrine, to this country, no alkaloid was found in it after
the first year of growth (Nielsen and McCausland, 1928).
2. Properties of ephedrine
a. Isolation. Ephedrine, having the solubility reactions of a
typical alkaloid, is very easily separated from an extract of the plant
The following procedure has been found satisfactory.
The powdered crude drug is extracted with 60 per cent alcohol,
the extract concentrated and treated with strong ammonum hydroxide
or sodium carbonate. This causes precipitation, and filtration is
necessary: ephedrine is present in both precipitate and filtrate, so that
both must be dealt with. The akaloid is extracted from them by
means of chloroform or ether. Upon removal of the solvent the
residue is neutralized with dilute HC1 or H 2 S04, thus forming the cor-
responding salt of the alkaloid, which is finally purified and repeatedly
crystallized from absolute alcohol. It is obvious that a chemical
assay of ephedra-bearing plants is readily carried out, and this is
fortunate because no satisfactory bio-assay has been developed.
b. Yield. Different investigators have obtained widely divergent
results, even with the same plant, as shown in table 1. Generally
speaking, the earlier workers obtained lower yields than the more
recent ones, most of whom have succeeded in isolating more than 1
per cent of total alkaloids from the Chinese plants: of this 80 per
cent or more is ephedrine. The Indian species E. pachydada and
E. intermedia var. tibetica have a distinctly lower ephedrine content
than the Chinese.
Read and his associates in Peiping have made careful studies of this
question. They (Feng and Read) find that the low yield of ephedrine
obtained by previous workers was due to incomplete aJkalmization of
the percolate before extraction with chloroform or ether, and em-
10
K. K. CHEN AND CARL F. SCHMIDT
phasize the necessity of adding a large excess of ammonium hydroxide
in order to liberate the alkaloids completely. They have also studied
the variations in yield of ephedrine from different parts of the plant
and at different seasons of the year (Feng and Read, 1928). They
find progressive increase in total ephedrine content from spring to
autumn, the maximum being attained just before the frosts. The
old Chinese custom of collecting the plant in the autumn therefore
appears to be based upon sound observation. During the flowering
season the male plant contains more alkaloid than the female, the
TABLE 1
Assay of Ephedras reported by different workers
Nagai
Chen
Masucci and Suto
Schoetzon and Needham
Neilson, McCaualand and
Sprunt
Williams
Feng and Read
Feng and Read
Chopra, Dikshit and Pillai
Read and Feng
Chopra, Dikshit and Pillai
Read and Feng
Chopra, Dikshit and Pillai
difference being greatest in May. After the fruiting season the alka-
loid content is practically equal in plants of both sexes. With respect
to the distribution of alkaloid in different parts of the plant, these
investigators find (in E. equisetina) that the nodes contain much less
ephedrine than the internodes, and that the root, berries, seeds, and
woody stalks contain none at all. Similar conclusions were reached
by Chopra and his associates'with respect to Indian species of Ephedra.
The special tissue of the plant stem which is concerned in manu-
facturing or storing ephedrine has not been determined. Nothing is
known about the manner in which it is synthesized by the plant or
8FECTE8
Ma Huang
TOTAL AJJEA-
LOIDS, PEK
CENT OS CRUDE
DITTO
31-0 40
KPH jcngTtinc.
PER CENT 01
THE TOTAL
Ma Huar>g
02-0 09
Ma Huang
30
Ma Huang
0.40-0 86
Ma Huang
20-0 90
Ma H^ang , . . ,
64-1 43
E. Eguisetina.
1 75
85-90
B. Sinica,
1 32
80-85
E. vulgaris
1 02-1 27
50
E. vulgaris
1.65-1 70
70-80
E pachyclada
1 8
30-36
E. pachyclada
E. intermedia var. Tibetica
1 15
0.25-0 60
30-40
EPKEDEINE AND RELATED SUBSTANCES 11
the circumstances under which it may be transformed into its optical
isomer, pseudoephedrine, or demethylated or methylated within the
plant. A study of the climatic and soil conditions under which the
plant would produce its maximum yield of ephedrine could be made
with profit.
c. Recent commercial development. The recent popularity of ephe-
drine has led to the development of a considerable industry in China.
Ephedrine has been upon the market for more than 30 years. It has
been listed in E. Merck's Index since 1896. Japanese manu-
facturers (Dainihon Seiyaku Kabushiki Kaisha, of Osaka, later suc-
ceeded by the firms of Tanabe and Takeda) also prepared ephedrine,
and the proprietary preparation Asthmatol contained ephedrine.
As far as is known to the reviewers, these were the only commercial
supplies of ephedrine in the world prior to 1924, and the quantities
produced were relatively insignificant, since the drug was scarcely
used at all except for chemical investigations. According to Mr. G.
Woodard, Assistant Trade Commissioner of the United States at
Shanghai, Ma Huang was exported almost exclusively through
German firms for the past 30 years. Read (1928) states that Ma
Huang was probably never exported from Tientsin prior to August,
1926, but from this time the trade developed rapidly. By the end of
1926 the exports from Tientsin alone, and to the United States alone,
amounted to 224,058 pounds, valued at $17,753, during 1927 they were
622,060 pounds and $64,840, and for the first 11 months of 1928 they
were 1,003,700 pounds and $69,300. (The figures for 1926 and 1927 are
cited by Read; those for 1928 were furnished by Mr. A. G. Ward,
U. S. Vice-Consul at Tientsin.) In addition to the crude drug,
ephedrine hydrochloride, prepared by the Department of Chemical
Products of Peiping Union Medical College, was exported through
Tientsin as follows: in 1926, 12$ pounds, valued at U. S. $3,612;
in 1927, 23 pounds and $7,490; in 1928 (to December 1) 20 pounds and
$3,688. Ma Huang has also been exported from Shanghai and
Hankow, but the quantities concerned are unknown to the writers:
it is certain that the above figures underestimate the Chinese trade
in this drug. Furthermore, ephedrine-containing plants are also
exported from Osaka and Tokyo, Japan, and from Karachi and
Rawalpindi, India. The world supply of these plants appears to have
12 K. K. CHEN AND CARL F. SCHMIDT
satisfied the demand during 1927, and is now greater, for the average
price of Ma Huang shipped from Tientsin to the United States during
1927 was U. S. $10.43 per 100 pounds, while during 1928 it fell to
$6.91.
In contrast with the two concerns one German, one Japanese
who were the sole purveyors of pure ephedrine prior to 1924, the drug
is now being prepared by eight firms in the United States, by one in
Canada, by three in England, by two in Germany, by three in China,
by four Japanese companies, and by two in India. There may be
others of which the writers are unaware.
d. Physical and chemical characteristics. The alkaloid ephedrine
is deposited from an ether solution as an oily substance, but colorless
and odorless crystals appear as needles or rosettes on standing or
recrystallization. These melt at 34-40C. and boil above 200C.
The specific rotation, [a], of the base is between 6 and 7.5.
The alkaloid is soluble in ether, chloroform, alcohol, petroleum
ether, and water, the solutions being strongly alkaline to litmus
paper. The crystallography of ephedrine has been investigated by
Schwankte, and Walcott (quoted by Peterson, 1928). Geppert in-
vestigated its effects upon the surface tension of water. A peculiar
reaction of ephedrine is the formation of the hydrochloride when it is
shaken with chloroform: this was pointed out by Peterson (1928),
and is responsible for the high melting point incorrectly reported by
Chen (1925) for ephedrine base.
For laboratory and clinical uses the hydrochloride and sulphate
derivatives are most commonly used. The hydrochloride appears as
white odorless crystals, with a melting-point of 214-220, [a] 33 to
35.5; it contains 17.3 to 17.7 per cent of C~, is soluble in water
and alcohol, insoluble in chloroform, ether, and paraffine oil. The
sulphate occurs as fine, white, odorless crystals, melting at 240-243C.
[]" -29 to -30, containing 21.8 to 23.1 per cent of SCV -, soluble
in water and hot alcohol, insoluble in ether, chloroform, and paraffine
oil.
Solutions of ephedrine or its salts react with few of the alkaloidal
reagents. With Mayer's reagent there is a turbidity or white pre-
cipitate, according to the degree of concentration. Tsiang and Brown
(1927) described characteristic micro-crystalline reactions when
EPHEDBINE AND RELATED SUBSTANCES 13
ephedrine is treated with Millon's reagent, gold chloride, platinic
chloride, or Kraut's reagent. The most serviceable qualitative reac-
tion of ephedrine is that with copper sulphate and sodium hydroxide,
which was first pointed out by Nagai (1892) : a purple color appears,
which is extractible with ether. This test is sensitive to one part of
ephedrine in 400, and if the concentration exceeds 1 in 40 a pinkish
purple precipitate is formed, and this is completely soluble in ether.
The chemical behavior of ephedrine has been exhaustively studied
by E. Schmidt, Nagai, E. R. Miller, Flaecher, Calliess, Emde, and
others. Probably the most important property is its stability:
ephedrine solutions are not decomposed by exposure to light, air, or
heat, and age apparently does not affect their activity. Thus, a
solution of ephedrine hydrochloride, prepared and sealed in a sterile
ampule by the authors on December 23, 1923, showed no change in
appearance when opened on March 14, 1929, and produced the custom-
ary pressor response when injected into a pithed cat. Kendall and
Witzmann (1927) have demonstrated the great resistance of ephedrine
to oxidation, as compared with epinephrine: the former is not oxidized
by dibromphenolindophenol, naphtholdichlorindophenol, methylene
blue, or indigo carmine, while the latter is oxidized by all these agents.
e. Structure and isomerism. The chemical constitution of ephedrine
has been studied by Ladenburg and Oelschlagel, Nagai, E. Merck,
E. Schmidt, E. R. Miller, Rabe, Ogata, and others. The empirical
formula has been definitely established as C 10 Hi B ON, the structural
formula as C^g-CHOH-CHCHs-NHCHs, or /3-phenyl-jS-hydroxy-
a-methyl-ethyl-methyl amine, or l-phenyl-2-methylaminopropanol-l,
or a-hydroxy-)9-methylamino-propyl benzene:
CHOH-CHj-NHCHj CHOH-CECHi-NECHa
Epinephrine Ephedrine
Its chemical similarity to epinephrine is obvious.
The above graphic formula of ephedrine contains two asymmetric
carbon atoms, so that two sets of stereoisomers, making six in all, are
14 K. K. CHEN AND CARL P. SCHMIDT
possible. All have been prepared synthetically (see the following
section); they are designated /-, d- } and dZ-ephedrines, d-, 1-, and
<#-pseudoephedrines, the dl forms being optically inactive racemic
mixtures. Only two occur in nature, namely /-ephedrine, which is
the ephedrine now in use, and d-pseudoephedrine, which is also found
in Ma Huang, and which is the pseudoephedrine first isolated by
Merck from European Ephedra, and recently prepared by Chou and
Read (1926) from Ma Huang extracts from which ephedrine had been
removed. This is the pseudoephedrine of current literature. Pseudo-
ephedrine is quite unlike ephedrine in melting-point (118C.), optical
rotation ( [a]" + 50) and, to a certain extent, in physiological effects.
It is of particular interest, however, because ephedrine can readily
be converted into it under certain conditions, which were studied by
E. Schmidt, Nagai, and Calliess, more recently by Chou (1926).
The literature dealing with the isomerism of these alkaloids was
reviewed by Chen and Kao (1926). Emde (1928) has obtained evi-
dence that the OH and NHCH 8 groups are distant from each
other in the ephedrine molecule but close together in the pseudo-
ephedrine molecule.
/. Other alkaloids occurring in Ma Huang. In addition to ephedrine
and pseudoephedrine, three other related (but not isomeric) alkaloids
have been isolated from Ma Huang. Smith (1927, 1928) obtained
Z-methyl-ephedrine and nor-rf-pseudoephedrine. Nagai and Kanao
(1928) confirmed these findings, and succeeded in isolating a third
alkaloid, namely, ^-methyl-pseudoephedrine. It appears therefore,
that ephedrine, like several useful alkaloids, occurs in nature along
with closely related substances, though of these only pseudoephedrine
occurs in appreciable quantity.
g. Synthesis of ephedrine. E. Schmidt and his associates made
various attempts and advances toward the synthesis of ephedrine.
Fourneau (1904) prepared a compound having the formula of ephe-
drine. He and his associates later succeeded in the synthesis by
different methods. His process was patented in England (1927).
Nagai accomplished the synthesis in 1911 and patented his product
in Japan, the United States, Canada and England, under the name
of Methylmydriatine. All these products were racemic, as is always
the case when an optically active substance is synthesized. However,
EPEEDKINE AND BELATED SUBSTANCES 15
according to Ogata (1919), Nagai succeeded in 1918 in resolving his
product into I- and ^-ephedrines. Recently, Nagai (1927) has stated
that he was able to synthesize two racemic ephedrines, one melting
at 40, the other at 70, and in separating each into its d- and /-com-
ponents by means of tartaric acid: the pair obtained from the mixture
melting at 70 he called isoephedrines (identical with pseudoephe-
drines). Spath and Gohring (1920) described their complete success
hi the synthesis and separation of all six isomers. Eberhard (1915)
also succeeded in synthesizing racemic ephedrine. Kanao (1927)
reported the success of his attempts to synthesize and separate the
six isomers, confirming the results of SpS.th and Gohring. E. Merck
has recently placed synthetic racemic ephedrine on the market, under
the name of Ephetonm; the process of preparation is patented in
Germany and England. Manske and Johnson (1929) and Skita and
Eleil (1929) have recently achieved new syntheses of ephedrine.
Fourneau and Nicolitch, Manske and Johnson, and Neuberg, Jacob-
son and Wagner employed chemical agents other than tartaric acid
in the resolution of racemic ephedrine.
It is obvious that the final confirmation of the deduced structure of
ephedrine namely, synthesis of the substance has been furnished
repeatedly. At present the natural product is more widely used than
the synthetic and at the time of writing American manufacturers are
supplying only natural ephedrine.
m. PHASMACOLOGICAL ACTION
Chen and Schmidt (1924) called the attention of the Western world
to ephedrine in the belief that the actions of the drug were essentially
sympathomimetic and that it should achieve a usefulness similar to
that of epinephrine. This belief has been strengthened by subsequent
clinical experience, and appears to be amply justified. However,
when the actions of ephedrine are compared with the pattern of
sympathomimetic effects i.e., the actions of epinephrine in the
laboratory, differences are perhaps more frequent than analogies, and
there has recently been a tendency on the part of several investigators
to emphasize the differences as indicative of an absence of any sympa-
thomimetic effect on the part of ephedrine. It is scarcely to be ex-
pected, of course, that two different substances, however closely
16 Z. K. CHEN AND CARL P. SCHMIDT
related, would possess physiological effects that are identical in all
respects, but if it should be proved that the important actions of
ephedrine are fundamentally different from those of epinephrine the
present attitude of physicians toward ephedrine would have to be
radically altered. On the whole, there appears to be no conclusive
evidence that the actions of ephedrine that are of therapeutic impor-
tance are not sympathomimetic, and there is considerable evidence
that they are. On the other hand, there is scarcely any respect in
which the effects of ephedrine are identical with those of epinephrine,
and there are several instances in which the two substances have
opposite actions upon the same structure or function.
1. Action on lower forms of life
Very little work has been done along these lines. Macht (1929),
who has made a systematic study of the toxic effects of various sub-
stances upon living plant organisms found that ephedrine was much
less toxic than epinephrine to the seedlings of Lupinus Aldus, a con-
centration of 1 in 5,000 of ephedrine having a phyto-toxic index of
75 per cent. This is in accord with other observations of the same
author, indicating that a drug of animal origin is more toxic to plants
than one of vegetable origin. In the sea crab, Palaemon, kept in
1 to 1000 solution of ephedrine, a temperature of 36 induces heat
narcosis in 30 minutes (Frohlich and Kreidl, 1921).
Nadler reported interesting results from experiments with the
squid (Loligo pealii). He found that epinephrine and ephedrine,
injected subcutaneously, produced local blanching, which was sup-
posedly due to inhibition of smooth muscle of the chromatophore
system. The effect of ephedrine differed from that of epinephrine in
two respects, however. First, the blanching was much slower in its
appearance when ephedrine was used, though it lasted 8 hours or more
instead of 10 minutes, which was the duration of the epinephrine
effect. Second, the animals injected with ephedrine showed a diffuse
generalized reddish coloration excepting at the injected area; this
coloration was also produced by intravascular or oral fl.rhrnniatrfl.tion
of the drug. Since excitement or irritation of the animal likewise
caused the same color change, it was ascribed to stimulation by
ephedrine of the central nervous system of the animal; epinephrine
EPHEDEINE AND RELAXED SUBSTANCES 17
apparently had no such effect. These results indicate that the action
of ephedrine upon this animal is twofold: a peripheral epinephrine-like
one, and a stimulant one on the central nervous system.
Nadler also found that a number of substances produced peripheral
effects opposite to those of epinephrine and ephedrine, namely, a local
deep coloration at the site of injection. These were parathyroid and
anterior pituitary extracts, posterior pituitary extract, and barium
chloride. The last two are known to stimulate smooth muscle fibers
directly, irrespective of their innervation (i.e., they are musculotropic),
and the effects hi the squid were thought to be due to contraction of
the chromatophore musculature. He found that epinephrine or
ephedrine, injected in sufficient quantity into the red zone produced
by injection of any of these agents, was able to antagonize the effect
and produce local blanching.
This is the only investigation, upon one of the lower forms of lit e, of
the fundamental nature of the action of ephedrine. The conclusion
was that the action of ephedrine is epinephrine-like (sympathomimetic)
and not pituitrin-like (musculotropic).
2. Actions on the circulation
These are probably the most striking effects of ephedrine in the
common laboratory animals, and it is somewhat strange that they
were not investigated until comparatively recent times. If they had
been, the present status of ephedrine might have been attained several
decades ago.
a. The effect upon blood pressure. The first work that of Miura
(1887) led to the conclusion that ephedrine is essentially a circula-
tory depressant. The doses used by him were excessive (fatal)
ones, and cardiac depression evidently dominated the picture. Grahe
(1895) reported a slight rise of blood pressure of curarized dogs upon
subcutaneous or intravenous injection of ephedrine or pseudoephedrine,
but his published tracings show barely detectable effects. He also
found that subsequent injections led to a fall in pressure. The first
demonstration of the characteristic pressor effect of ephedrine was that
of Hirose (1915), who injected the drug intravenously in anesthetized
rabbits. Amatsu and Kubota (1917) confirmed these results, and
added the observation that the rise in pressure was not prevented by
18 K. K. CHEN AND CARL F. SCHMIDT
destruction of the medulla or by paralytic doses of chloral hydrate.
Chen and Schmidt (1924) demonstrated similar effects in cats and
dogs, and emphasized the relatively long duration of the effect of
ephedrine, the diminution, disappearance, or reversal of the effect
upon repeated injections, and the ability of ephedrine to raise blood
pressure when taken by mouth. Since then many workers have con-
tributed to the subject, and the principal features in the circulatory
actions of ephedrine are well established.
Ephedrine causes a rise in blood pressure of anesthetized dogs when
injected intravenously in dosage of 0.005 to 30 mgm. per kilogram,
but the greatest effect is produced by doses of 1 to 10 mgm. per kilo-
gram: following such injection, blood pressure rises by 100 or more
millimeters of mercury and is maintained at this level for at least IS
to 25 minutes. In unanesthetized dogs, 5 to 10 mgm. of ephedrine
per kilogram, by vein, was found by Pennetti (1928) to cause a rise in
pressure lasting 3 to 4 hours.
The pressor effect of ephedrine appears to be less marked in rabbits
than in cats and dogs (Kreitmair, 1927). The minimum pressor dose,
injected intravenously, was found to be 0.05 mgm. per kilogram in
rabbits, while l/50th of this quantity was effective in cats.
Large quantities of ephedrine (40 to 65 mgm. per kilogram) in-
jected intravenously in dogs, cause only a fall in blood pressure
(Chen and Meek, 1926) : these are close to the fatal dose. Kreitmair
(1927) states that 10 mgm. or more per kilogram injected into a vein
causes a fall in blood pressure in cats. This is the type of effect
observed by Miura (1887), who apparently did not try smaller doses.
When the pressor effect of ephedrine is compared with that of
epinephrine, several outstanding points of difference are apparent.
First, the effect of epinephrine is much more intense but much less
prolonged than that of ephedrine: under optimal conditions, employ-
ing intravenous injections in cats, the rise in pressure produced by
epinephrine is 100 (Nagel, 1925) to 142 (Chen) times as intense as that
of the same quantity of ephedrine, but the effect of ephedrine com-
monly persists 7 to 10 times as long as that of epinephrine (Chen).
Second, the intensity of effect of epinephrine is so closely proportional
to the quantity injected that the pressor response can be employed
in assaying epinephrine preparations (United States Pharmacopoeia,
EPHEDRINE AND BELATED SUBSTANCES 19
Ninth Revision); this is distinctly not the case with ephedrine, the
circulatory effects of which are by no means proportional to the quan-
tity injected (Chen and Schmidt, 1924) ; they may be less from large
doses than from smaller ones. Third, following an intravenous injec-
tion of epinephrine blood pressure frequently falls from the peak of the
pressor effect to a subnormal level, rising slowly to normal; t.ln'g is not
true of ephedrine, following which pressure simply falls very gradually
to normal (Kreitmair, 1927). Fourth, when epinephrine injections
are repeated the same degree of effect will be obtained from each;
with ephedrine, however, the first dose is by far the most effective one,
and upon repetition the pressor effect of each becomes progressively
less until it disappears completely or is replaced by a depressor effect
(Chen and Schmidt, 1924). This latter feature has been noted re-
peatedly (Rowe, 1927; Rudolf and Graham, 1927; Kreitmair, 1927;
Pittinger, 1928; Launoy and Nicolle, 1928) in cats, dogs, and rabbits,
anesthetized or pithed. Its explanation involves factors which are
also responsible for most, if not all, of the other differences between
the circulatory effects of ephedrine and epinephrine, and the observa-
tions bearing upon this question may properly be considered at this
time.
The extent to which the circulation becomes "tolerant" to repeated
injections of ephedrine has been found to depend upon the size of the
dose. Thus, comparatively large quantities (about 5 mgm. per kilo-
gram), injected rapidly and at frequent intervals (5 to 10 minutes)
very quickly become ineffective and soon lead to a depressor effect
from each injection. On the other hand, small doses (0.02 to 0.05
mgm. per kilogram) may show cumulative effects (i.e., a step-like
rise in pressure to a sustained high level) if injected at close intervals
(Chen, 1926), and if time is allowed for pressure to recover between
injections each may sometimes though by no means always
produce the same pressor effect. The explanation advanced (Chen
and Schmidt, 1924) for the decreasing effectiveness of repeated injec-
tions of ephedrine is that maximal pressor effects are soon developed,
and that additional quantities of the drug are then incapable of
producing further stimulant effects. It has been suggested (Chen and
Meek, 1926) that the "receptors" with which ephedrine combines
may be fewer in number, or more easily saturated, than those of
20 K. K. CHEN AND CABi P. SCHMIDT
epinephrine, which would account for the absence of progressive effects
as the dose of ephedrine is increased above the optimum level. It
seems probable that the greater persistence of ephedrine actions
depends upon a more stable union with receptor substance than is the
case with epinephrine and if the ephedrine receptors are saturated
early the lack of progressive effect from repeated injections of ephe-
drine is accounted for. When the quantities of ephedrine are small
this saturation would not be accomplished until a number of injec-
tions have been made. Such explanation appears to harmonize with
experimental observations, and is the best available at present; it is,
of course, purely hypothetical.
The depressor effect of ephedrine was attributed by Chen and
Schmidt (1924) to cardiac depression an effect which is well known
and will be considered in the following section. It is wholly unlike
the depressor action of epinephrine, which can be demonstrated with
minm\al doses and is apparently due to stimulation of vasodilator
nerve endings (Dale: Jburn. Physiol., 1906, xxxiv, 163): with ephe-
drine, a first injection is always purely pressor unless it is very large;
a depressor effect from a small or moderate dose can be demonstrated
only after maximal pressor effects have been produced by previous
injections, and there is no evidence that any dose of ephedrine can
produce a vasodilator effect comparable with that of epinephrine.
The fact that the pressor effect of epinephrine is often followed by a
depressor (vasodilator) one, while that of ephedrine is simply followed
by recovery to normal, also indicates that the ability to stimulate
vasodilators is either lacking completely La ephedrine, or is very much
less conspicuous than is the case with epinephrine. It may be noted
also that the pressor action of ephedrine is more affected by the con-
dition of the subject than is the case with epinephrine. Animals whose
blood pressures have been lowered by trauma, operative procedures,
hemorrhage, etc., show much less pressor effect than normals, and
are more likely to show only a fall in pressure following a moderate
dose of ephedrine (Chen, 1925). Deep anesthesia and consequent
hypotension also increase the probability of fall in pressure after only
a few injections of ephedrine (Chen, 1925) . Under such circumstances
increasing the dose of ephedrine would be more likely to lead to fall
than to rise hi blood pressure a contingency that is not encountered
with epinephrine.
EPHEDEINE AND BELATED SUBSTANCES 21
In brief, it appears that the capacity of ephedrine to raise blood
pressure is limited by two factors: first, by its relative weakness as
a circulatory stimulant, perhaps because there are only relatively few
"receptors" with which it can combine, and additional quantities of
the drug are incapable of producing further effects once these have
been saturated; second, by the depressant action of ephedrine upon
the heart an effect that is masked by the pressor effect until the
latter has become maximal, or unless overwhehning quantities are
injected. Epinephrine is not subject to these limitations to anything
like the same degree as ephedrine. This suggests that a mixture
of the two drugs might possess the virtues of both the intensity of
epinephrine and the persistence of ephedrine while TnimTnizing their
respective disadvantages the evanescence of epinephrine and the
danger of cardiac depression by ephedrine. This has actually been
found to be the case.
Thus, Chen and Meek (1926) found that upon intravenous injection
of ephedrine and epinephrine in dogs there was summation, both in
intensity and duration, of the pressor effect. Launoy and Nicolle
(1928) report an actual potentiation when such injections are made
in unanesthetized rabbits, the rise in pressure being greater than the
sum of the effects of both drugs given separately. Cs6pai and Doles-
shall (1928) found that ephedrine sensitizes the human circulation to
intravenous injections of epinephrine, the influence being especially
marked in cases of hyperthyroidism; they believe that ephedrine
sensitizes sympathetic nerve endings just as thyroxin sensitizes the
cells to the action of hormones.
The action of ephedrine upon the human blood pressure has now
been studied extensively, and with quite uniform results. The first
study was that of Miller (1925), who reported rise in pressure in 70
out of 84 individuals given a dose of 50 to 125 mgm. of ephedrine
orally or by subcutaneous injection. In 7 cases pressure was not
altered, while in 6 it fell. The rise in pressure varied from a few
millimeters to 65, and its duration was 6 to 8 hours. Similar results
were reported by Rowntree and Brown (1926), Pollak and Robitschak
(1926), Rudolf and Graham (1927), Hess (1926), Jansen (1926),
Kesten (1927), Middleton and Chen (1927), Althausen and Schu-
macher (1927), Wu and Read (1927), Cs6pai and Fernbach (1928),
22 K. K. CHEN AND CARL F. SCHMIDT
Radoslav and Stoicesco (1927), and Pennetti (1928). Anderson and
Homan (1927) observed a rise in pressure in children given 15 mgm.
of ephedrine hydrochloride. The results of Rowntree and Brown
(1926), and of Hess (1926), indicate that blood pressure can be main-
tained at an elevated level for several days by means of daily ad-
ministration of ephedrine. All observers agree that ephedrine is
effectively absorbed following oral administration, and Hess (1926)
has shown that rise in blood pressure also occurs following rectal ad-
ministration of ephedrine, in dosage of 2 mgm. per kilogram, as
suppository, hi miTTr or dissolved in the proctoclysis fluid. Intra-
venous injection was first tried by Miller (1925), subsequently by
Jansen (1926). The effects are more marked than those of other
routes of administration, but last only 15 to 30 minutes (Jansen).
The influence of disease upon the pressor effect of ephedrine in
man has been studied by several workers. In Graves' disease, in
which there is conspicuous sensitization to epinephrine, Pollak and
Robitschek (1926) reported unusually marked pressor effects from
ephedrine, but Cs6pai and Fernbach (1928) concluded that there is no
sensitization to ephedrine in Graves 5 disease. In asthma, Thomas
(1926) and MacDermot (1926) found no rise in pressure following
oral administration of ephedrine, and a similar statement was made
in an earlier review by Chen and Schmidt (1926). However, studies
of larger series of cases by Althausen and Schumacher (1927) andMid-
dleton and Chen (1927) have shown that ephedrine raises blood pres-
sure in asthmatic patients, possibly less frequently than in normals,
but to as high a level and for as long a time. Pennetti (1928) tried
ephedrine in a single case of myxedema and found a fall in blood pressure
from 210 to 145 mm. of mercury.
The effect of repeated doses of ephedrine, taken by mouth, upon the
blood pressure of human beings has been investigated by Rowntree
and Brown (1926) and by Chen (1928). It appears that when a
therapeutic dose (50 mgm.) is taken by mouth every two to three
hours the first causes the most marked rise in pressure, the subsequent
ones causing further but smaller rises in the already elevated pressure
and mamtaining it at an abnormally high level as long as the drug is
given regularly. These results are therefore similar to those obtained
by intravenous injections of small doses (0.02 to 0.05 mgm. per
EPEEDBINE A2STD RELATED SUBSTANCES 23
kilogram) at short intervals in anesthetized dogs, and appear to indi-
cate that the pressor effect of such dosage is not nearly maximal.
The circulatory effect of a single dose of ephedrine, taken by mouth,
evidently disappears completely within 14 to 24 hours, a second dose
of the same size then producing practically the same effect as the first
(Chen, 1928).
The effect of ephedrine upon venous pressure was studied by Chen
and Meek (1926) in two dogs, one of which was atropinized. In
each, a slight fall in venous pressure coincided with the rise in arterial
pressure.
b. The action on the heart. The first investigations of the physio-
logical effects of ephedrine disclosed its power of depressing the heart.
Miura (1887) observed that lethal doses of ephedrine caused diastolic
arrest of the frog's heart. Grahe (1895) found that ephedrine or
pseudoephedrine, applied to the frog's heart by irrigation or injected
intravenously, caused depression and irregularities, and that a heart
arrested by either drug could not be made to beat by means of atro-
pine, though a heart arrested by muscarine could be made to beat when
treated with ephedrine or pseudoephedrine. Amatsu and Kubota
(1917) obtained similar results with frog's heart studied by Engelman's
and Straub's methods, confirming the inability of atropine (as well as
camphor) to overcome the depressant effect of ephedrine. Chen
and Schmidt (1924) found only depression of the frog's heart irrigated
with ephedrine.
Subsequent investigations have confirmed the conclusion that
ephedrine is essentially depressant to the frog's heart, while showing
in addition that small quantities may exert an inconspicuous stimulant
effect. Chen and Meek (1926) found that ephedrine sulphate,
applied to the heart in concentration of 1 in 1,000, may cause accelera-
tion by a few beats per minute, but a 1 in 100 solution was purely
depressant to rate and amplitude. Barlow and Sollmann (1926),
who perfused the heart by the method of Howell and Cooke, found
pure depression with concentrations of ephedrine sulphate of 1 in
10 B or stronger, rate, force and output being Himim'shed, and with
1 in 10 s dilutions complete heartblock was elicited; stimulation was
occasionally observed with dilutions of the order of 1 in 10 7 , being
manifested as an increase in rate and amplitude, but the increase
24 K. K. CHEN AND GAEL P. SCHMIDT
rarely exceeded 10 per cent. Kreitmair (1927) noted increase in
amplitude of the frog's heart perfused by Straub's method with 1 in
10 4 ephedrine hydrochloride; rate was not affected, and higher con-
centrations were purely depressant, 1 in 100 causing arrest that could
be combated by means of perfusion with 1 in 10 4 dilution of epineph-
rine, with calcium, or with histamine, but was not reversible upon
simple perfusion with pure Ringer's solution, and was not affected by
atropine. Gradinesco (1927) also found that epinephrine is able to
restore the beat to the frog's heart arrested by perfusion with ephe-
drine. Gomes da Costa (1927) reported stimulant effects of dilute
solutions of ephedrine upon the perfused frog's heart, but LeVy and
Boyer (1927) found only depression when any effect was evident.
M6hes and Kokas (1929) likewise observed depression of the frog's
heart perfused with a 1 in 50,000 dilution of ephedrine, and believed
that the effect was partly removed by small quantities of atropine.
The hearts of certain invertebrates have also been studied with
respect to the effects of ephedrine. L6vy and Boyer (1927) studied
the heart of the snail (Helix pomatia) and found systolic contracture
with a 1 in 20 solution of ephedrine; weaker solutions (1 in 100, 1 in
1,000) caused a slowing in rate and an increase in strength of con-
traction, with periodic variations. Bain (1929) perfused the hearts
of crabs (Maia squinado, Cancer pogurus, and Carcinus moenas)
with ephedrine, among other drugs, including epinephrine which, in
1 to 50,000 dilution caused a marked increase in rate and tone of the
hearts: ephedrine was used in the same dilution as epinephrine, and
produced no effect whatever. Apparently a stronger solution of
ephedrine was not used, so that one can conclude only that ephedrine
is weaker than epinephrine in its effects upon these hearts, as upon all
others.
The isolated heart of the toad was perfused with ephedrine and
pseudoephedrine by Loo and Read (1928) : they usually found depres-
sion of amplitude of beats with 1 in 20,000 ephedrine following
pseudoephedrine but ocasionally ephedrine caused acceleration.
The turtle's heart was perfused with ephedrine by Chen and Meek
(1926): dilutions of 1 in 10,000 sometimes accelerated the rate
slightly, but 1 in 1,000 or 1 in 100 caused bradycardia, usually with
decrease in amplitude, culminating in diastolic arrest.
The action of ephedrina.cm -tlie wt|ip^to*te^ -was investigated
by Chen and Schmidt (1924) as4 fey C^JMMeek (1926), Pulse
rate in the intact unanesthetigeci 4o^fe?^&aly flowed, occasionally
accelerated, when qpbedvm Is^^ete^.-^ojKMtaniecaisly or intra-
venously; in the wfti^^i anfml acetottfco* is cesissjenly ob-
served following i&tmv&Qi3s InjeetMHx of -less *ha&,i s&g&t* $e* laio-
gram, though a&ej^aarg^.goses (1 tJ$ mgD^ perfefioam j$$nj.is}
commonly seeav Atropbs c$pjgiafed^,$lx>Kshes or
bradycardiay which is tbl^to bfc ix^rd4^ a reflex eSect of
in blood pressure, the stewing being greater is splmalfa whose
mhibitory centers are not depressed by anesthesia* This explanation
is, however, called into question by the recent experiinents of Pene&etti
(1928), who found that section of the vagi or injection of atropine in
unanesthetized dogs does not usually accelerate the heart slowed by
ephedrine. Confirmation of these results is highly desirable. Coelho
(1929) reports that in dogs narcotized with chloralose, ephedrine, hi
dosage of 1 to 20 mgm. per kilogram, causes acceleration of the heart.
The strength of the beats of mfl-mTnalian hearts has also been found
to be increased by ephedrine. Chen and Schmidt (1924) recorded the
contractions of part of the right ventricle (myocardiograph) and found
them markedly increased by ephedrine. The effect was not pre-
vented by section of the vagus nerves or by atropine, was not due to an
atropine-like effect upon cardio-inhibitory nerves, and was fully
comparable with that of electrical stimulation of the accelerator nerve
or of injection of epinephrine. They also showed that ephedrine
caused increase in rate and amplitude of ventricular contractions
when applied locally to the stellate ganglia a feature in action that is
not shared by epinephrine (Chen and Meek, 1926). Intravenous
injection of ephedrine caused still further acceleration and augmenta-
tion. Large quantities of ephedrine (40 to 55 mgm. per kilogram by
vein) are apt to cause acute cardiac depression (Chen and Meek, 1926).
The cardiac stimulant action of small quantities of ephedrine and the
depressant action of large quantities have also been observed by
Kreitmair (1927) on cats and by Launoy and NicoUe (1928) on rabbits.
Chopra, Dikshit, and Pillai (1929) found increase in auricular con-
tractions in cats given 2 mgm. injections, the ventricles being un-
affected, while with 5 mgm. both auricles and ventricles were
depressed.
26 K. Z. CHEN AND CARL P. SCHMIDT
It has been shown by La Barre (1928) that ephedrine does not lead
to ventricular fibrillation in cats under chloroform anesthesia; in
this respect ephedrine differs from epinephrine.
Studies of the effect of ephedrine upon the cardiac output of
dogs were made by Chen and Meek (1926) by means of cardiometric
and teleoroentgenographic methods. They concluded that in the
(anesthetized, atropinized) dog there is a distinct and constant in-
crease in volume output per minute at the time of increase in pulse
rate and rise in blood pressure. Wilson, Pilcher, and Harrison (1928)
employed the Fick principle to measure cardiac output of unanesthe-
tized dogs, and found that ephedrine caused an increase in minute
volume, especially when the drug was given subcutaneously or by
mouth. Halsey, Reynolds, and Blackberg (1927) employed the same
methods but obtained opposite results, i.e., ephedrine was found to
decrease the cardiac output of unanesthetized dogs as well as of dogs
narcotized with chloroform or chloral hydrate. It should be noted
that results obtained by this procedure are frequently opposed to
those obtained by other methods. For example, digitalis, which has
been universally regarded as a stimulant to cardiac muscle and is
found to be such by other methods of investigation, decreases cardiac
output as measured by the Fick method and appears to be essentially
a cardiac sedative (Harrison and Leonard: Jour. Clin. Invest., 1926,
iii, 1) ; and quinidine and chloral hydrate, which, by other methods of
investigation, are shown to be marked cardiac depressants, appear
as cardiac stimulants according to the results obtained by this method
(Halsey, Reynolds, and Blackberg, 1927). Until such discrepancies
are satisfactorily explained it is impossible to evaluate the results
obtained with respect to ephedrine.
Electrocardiographs studies made by Chen and Meek (1926)
in unanesthetized and anesthetized animals, showed that small doses
(5 to 10 mgm. per kilogram by vein in dogs) did not alter the contour
of the curve, apart from the T-wave, which might be flattened, in-
verted, or occasionally augmented. Massive doses (40 to 75 mgm.
per kilogram), given intravenously to dogs and rabbits, appeared to
depress the automatic and conducting systems in descending order,
that is, from sino-auricular node to the ventricular terminations of the
Purkinje system: there were, in the order of their appearance, brady-
EPEEDRENE AND RELATED SUBSTANCES 27
cardia, prolongation of the P-R interval, partial auriculo-ventricular
block, nodal rhythm, ventricular automatism or extrasystoles, bundle
branch block, finally ventricular fibrillation. Similar results were
obtained by Coelho (1928) in dogs narcotized with chloralose.
The isolated mammalian heart has also been studied: Chen and
Schmidt (1924) and Chen and Meek (1926) found that the rabbit's
heart perfused according to LangendorfF's method was stimulated in
rate and strength of beats by low concentrations (1 in 100,000) of
ephedrine sulphate, while stronger solutions (1 in 10,000, 1 in 5,000)
caused depression of both rate and strength; still stronger solutions
(1 in 2,000) brought about partial block, and 1 in 1,000 caused prompt
failure (Chen and Meek, 1926). Similar results were obtained by
Chopra, Dikshit, and Filial (1929), and by Pennetti (1928); the latter
found that epinephrine was able to revive a heart arrested by
ephedrine.
The effects of ephedrine upon the human heart have received con-
siderable study. The effect upon pulse rate was observed by Chen and
Schmidt (1924) in a small series of cases, all of whom showed a slowing
after oral or subcutaneous administration of ephedrine. Miller
(1925), in a much larger series, found slowing of the pulse duiring the
rise in blood pressure in the majority, but in 16 of his 84 subjects
pulse rate was accelerated by ephedrine. Pulse rate and blood
pressure returned to normal at about the same time. Rowntree and
Brown (1926) noted acceleration of the pulse as frequently as slowing,
and Middleton and Chen (1927) observed that acceleration was pro-
duced more frequently than slowing. In the experience of Hess
(1926) and of Rudolf and Graham (1927), a decrease in pulse rate was
the more frequ'ent result of ephedrine, but in the cases of Jensen
(1926) acceleration was the more frequent. In some cases in all these
series pulse rate was unaffected. On the whole, the effect of ephedrine
upon the rate of the human heart appears to be of the same nature as
that upon the dog's heart, namely, acceleration or slowing, depending
upon conditions which are not well understood. The influence of
atropine upon the cardiac effects of ephedrine in man has apparently
not been investigated, but it may be inferred that bradycardia follow-
ing a therapeutic dose of ephedrine is a reflex effect of the rise in blood
pressure.
28 K. K. CHEN AND CARL F. SCHMIDT
Evidence that ephedrine increases the strength of contractions of
the human heart was obtained by Miller (and Pendergrass) (1925)
by means of fluoroscopic observations of three individuals, in every
one of whom the excursion of the ventricular and aortic shadows was
greater after ephedrine than before. At the same time the apex
impulse became visibly and palpably more forceful and the heart
sounds became louder. These observations furnish an explanation of
the palpitation which is commonly complained of by patients receiving
ephedrine. Miller (1925) has also called attention to the occasional
appearance of systolic murmurs in patients who had normal sounds
before ephedrine was given, and to the intensification of existing
systolic murmurs by ephedrine. These murmurs may be heard at the
apex alone, at the base alone (in either aortic or pulmonary area),
or in all these areas. He suggested that they might be the result of
distention of the cardiac chambers leading to the relative stenosis of
aortic or pulmonary orifices, or to relative insufficiency of the mitral
valve.
Electrocardiographic studies of the effects of ephedrine in man were
made by Middleton and Chen (1927) in 11 patients, the drug being
taken by mouth; seven showed no change, four developed ventricular
or auricular extrasystoles, these being most marked in a patient with
chronic myocarditis in whom systolic blood pressure fell 30 mm.
following ephedrine. Pennetti (1928) studied the electrocardiograms
of 8 subjects with normal cardiovascular systems upon subcutaneous
injection of 50 mgm. of ephedrine. Five of these showed perfectly
normal tracings after the drug was- given, while in three there was some
change decrease or increase in height of the R wave and prolonga-
tion of the S wave, and in one the T wave became diphasic.
The observations bearing upon the action of ephedrine upon the
heart may be summarized as follows : there is no doubt that ephedrine,
in large dosage, is depressant to the amphibian or mammalian heart,
and may cause acute cardiac failure. This action is apparently exerted
directly upon the muscular and neuromuscular tissues of the heart,
and is independent of effects upon the cardiac nervous mechanism.
The cardiac stimulant effect of smaller quantities of ephedrine is like-
wise well marked in the case of the mammalian and human heart, less
so in the amphibian heart. This effect is fully comparable with that
EPHEDRINTS AND RELATED SUBSTANCES 29
of excitation of the accelerator nervous mechanism of the heart, 'by.
means of electrical stimuli or epinephrine. The effect of ephedrine
differs from that of epinephrine in that it is apparently exerted not
only upon the extreme peripheral parts of the accelerator system, but
upon its ganglia as well. 1 In the cardiac effects of ephedrine one sees
the same general differences from epinephrine that are evident in the
effects upon blood pressure: ephedrine effects are less intense but much
more prolonged, and upon increasing or repeating the dose of ephe-
drine the stimulant effect is increased little or not at all, or may be
replaced by a depressant effect. The ability of ephedrine to increase
the rate and force of heart beats is limited not only by an apparently
small number of receptors, but also by its capacity for depressing heart
muscle. Its cardiac stimulant effect cannot be made as intense as
that of epinephrine by increasing the dosage and this fact, together
with the deleterious effects of large doses upon heart muscle, make the
intravenous or intracardiac administration of ephedrine inadvisable
when stimulation is needed in an emergency.
c. The action on blood vessels. Ephedrine produces vasoconstriction.
This was first demonstrated in 1917 by Amatsu and Kubota by means
of perfusion experiments. They observed constriction of vessels of
frogs' legs upon perfusion with a concentration of 1 in 10,000 of
ephedrine hydrochloride; the vessels of the ear of the rabbit were
constricted by solutions ranging from 1 in 2,000 to 1 in 20,000; con-
striction was also noted in the perfused vessels of the intestine,
spleen, and kidney of the dog. Their results have been connrmed by
perfusion experiments made by Chen and Schmidt (1924) on the dog's
kidney, by Chen and Meek (1926) on the kidney, spleen, and leg of
the dog, by Barlow and Solhnann (1926) and by MShes and Kokas
(1929) on the frog, by Loo and Read (1928) on the toad, the latter
finding a 1 in 20,000 solution effective. Other workers, while agreeing
that ephedrine is a vasoconstrictor, found it a much less powerful one
than these results would indicate. Thus, Kreitmair (1927) found
1 This has been recently denied by Tainter (1929) who found that ephedrine, applied
to the stellate ganglion, caused cardiac acceleration only exceptionally, and that similar
effects could be produced by application to the pleura itself. He calls attention to the
acidity of ephedrine solutions as a probable factor in the result obtained by Chen and
Schmidt (1924).
2988 G I
30 K. Z. CHEN AND CAB1 F. SCHMTOT
constriction of frog's vessels with a 1 in 10 dilution of ephedrine,
but none with a 1 in 100 solution; Gradinesco (1927) found only slight
constriction with a 1 in 100 solution, and Schaumann (1928) obtained
only slight constriction with concentrations less than 1 in 1,000.
The last-named investigator found that a very small amount of epi-
nephrine augmented the constrictor action of ephedrine, and that re-
peated applications or an increase in concentration of ephedrine were
less effective, ineffective, or might cause dilatation of vessels.
Plethysmographic investigations have also disclosed the ability of
ephedrine to constrict blood vessels, and have furnished additional
information concerning its relative effectiveness upon different parts
of the vascular system. Chen and Schmidt (1924) reported that
intravenous injection of ephedrine in dogs caused immediate decrease
in volume of the kidney only, and this decrease was followed by in-
crease to a level far above normal. Increase in volume as blood pres-
sure rose was usually observed in the intestines and invariably in the
leg. Chen and Meek (1926) obtained similar results; they also re-
corded volume of the spleen and found it usually decreased during the
rise in blood pressure produced by ephedrine. Rudolf and Graham
(1927) noted that the volumes of intestines and leg of the dog were
slightly increased at first, but subsequently decreased, indicating
delayed vasoconstriction. Gradinesco and Marcu (1927) reported
increase in splenic volume; kidney volume was increased following
small doses, but with large ones it was first decreased, then increased.
Lim, Necheles and Ni (1927), who recorded the volume of the vivi-
perfused stomach of the dog, obtained evidence of vasoconstriction by
ephedrine, but a slight increase in volume was sometimes noted.
These results leave no doubt concerning the ability of ephedrine to
constrict certain blood vessels, nor concerning its status as a vaso-
constrictor that is much less powerful and uniform in its effects than
epinephrine. Yet it appears that the vasoconstrictor action of ephe-
drine, like that of epinephrine, is essentially peripheral, and is not
dependent upon stimulation of the vasomotor center or other parts
of the central nervous system. This was shown by Amatsu and Ku-
bota (1917), and by Chen and Schmidt (1924), who found ephedrine
effective hi raising the blood pressure of animals whose central nerv-
ous systems were destroyed or paralyzed. The same conclusion was
EPHEDRINE AND RELATED SUBSTANCES 31
reached by Marcu and Gheorghiu (1927) as a result of observation of
simultaneous changes in carotid and crural blood pressures, and by
Heymans (1928), who employed crossed-circulation experiments to
exclude the central nervous system; the former found that ephedrine
still raised blood pressure after exclusion of cardiac and splanchnic
effects. But since plethysmographic experiments have shown that
vasoconstriction is evident only in certain organs (kidney, spleen)
as blood pressure rises following ephedrine it is clear that the effect is
not exerted in the same degree upon all blood vessels a conclusion
that is equally applicable to epinephrine.
Concerning the part of the vascular bed that is affected by ephe-
drine, little information is available. Kreitmair (1927) reported that
a 1 per cent solution of ephedrine, locally applied to the web or tongue
of a frog, causes constriction of arterioles and obliteration of capil-
laries. Chen (unpublished) studied the circulation of the frog's
tongue, web, mesentery, and kidney, but was unable to detect any
significant changes upon local application or intravenous injection of
ephedrine until a sufficient quantity had been given to depress the
heart, when the observed effects could be attributed wholly to cardiac
depression. H. C. Hou (personal communication) obtained practi-
cally the same result. It appears, therefore, that ephedrine has not
the intense constrictor action upon the extremely peripheral parts
of the vascular bed that is so conspicuous a feature in the case of
epinephrine. This may explain to a considerable degree the greater
readiness with which ephedrine is absorbed into the circulation; it
also makes ephedrine unsuitable for combination with local anesthetic
mixtures.
The action of ephedrine upon blood vessels that are not markedly
constricted by epinephrine (coronary, pulmonary, cerebral) has not
been studied systematically. Chen and Schmidt (1924) found that
ephedrine, like epinephrine, increased the outflow from the coronary
vessels of the rabbit's heart perfused by Langendorff's method.
Schmidt (1928) reported increase in venous outflow from the brains
of dogs and cats given pressor doses of ephedrine, as well as epineph-
rine, but pituitrin had the same sort of effect. The effects upon the
pulmonary circulation apparently have not been studied.
Some information has been obtained concerning the action of
32 Z. K. CHEN AND CARL P. SCHMIDT
ephedrine upon human blood vessels. Marcu (1926) applied a ple-
thysmograph to one arm and a cuff for sphygmomanometry to the
other. He concluded that minimal doses of ephedrine (less than 1
mgm. by vein) caused dilatation followed by constriction of abdominal
vessels, while small doses (less than 10 mgm.) caused generalized con-
striction in splanchnic and other vessels; larger doses had the same
general effect, but constriction of abdominal vessels became relatively
more marked. Apparently the splanchnic circulation of man is most
susceptible and is most powerfully affected by ephedrine, and this is in
harmony with the results of plethysmographic experiments in ani-
mals. Rowntree and Brown (1926) studied the effects of intradermal
injection of 10 per cent ephedrine in saline solution. The reaction
was a small red central area surrounded by a patchy white border of
irregular outline and inconstant appearance; reflex erythema was
frequent. Epinephrine, similaly injected, caused a small white cen-
tral area, surrounded by a zone of erythema. This confirms the
results obtained by observation of the effects of ephedrine on capil-
laries of the frog in indicating that ephedrine has little or no con-
strictor effect upon capillaries. The ability of ephedrine to constrict
the vessels of the nasal mucous membrane of man when the drug is
taken by mouth has been proved repeatedly and will be considered in
the section dealing with clinical uses.
3. The action on respiration
Apart from its effect upon the respiratory passages, which are due
wholly to peripheral actions, ephedrine is a stimulant to the respira-
tory center, resembling caffeine in its effects. In intact am'-mals small
doses of ephedrine (5 mgm. per kilogram subcutaneously, 1 mgm. per
kilogram by vein) have no significant effect upon respiratory rate or
depth, and the same is true of human beings given therapeutic doses
(Jansen 1926). In anesthetized animals the results appear to be
somewhat variable hi detail but stimulation is a common result.
Fujii (1925) found that the respiration of urethanized rabbits was
increased in rate and decreased in depth by ephedrine hi dosage of
10 mgm. per kilogram. Kreitmair (1927), using cats anesthetized
with urethane and ether, found that 5 mgm. of ephedrine per kilo-
gram caused increase in depth of respiration, rate being unaffected.
EPHEDBJNE AND RELATED SUBSTANCES 33
Suzuki (1928) gave larger doses (30 mgm. per kilogram) to rabbits
and noted as a rule an increase in depth with decreased rate of breath-
ing, though occasionally rate was increased markedly. Schmidt
(1929) found that ephedrine was more regularly effective than any
of the conventional respiratory stimulants in combating extreme
respiratory depression due to morphine. Toxic or lethal doses of
ephedrine always produce acceleration of respiratory rate immediately
before final failure of breathing, in intact or anesthetized animals
(Miura, 1887; Chen, 1926; Kreitmair, 1927); this may be due to a
large extent to acute circulatory depression.
The action of ephedrine upon the respiratory center seems to con-
sist of two distinct components: first, an increase in blood supply of
the center, due to the pressor effect; second, a direct stimulant action
upon the cells of the center. The result of ephedrine action is there-
fore equivalent to that of a combination of epinephrine and caffeine.
Ephedrine appears to be the most useful single respiratory stimulant
that is available at present (Schmidt, 1929) .
4. The action on smooth muscle
In the effects that have been considered up to this point ephedrine
differs only quantitatively from epinephrine. When the actions of the
two agents are compared upon smooth muscle in general however,
it is soon evident that the effects of ephedrine are sometimes opposite
to those of epinephrine. Since the latter are due, in so far as is known
at present, wholly to stimulation of the sympathetic ionervation of the
muscle, it is clear that ephedrine either lacks this power or else applies
it to the various parts of the sympathetic system with relative intensi-
ties that are different from those of epinephrine.
a. Pupil. Ephedrine produces mydriasis when applied locally to
the conjunctiva or when absorbed into the circulation. This was first
demonstrated by Miura (1887) and by Takahaski and Miura (1889)
in dogs, cats, and rabbits, as well as humans; the pupils of chickens
and pigeons were not dilated by ephedrine. These earliest workers
left little to be added to the analysis of this feature in the action of
ephedrine. They found that the light and accommodation reflexes
were not abolished by the drug; that electrical stimulation of the oculo-
motor nerve caused contraction of the pupil dilated by ephedrine;
34 K. E. CHEN AND CARL P. SCHMIDT
that section of the cervical sympathetic nerve or extirpation of the
superior cervical ganglion did not prevent ephedrine mydriasis;
that the latter could be diminished or overcome by means of muscarine,
pilocarpine, or physostigrm'ne, as well as nicotine; that atropine did not
cause further mydriasis after ephedrine had produced its complete
effect. They concluded (1889) that ephedrine mydriasis is due to
stimulation of the sympathetic pupillo-dilator mechanism and does
not involve paralysis of the parasympathetic (oculomotor) pupillo-
constrictors. The results have been confirmed in all respects by Grahe
(1895), by Hirose (1915) and Miura (1912) on enucleated eyes of frogs,
by Chen and Schmidt (1924) on the eyes of dogs, cats, rabbits and men,
by Koppinyi (1928) on the eyes of guinea-pigs, and by Poos (1927)
on the isolated sphincter and dilator muscles of the eyes of rabbits
and calves. The latter was able to show that ephedrine like epineph-
rine and cocaine causes increase in tone of the dilator muscle,
decrease in that of the sphincter; the stimulant effect upon the dilator
was augmented by increasing the alkalinity of the solution. This
may explain the result obtained by Munch (1928), confirmed by Swan-
son, Thompson and Rose (1929), that ephedrine base is a more power-
ful mydriatic in the cat than is the alkaloidal sulphate or hydro-
chloride.
Chen and Schmidt (1924) confirmed the results of Miura, adding the
observation that ephedrine does not cause loosening of corneal epi-
thelium. Kreitmair (1927) stated that while ephedrine injected
intravenously is about equally effective in causing mydriasis in dogs,
cats, and rabbits, local application to the conjunctiva causes much less
mydriasis in cats than in the other animals.
Comparing the pupillary effects of ephedrine with those of epineph-
rine, an essential difference is at once evident in the fact that while
epinephrine has little or no effect upon the normal pupil, whether the
drug is applied locally or injected intravenously, ephedrine is a highly
effective dilator of the normal pupil, by any mode of administration.
Schmidt (unpublished results) recently compared the effects of the two
drugs upon the pupils of three rabbits each of whom had had the left
superior cervical sympathetic ganglion removed several months pre-
viously: epinephrine, locally applied to both eyes or injected intra-
venously, dilated only the pupil of the operated side, while ephedrine,
EPHEDRINE AND RELATED SUBSTANCES 35
similarly exhibited, dilated both pupils, but the normal one more
markedly than the other; pituitrin, locally applied, did not dilate either
pupil. In these animals, as well as in the ones previously used by Chen
and Schmidt (1924), cocaine dilated only the normal pupil. It is
obvious that denervation does not sensitize the pupil to the effect of
ephedrine as it has long been known to do to that of epinephrine. On
the other hand, the structures upon which ephedrine acts to produce
mydriasis do not degenerate after excision of the superior cervical
ganglion, as appears to be the case with those upon which cocaine acts.
Yet the action of all three drugs is essentially peripheral, as shown not
only by the fact that the effect is limited to the eye to which they are
applied, but also by the results obtained with the excised surviving
muscle (Poos, 1927). The sensitization of the denervated pupil to
epinephrine was attributed by Meltzer and Auer (1904) to the re-
moval of inhibitory influences exerted by the ganglion upon the peri-
pheral receptors with which epinephrine reacts, assuming that the
latter do not degenerate under such conditions. On this basis, it
would be necessary to conclude that cocaine acts upon receptors all of
which degenerate following removal of the ganglion, and that ephe-
drine, the effects of which are weakened but not abolished by such
removal, acts partly upon cocaine-like receptors and partly upon
epinephrine-like ones.
b. Gastro-intestmal tract. In contrast with the effects of epineph-
rine, which are uniformly like those of stimulation of the sympathetic
innervation of this system, the effects of ephedrine appear to be
irregular and uncertain.
The effects upon the oesophagus were studied by To (1921), using
the isolated organ of the frog. He found that ephedrine relaxed its
tone in concentration of 1 in 2,000, and exerted a potentiating effect
when given together with atropine or papaverine.
The crop muscles of the pigeon were found by Hanzlik and Butt
(1928) to be thrown into contraction by ephedrine in dosage of 10 to 20
mgm. per kilogram; the effect involved both circular and longitudinal
musculature, lasted 5 to 10 minutes, and was not prevented by atro-
pine, though it was reduced by cocaine.
The effects of ephedrine upon the stomach in situ were studied in
unanesthetized dogs with permanent fistulae by Kinnaman and Plant
36 K. K. CHEN AND CARL P. SCHMIDT
(1927); they gave 5 mgm. of ephedrine per kilogram by vein, and
found prompt and marked relaxation of gastric tone with inhibition
of gastric motility, lasting 4 to 5 hours. Schmidt (unpublished)
recently had the opportunity of repeating this experiment upon a
single dog; following subtutaneous injection of 1 mgm. of ephedrine
per kilogram, there was relaxation of tone and inhibition of gastric
peristalsis for about 2 hours. In none of these experiments was there
any trace of a stimulant action by ephedrine upon the gastric muscle
of the unanesthetized dog, and inhibition (the epinephrine-like effect)
was uniformly observed. M'Crea and Macdonald (1928) found that
ephedrine, like epinephrine, inhibited gastric peristalsis and caused
fall in intragastric pressure of anesthetized cats. The effects of
ephedrine upon the human stomach have also been investigated.
Pollak and Robitschek (1926) made roentgenologic studies: they
observed an increase in gastric peristalsis, leading to expulsion of the
barium meal into the duodenum, J to 1 minute after the subject had
swallowed 20 drops of 10 per cent solution of ephedrine. They state
that epinephrine caused a similar effect, which, they believe, may have
been due to direct excitation of the musculature or to reflex stimula-
tion consequent upon irritation of the mucous membrane. Marcu and
Savuiesco (1928) recorded gastric motility by means of a balloon which
was swallowed and connected to a water manometer; upon intrave-
nous injection of 1 cc. of a 1 in 500,000 solution (0.002 mgm.) of ephe-
drine they observed transitory contraction of the stomach, 0.02 to
0.05 mgm. had no effect, while 0.1 mgm. caused inhibition of contrac-
tions for about 10 minutes; upon intravenous injection of 20 mgm. of
ephedrine, there was marked and prolonged inhibition of gastric move-
ments, with a stimulant after-effect.
The effects upon the small intestine in situ have received less atten-
tion. Using unanesthetized dogs with fistulae of the ileum, Kinnaman
and Plant (1927) found that ephedrine, injected intravenously, uni-
formly caused immediate relaxation and inhibition of motility, fol-
lowed by a stimulant effect that became more marked as the dose was
increased. With 0.5 to 1 mgm. per kilogram inhibition was marked,
lasted 30 minutes to 2 hours, and was followed by only slight stimu-
lation, but with 5 mgm. per kilogram the period of inhibition was
shorter and the stimulant after-effect was more marked. Schmidt
EPHEDRINE AND RELATED SUBSTANCES 37
(unpublished experiments) tried the effect of intramuscular injections
of 2 mgm. of ephedrine per kilogram in four unanesthetized dogs with
fistulae of the ileum, making 13 observations in all. In eight, there
was pure decrease in motility, ranging from slight to marked; in two
there was no distinct effect; in two there was brief inhibition followed
by increase in motility; in only one case was there pure stimulation
after ephedrine, and this was insignificant compared with the effect
of local application of an aromatic water or intramuscular injection of
5 mgm. of morphine.
The large intestine in situ showed only depression of tone and motility
in every one of the few observations made. K inn am an and Plant
(1927} found this to be the case in unanesthetized dogs with colonic
fistulae, and Schmidt (unpublished), using two such dogs, saw distinct
decrease in tone and prolonged inhibition of motility following intra-
muscular injection of 2 mgm. of ephedrine per kilogram, if active
movements were present before the drug was given; if not there was
no effect. As far as we know there has never been any sign of a
stimulant effect by ephedrine upon the large intestine in situ.
The results of experiments upon the gastro-intestinal tract in situ
therefore indicate that the effects of ephedrine are, on the whole, very
similar to those of epinephrine. With isolated strips of intestinal
muscle, surviving in a warm saline solution, the results are much less
uniform, some workers finding that ephedrine is only depressant,
others reporting depression and stimulation, still others observing
only stimulation. Thus, Amatsu and Kubota (1917) found ephedrine
to be essentially depressant to isolated intestine of cats and rabbits,
and the same result was obtained by To (1921), by Fujii (1925), and
by Chen and Schmidt (1924) in rabbits. The last-named investi-
gators found that the inhibitory effect of ephedrine could be readily
overcome by means of pilocarpine or barium, and was not prevented
by nicotine, thus showing that the effect was not due to depression
of parasympathetic nerve endings, muscle fibers, or intrinsic ganglia
(plexus of Auerbach). Subsequent workers have failed to confirm
these results. Nagel (1925) found ephedrine to be purely stimulant
to the isolated intestine of the rabbit and cat; the inhibitory effect
of epinephrine could be overcome by ephedrine. Kreitmair (1927)
found the isolated intestine of the cat to be relaxed by low concen-
38 K. K. CHEN AND GAEL P. SCHMIDT
trations (1:1,000,000 to 1:100,000) of ephedrine, but slightly stimu-
lated by a stronger one (1 : 6,000) ; the latter effect could be prevented
completely by atropine. Reinitz (1928) reported that isolated rabbit
intestine was sometimes inhibited, often stimulated, sometimes inhi-
bited and then stimulated, by the same concentration of ephedrine;
he stated that atropine had no significant influence upon the stimu-
lant response. M6hes and Kokas (1929) reported stimulation of
isolated rabbit intestine by weak concentrations (1:150,000 to
1:50,000) of ephedrine, relaxation with a stronger one (1:10,000).
Rudolf and Graham (1927) found only slight and transitory depres-
sant effects by ephedrine upon isolated rabbit intestine. Lim and
Chen (1928) noted only stimulation of cat intestine, isolated but
with intact circulation, upon the addition of ephedrine. De Eds,
Rosenthal, and Voegtlin (1928) reported pure stimulation of rabbit
intestine exposed to a 1:5,000 solution of ephedrine, and Halsey
(1928) found no instance, among many preparations of isolated rabbit
intestine, of anything but stimulation by ephedrine.
Isolated large intestines of the rabbit were found by Kreitmair ( 192 7)
to be affected like the small by ephedrine, i.e., they were depressed
by weak solutions, stimulated by strong ones and the latter effect could
be prevented by atropine. Thienes (1929) reported that epinephrine
depression of isolated large intestines of cats, rabbits, dogs, rats and
guinea-pigs was antagonized by ephedrine.
It may safely be assumed that any of these preparations would have
been inhibited by epinephrine, so that it is very evident that the effects
of ephedrine upon isolated muscle of the gastro-intestinal tract are
inconstant. A probable explanation for this will be presented later
(page 52) . It should be pointed out here that the effects of ephedrine
upon movements of the gastro-intestinal tract in situ appear to be
much more nearly like those of epinephrine than is the case when the
two agents are tested upon isolated muscle preparations. The reason
for this is unknown: it is possible that central nervous influences or
indirect actions through the suprarenal glands (see page 55) play a
part in these effects of ephedrine in the living animal. Whatever the
explanation, the effects upon the gastro-intestinal tract in situ are
those which are of therapeutic importance, and there is no evidence
at present that ephedrine can properly be employed as a stimulant
to gastro-intestinal motility.
EPHEDRINE AND RELATED SUBSTANCES 39
c. Uterus. All of the data available at present were obtained -with
isolated tissue excepting a few experiments of Chen and Schmidt
(1924), who found that the dog's uterus in situ was stimulated by
ephedrine. To (1921) reported that the isolated uterus of the rabbit
or rat was depressed by dilute solutions of ephedrine (1:20,000 and
1 : 100,000 to 1 : 10,000 respectively), while stronger solutions (1 : 10,000
and 1:3,300 to 1:^2,000 respectively) caused stimulation. Chen and
Schmidt (1924) found that the isolated rabbit uterus was uniformly
stimulated by ephedrine, with only one exception the uterus of a
recently delivered rabbit. Stimulation was the only effect of ephe-
drine upon isolated uterus in the experiments of Fujii (1925) on rabbits,
of Nagel (1925) on guinea pigs, of Kreitmair (1927) on rabbits, of
De Eds and Butt (1927) and De Eds, Rosenthal, and Voegtlin (1927)
on rabbits and guinea-pigs, of Thienes (1929) on cats, rabbits, dogs,
rats and guinea-pigs, of Reinitz (1928) on rabbits, and of Curtis (1929)
on guinea-pigs and cats. The uterus of the albino rat, however, is
uniformly relaxed by ephedrine (Liljestrand, 1927).
These results are quite unlike those obtained with epinephrine, which
usually relaxes the isolated non-pregnant uterus of the cat and fre-
quently relaxes the non-pregnant guinea-pig uterus. In fact Thienes
(1929) found that ephedrine prevented the inhibitory effect of epineph-
rine upon various uteri. Reinitz (1928) reported that very small
quantities of ephedrine augment the (stimulant) effect of epinephrine
upon the isolated rabbit uterus, but larger quantities reduce it.
In general, the action of ephedrine upon the isolated uterus is char-
acteristically a stimulant one, and bears no constant relation to the
action of epinephrine. Whether the same is true of the effects upon
the intact uterus in situ has not been determined, for no experiments
have as yet befen made with animals whose uteri are relaxed by
epinephrine.
d. Urinary tract. Hofbauer (1928) tested the effect of ephedrine
upon the isolated ureter of the pig: he found that the rate of contrac-
tions of both circular and longitudinal muscle was increased by ephe-
drine, and that it was occasionally possible, by means of ephedrine,
to restore contractions after they had been arrested by sodium glyco-
cholate; the effects of epinephrine were qualitatively the same but
it was a much more powerful stimulant than ephedrine. His results
have been confirmed by Roth on the dog's ureter.
40 K. K. CHEN AND GAEL P. SCHMIDT
Macht (1929) studied the effects of ephedrine upon the trigonal
and fundus portions of the urinary bladders of rabbits, cats and rats.
It has been shown repeatedly that epinephrine causes contraction of
the trigone and relaxation of the fundus. Ephedrine caused con-
traction of both portions. Liljestrand (1927) obtained the same
results with the rabbit's bladder.
e. Bronchi. One of the most useful therapeutic actions of ephe-
drine is its ability to relieve or to prevent the paroxysms of asthma.
Animal experimentation has shown from the start that ephedrine,
like epinephrine, is able to relax bronchial spasm induced by various
poisons. Amatsu and Kubota (1917) were the first to demonstrate
this effect in rabbits whose bronchi had been thrown into spasmodic
contraction by means of pilocarpine, muscarine, or peptone. They
also found that isolated bronchial muscle of the cow was relaxed
by ephedrine, even in such low concentration as 1 in 80,000. These
results led them to recommend ephedrine in the treatment of asthma.
Chen and Schmidt (1924) observed relaxation of the bronchial spasm
produced by physostigmine in a dog, and stated that the effect of
ephedrine was weaker than that of epinephrine. Kreitmair (1927),
Villaret, Justin-Besancon, and Vexenat (1929), and Swanson (1929)
have confirmed these results by various methods, but Halsey (1928)
reported only exceptional bronchodilatation by ephedrine. It is
generally agreed that ephedrine may fail to relax bronchial spasm
when epinephrine is effective. It is generally assumed that the
bronchodilator action of ephedrine is analogous to that of epinephrine
and is due to stimulation of sympathetic nerves, which are inhibitory
to this muscle; this has not, however, been definitely proved to be
true. The effect is largely if not wholly peripheral, for it is elicited
in excised tissue and in pithed animals.
5. Action on secretions
a. Saliva. Grahe in 1895 studied the action of ephedrine and
pseudoephedrine on the submaxillary flow in a dog and found that the
first intravenous injection has no effect while repeated injections
gradually diminish the flow. Chen and Schmidt, and Chen investi-
gated the same question in a series of dogs. In anesthetized animals,
ephedrine in a dosage of 1 to 2 mgm. per kilogram produces inconsistent
EPHEDEJNE AND RELATED SUBSTANCES 41
results. Occasionally it increases the submaxillary flow, and this
occurs in spite of atropinization, but in the majority of cases it has
no effect. Larger doses (25 mgm. per kilogram or more) in non-
anesthetized dogs may cause profuse salivation. When a dose
slightly below the M.L.D. is administered, the increase in salivary flow
is a constant feature.
b. Gastric secretion. Chen in Lim's laboratory studied the action
of ephedrine on the gastric secretion in dogs with Pavlov or Heiden-
hain pouches. Ephedrine injected subcutaneously unmistakably in-
creases the gastric secretion both in volume and in acidity, although
to only a small extent. There is no difference between the Heidenhain
and Pavlov preparations.
c. Pancreatic secretion. In anesthetized dogs with a cannula in the
pancreatic duct ephedrine, given intravenously, does not change the
pancreatic secretion, as shown by Chen. In non-anesthetized dogs
with a pancreatic fistula, subcutaneous injections of ephedrine also
gave negative results. Fonseca and Trincao (1928) reported that
ephedrine caused decrease in pancreatic secretion.
d. Intestinal secretion. Dogs with Thiry-Vella fistula do not show
any response in their intestinal secretions to the subcutaneous injec-
tion of ephedrine, as reported by Chen.
e. Bile. In acute experiments with anesthetized dogs, there is no
demonstrable alteration of bile flow after ephedrine injected intra-
venously (Chen) . The same can be said for non-anesthetized animals
with a pancreatic biliary fistula when ephedrine is injected subcu-
taneously. Kreitmair, using larger doses (50 to 100 mgm. per dog),
found an increase of bile flow from the biliary fistula, with a reduction
of the dry matter. The increase in volume continues for more than
three days.
/. Sweat. Chen and Schmidt determined the sweat secretion of an
anesthetized cat and could not detect any increase after ephedrine
was injected into the paw. Kreitmair arrived at the same conclusion.
In men a therapeutic dose of ephedrine occasionally produces
diaphoresis. It is interesting to note that perspiration caused by the
use of Ma Huang, firmly believed in by the Chinese and described by
Li Shih-Cheng in his Pentsao Kang Mu, although not experimentally
proved in animals, has been clinically confirmed in many reports.
42 K. X. CHEN AND CARL P. SCHMIDT
g. Lymph. With the cooperation of M. Kayumi, Chen and Schmidt
studied the influence of ephedrine on lymph flow, collected from the
thoracic duct of anesthetized dogs. It regularly causes an increase
in lymph, which reaches its maximum about 15 minutes after the
intravenous injection.
h. Urine. In anesthetized dogs the urine flow appears to follow
the plethysmograph of the kidney volume, as observed by Chen and
Schmidt. There is suppression during the primary vasoconstriction,
but an increase during the secondary dilatation. After repeated
doses the urine is invariably suppressed. Intact rabbits which receive
daily intravenous injections of ephedrine show a well marked diuresis.
Starr, cooperating with T. G. Miller, studied the output of urine in a
series of 16 men, in correlation with the systolic blood pressure. He
divided his results into three groups: (1) those showing a rise of blood
pressure without diuresis and with albuminuria; (2) those showing no
rise in pressure with no diminution of urine and no albuminuria; and
(3) those showing a rise of pressure with diuresis and albuminuria.
The occurrence of albumin in the urine is transitory, for it disappears
when the effect of the ephedrine wears off. In those that show an
increase in pressure but no diuresis, the albuminuria is due to renal
vasoconstriction, while in those that show rise in pressure and increase
in urinary output, it is probably due to the alternate constriction and
dilatation of the glomerular functional units. Kreitmair observed
diuresis on himself after the ingestion of 50 mgm. of ephedrine, lasting
for 2 to 3 hours. Gradinescu and Marcu also call attention to the
fact that the variation in urine flow depends on vascular changes.
6. Action on the blood
a. Blood cells. Hess reported leucocytosis after ephedrine, reaching
its maximum at the same time as the blood pressure attains its highest
level. Marcu and Petresco studied the blood changes in men on
intravenous injection of ephedrine. A dose of 20 mgm. increases the
leucocytes within the first five minutes, lasting for more than one hour
and 40 minutes. The leucocytosis consists chiefly of lymphocytosis.
The red blood corpuscles are also increased, with a corresponding
increase in hemoglobin. The maximum is attained in about 40 min-
utes. Ephedrine in a dosage of 60 mgm., given intravenously, pro-
EPHEDRINE AND BELATED SUBSTANCES 43
duces a leucocytosis and erythrocytosis which, lasts for two hours or
longer. These changes, the authors believe, indicate a concentration
of the blood. Pathological conditions apparently modify this reaction.
Thus, Marcu and Petresco observed with a dose of 20 mgm. intra-
venously a decrease of red blood corpuscles and leucopenia in a case
of Addison's disease, and leucopenia but erythrocytosis in a case of
Hodgkin's disease. Binet, Arnaudet, Fournier and Kaplan observed
an increase in platelets hi addition to erythrocytosis and leucocytosis
hi chloralosed dogs. The maximal increase in the platelets is reached
at the end of 5 to 15 minutes after the intravenous injection of 3 mgm.
of ephedrine per kilogram. According to these investigators the
increase in the formed elements of the blood is due to contraction of the
spleen, for splenectomy prevents this reaction and previous adminis-
tration of yohimbine, which paralyzes the contractors of the spleen,
abolishes such a response.
b. Blood chemistry. Chen and Schmidt studied the effect of ephe-
drine on the blood sugar in two anesthetized dogs. Their results
were inconclusive. Negative or doubtful results were obtained by
T. G. Miller in men, by Hess in men, by Kreitmair in rabbits, by
Rudolf and Graham in diabetics, by Tu in men, and by Haintz in
men. Hyperglycemia may be produced in animals by doses larger
than the pressor ones. Thus, Nagel determined the hyperglycemic
dose in rabbits to be 25 mgm. per kilogram, injected intravenously.
Wilson found it to be 10 to 15 mgm. per kilogram (intravenously
or subcutaneously) in dogs, and 20 to 30 mgm. per kilogram (intra-
venously) in rabbits. According to Nitzescu, hyperglycemia occurs
in dogs when they are in full digestion but is absent when they
are previously starved. The doses he used were 0.5 to 3.0 mgm.
per kilogram, given intravenously. The simultaneous administra-
tion of glucose and ephedrine does not increase the hyperglycemia
produced by glucose alone but lengthens its duration. A limited
increase in blood sugar in men with therapeutic doses (5 to 100 mgm.)
of ephedrine given orally was observed by Pollak and Rabitschek and
by Lublin. Radoslav and Stolcesco administered ephedrine to men by
intravenous injection. Doses of 5 to 90 mgm. produce a diphasic
reaction a primary hyperglycemia followed by hypoglycemia. The
blood sugar returns to normal in about two hours.
44 K. K. CHEN AND CARL P. SCHMIDT
After the intravenous injection of 20 mgm. of ephedrine, the serum
albumin increases to the extent of 10 parts per thousand and returns
to normal in 20 minutes, while the globulins are increased for two
hours, as determined by Marcu and Petresco. The concentration of
albumins and globulins occurred in both healthy individuals and in a
case of Addison's disease and another of Hodgkin's disease. Unlike
epinephrine, ephedrine does not raise the peptidase titer of the rabbit's
serum (Pfeiffer and Standenath).
7. Action on metabolism
a. Metabolic rate. T. G. Miller reported an increase in metabolic
rate in 4 cases with 100 to 125 mgm. of ephedrine injected subcu-
taneously. Rowntree and Brown also studied the calorigenic effects
of ephedrine, given by mouth, in several diseased conditions. In 3
cases of Addison's disease there was an increase in metabolic rate in
two but a decrease in the third. In a case of questionable Addison's
disease and 4 cases of hypotension, an increase was also demonstrated.
The effects seem to be transitory and an hour afterwards there may be
a tendency to a fall of metabolic rate. A patient with endocrine
obesity showed a decrease of 1 1 points with SO mgm., but with 100 mgm.
there was an increase of 13 points in 3 hours. In a case of pituitary
tumor there was a demonstrable increase of the basal metabolic rate
after 50 mgm. of ephedrine had been given. In rabbits, Duliere
observed only inconsistent changes in metabolism after the adminis-
tration of ephedrine.
b. Gaseous exchange. Schmidt (1928) demonstrated that ephedrine
increases both cerebral 2 consumption and COa liberation. Wilson,
Pilcher and Harrison, and Halsey, Reynolds and Blackberg also
observed an increase in 2 consumption with a tendency of the alveolar
CC>2 to fall. After giving fructose or glucose, the R.Q. is always
greater than 1, but if ephedrine and fructose are given at the same time
the R.Q. becomes less than 1. According to Lublin, this means the
inhibition of fat formation by ephedrine. In rabbits, Dulie're con-
stantly observed a decrease of R.Q. following the intravenous injec-
tion of ephedrine.
c. Body temperature. With toxic doses Miura in 1887 reported an
elevation of temperature in dogs, rabbits and mice. Like epinephrine
EPHEDRINE AND RELATED SUBSTANCES 45
and jS-tetrahydronaphthylainine, ephedrine, according to Hashimoto
(1915), slightly raises the body temperature (0.5 to 0.7C.) in normal
rabbits and it produces fever in those animals whose heat centers have
been punctured. The dose for the production of this response is 20
mgm. per kilogram. Notwithstanding, Suzuki recently reported a
slight fall in rectal temperature in rabbits, either normal, adrenalec-
tomized or with the splanchnic nerves sectioned, using a dose of 30
mgm. per kilogram, given intravenously.
8. Action on the central nervous system
Ephedrine appears to stimulate the central nervous system. Airila
in 1913 showed that chloralized rabbits can be awakened temporarily
by an intravenous injection of ephedrine (10 to 20 mgm.). Morita in
1915 obtained similar results in rabbits whose cerebral hemispheres
had been removed, and believes that the stimulation is subcortical.
In the squid, Loligo pealii, doses of 5 mgm. or more make it turn
blood-red within half an hour, the color persisting for twelve to twenty
hours or more, as observed by Nadler. Oral administration and injec-
tion into the circulation via the heart likewise produce this dark
coloration. The author attributes this change to stimulation of the
central nervous system. In men moderate doses of ephedrine some-
times cause tremor, nausea, and insomnia, which in all probability is
due to stimulation of the central nervous system. C. F. Schmidt
obtained evidence that ephedrine directly stimulates the respiratory
center. In anesthetized dogs, Johnson and Luckhardt found that
ephedrine in large doses, injected intravenously or subcutaneously,
causes a marked increase in the reflex excitability of the spinal cord,
as measured by the knee jerk. The action is not dependent on any
influence of the higher centers on the cord nor due to the hemodynamic
action of the drug, since the increase in excitability of the cord out-
lasts the rise of blood pressure.
9. Action on the peripheral nerves and voluntary muscles
The action of ephedrine on the motor nerves has been studied by
Read and Lin. They conclude that ephedrine potentiates the action
of novocaine on the frog's sciatic nerve. By the addition of 0.005
per cent of ephedrine to a 1 per cent solution of novocaine the tune
required for blocking of the motor impulse is lessened by 80 per cent.
46 K. K. CHEN AND CARL F. SCHMIDT
Ogata (1920) states that ephedrine has no local anesthetic action,
meaning that it is devoid of action on the sensory nerve endings.
Read and Lin, on the other hand, claim that a mixture of ephedrine
with epinephrine and potassium sulphate can produce, by the wheal
method, local anesthesia equal in intensity to that produced by a
mixture of similar proportions and strengths of novocaine, epinephrine
and potassium sulphate.
Amatsu and Kubota (1917) studied the effect of ephedrine on the
frog's gastrocnemius muscle. They found that a 0.1 per cent solu-
tion raises the threshold of stimulation (electric) and produces irregu-
lar contractions on repeated stimulation with a current of constant
strength, instead of a gradual fatigue curve.
10. Mode of action
In a previous review of this subject, Chen and Schmidt (1926)
divided the actions of ephedrine into three categories: the thera-
peutically useful ones, which are due to peripheral sympathomimetic
effects; the stimulant action upon the central nervous system; and the
depressant action upon heart muscle. The second and third types of
action were said to be exerted as a rule only by excessive dosage and
were regarded as undesirable or dangerous . Subsequent developments
have necessitated a modification in this characterization in so far as
the central nervous effects are concerned, for it is now certain that
they may be elicited by therapeutic doses in some individuals at least,
and may be useful in combating the action of narcotic poisons,
particularly upon the respiratory center. The action of ephedrine
upon the brain cells has not been analyzed, but it appears to be com-
parable with that of caffeine (Schmidt, 1928). The depressant action
upon heart muscle is essentially similar to that of any other myocardial
depressant, and the only practical importance of this type of effect
is that it imposes 1fmit.af.inns upon the therapeutic usefulness of the
drug. There is no disagreement among various workers with respect
to the central nervous and myocardial depressant effects of ephedrine.
The peripheral actions of ephedrine, which are of greatest interest
to the clinician, are not so simply disposed of. The earliest workers
in this field (Amatsu and Kubota, 1917; To, 1921; Chen and Schmidt,
1924) were impressed with the obvious similarity of the effects of
EPHEDRINE AND RELATED SUBSTANCES 47
ephedrine to those of epinephrine, and concluded that ephedrine is
a sympathomimetic substance. These effects include mydriasis with
preservation of light and accommodation reflexes, broncho-dilatation,
cardiac acceleration and augmentation, vasoconstriction, inhibition
of gastro-intestinal motility (hi many cases), hyperglycemia, and
occasional secretion of saliva by the atropinized submaxillary gland.
In fact no other explanation is possible for these effects, taken as a
whole. The question is not whether ephedrine produces sympa-
thomimetic effects but whether its important effects are due wholly
or even largely to such actions. During recent years considerable
evidence having been obtained, by a number of investigators, that the
peripheral effects of ephedrine differ qualitatively in some respects from
those of epinephrine, the conclusion has been drawn that ephedrine
owes some of its effects to direct excitation of smooth muscle, irre-
spective of sympathetic innervation. Those who have concluded that
ephedrine acts at least partly upon muscle fibers include Nagel (1925),
De Eds (1927), De Eds and Butt (1927), Pak and Read (1928),
M6hes and Kokas (1929) , and Halsey (1928) . The question has more
than theoretical importance, for if this conclusion is fully justified
ephedrine should be looked upon as a drug with the clinical usefulness
of pituitrin rather than that of epinephrine.
Decisive evidence upon a point of such fundamental importance as
this might well be sought in investigations of the action of the drug
upon simple organisms or preparations. The only pertinent investi-
gation of the action of ephedrine upon a lower form of lif e is that of
Nadler (1927), which has already been discussed (page 16). He
concluded that ephedrine is essentially sympathomimetic, not mus-
culotropic. However, the organism used by him is relatively complex,
and the exact mechanism of the responses studied has not been estab-
lished. The results seem to the reviewers to be suggestive but not
conclusive evidence upon the point at issue.
A relatively uncomplicated preparation of mammalian tissue is the
plexus-free strip of small intestine of the cat (Gasser: Journ. Phar-
macol. Exper. Therap., 1926, xxvii, 395). This apparently has not
been used to test the musculotropic power of ephedrine. One of the
reviewers (S.) recently tested 12 such preparations with ephedrine.
In no case was there any trace of stimulation, and depression was more
48 Z. K. CHEN AND CARL P. SCHMIDT
commonly observed with ephedrine than with epinephrine. The
number of observations was small, but all the preparations were active,
and it is reasonable to suppose that a conspicuous musculotropic action
would have been disclosed if present. These results lend no support
to the conception that ephedrine is musculotropic. In fact they
suggest rather that the direct action of ephedrine upon smooth
muscle is a depressant one, since ephedrine was more uniformly in-
hibitory than epinephrine.
Another suitable test-object would be blood vessels which are not
conspicuously affected by epinephrine, such as those of the coronary,
cerebral, and pulmonary areas. The only available information
concerning the action of ephedrine upon such structures is the state-
ment of Chen and Schmidt (1924) that coronary outflow from the
perfused mammalian heart was augmented, never decreased, by
ephedrine. This is far from conclusive evidence upon the point at
issue, since rate and force of cardiac contractions were also increased.
However, pituitrin regularly causes very marked reduction in coro-
nary flow in such preparations. If the latter is regarded as a repre-
sentative example of the effect of musculotropic agents, the result
with ephedrine indicates that the latter is not musculotropic. Further
information concerning the actions of ephedrine upon coronary,
cerebral, and pulmonary vessels is highly desirable.
The contention that ephedrine is capable of exerting stimulant
effects upon smooth muscle fibers irrespective of their innervation is
based upon observations of two general sorts. These are, the influence
of certain other substances (ergotoxine, yohimbine, cocaine, insulin)
upon the circulatory effects of ephedrine, and the action of ephedrine
upon various preparations of isolated smooth muscle. None of the
evidence so far obtained by these procedures appears to be decisive.
a. Circulatory responses. The fact that ergotoxine (ergotamine)
leads to a reversal of the blood pressure effect of epinephrine has led to
the employment of ergotoxine as a means of discriminating between
sympathomimetic and musculotropic effects on the part of other drugs
which raise blood pressure. Other things being equal, a given quan-
tity of the agent being tested should cause a fall in pressure after
ergotoxine if it is sympathomimetic, while if its effects are unaltered
by ergotoxine it must be musculotropic.
EPKEDJONE AND BELATED SUBSTANCES 49
Among those who have tested the influence of ergotoxine upon the
pressor response to ephedrine are Nagel (1925), Kreitmair (1927),
De Eds and Butt (1927), Chen (1928), and Curtis (1929). All found
that the pressor effect of ephedrine was reduced by ergotoxine, but
Curtis was the only one who reported complete absence of such effect
or an actual reversal after ergotoxine, though a reversal of epinephrine
effects was clearly demonstrated in every case. Curtis attributed his
success to the use of smaller quantities of ephedrine and larger doses
of ergotoxine than had been used by his predecessors. Until this is
confirmed, however, it appears proper to conclude that while ergo-
toxine may diminish or even prevent the pressor effect of ephedrine,
an actual reversal, similar to that of epinephrine, is not the charac-
teristic result.
These results have been interpreted as strong evidence in favor of a
musculotropic action by ephedrine, but such conclusion is by no means
obligatory, for two reasons: First, as has been emphasized repeatedly
(Chen and Schmidt 1924, 1926; Chen and Meek, 1926; Chen, 1928;
Curtis, 1928), the pressor effect of ephedrine is due more to increased
cardiac action than to vasoconstriction, while in the case of epi-
nephrine the reverse is true. It is well known that ergotoxine, in
quantity sufficient to paralyze vasoconstrictor receptors and therefore
to produce the epinephrine reversal, has much less effect upon the
cardiac accelerator system (see Chen, 1928). It is through the latter
system that ephedrine exerts much of its influence upon blood pressure.
Consequently one need not expect the pressor effect of ephedrine to
be abolished by ergotoxine until the latter is present in sufficient
quantity to paralyze the cardiac accelerator system, and Curtis (1928)
states that with sufficiently large doses of ergotoxine the pressor effect
of ephedrine can be completely prevented. These objections to the
conclusions derived from the ergotoxine experiments have been raised
by Chen (1928) and by Curtis (1928).
Second, it must be remembered that the epinephrine reversal by
means of ergotoxine presupposes a powerful stimulant action by
epmephrine upon vasodilator nerves, but there is no reason to believe
that ephedrine possesses such an action. For, as has already been
pointed out (page 20), the smallest effective doses of ephedrine pro-
duce only a rise in blood pressure, and as the effects of ephedrine wear
50 K. Z. CHEN AND CAKL P. SCHMIDT
away blood pressure returns to normal, not to a subnormal level.
One of the outstanding advantages of ephedrine over epinephrine as a
constrictor of nasal blood vessels is the absence of after-dilatation in the
case of ephedrine. There is no decisive evidence upon this point,
but these observations suggest strongly that the effects of ephedrine
upon blood vessels are dominantly if not exclusively motor (con-
strictor), while in the case of epinephrine inhibitory (dilator) actions
are conspicuous (Dale, 1906). The present situation is therefore
practically identical with that encountered by Barger and Dale (1910)
in their investigation of sympathorm'm etic bases. They found that
ergotoxine reduced but did not reverse the pressor effect of amino-
aceto-catechol or d^amino-ethanol-catechol, while it led to complete
reversal of the effects of methylamino-catechol or dZ-epinephrine.
The difference was attributed to a greater predominance of inhibitory
(vasodilator) actions on the part of the latter substances, though the
effects of all were regarded as purely sympathomimetic. The failure
of ephedrine to produce a fall in blood pressure after ergotoxine cannot
therefore be regarded as proof that ephedrine is not sympathomimetic.
The above considerations probably apply also to the effects of
yohimbine, which Raymond-Hamet (1927) found to exert an in-
fluence like that of ergotoxine: the pressor response to epinephrine
was inverted, while that to ephedrine was only reduced.
Cocaine is another agent which has been used to determine whether
a pressor drug is sympathomimetic or musculotropic, as a result of
the work of Tainter and Chang (1927). They found that a small dose
of cocaine augmented the pressor effect of epinephrine, but reduced
or abolished that of tyramine, the latter being regarded as musculo-
tropic. De Eds (1927) and Pak and Read (1928) found that cocaine
also reduced the pressor effect of ephedrine. Chen (1928) was unable
to confirm this conclusion; he believed that the result was due simply
to the fact that a second dose of ephedrine is less effective than the
first even if no cocaine is given between them. However, Tainter
(1929) has recently shown that cocaine, in dosage which augments
the pressor effect of epinephrine, may reduce or abolish that of
ephedrine.
These results have been interpreted as evidence that ephedrine is
not sympathomimetic, but musculotropic, in its circulatory effects.
EPHEDEJNE AND RELATED SUBSTANCES 51
Yet, as far as the reviewers are aware, no evidence has been presented
that cocaine augments the effectiveness of sympathetic nerve excita-
tion by anything but epinephrine, and this particular effect might
well be a drug synergism, peculiar to epinephrine, with no relation to
sympathetic stimulation per se. Nor is there any evidence that reduc-
tion of pressor effectiveness by cocaine is an index of musculotropic
action. In fact Tainter has recently reported (XIII International
Physiological Congress) that cocaine neither increases nor decreases
the effectiveness of barium and pituitrin. If one grants the validity
of the assumption that any agent, to be sympathomimetic, must
duplicate all of the peculiar effects of epinephrine, the cocaine test,
like the ergotoxine one, indicates that ephedrine is neither sympatho-
mimetic nor musculotropic.
Another agent which modifies the circulatory response to epine-
phrine much more than that to ephedrine is insulin. Cs6pai and
Pinter-Kovats (1927) found that insulin prevents the pressor effect
of epinephrine, but not that of ephedrine. The significance of this
observation, apart from an indication that the circulatory effects of
ephedrine are in some way different from those of epinephrine, is
unknown to the reviewers.
It seems to the reviewers that these various circulatory responses,
in the present state of our knowledge, can show only whether a sub-
stance does or does not elicit certain effects that are characteristic of
epinephrine. If they are to be used for the purpose of determining
whether a new drug is or is not likely to be of practical value as a
substitute for epinephrine, one must consider the fact that ephedrine,
which, according to all these tests, is not epinephrine-like, has amply
proved its practical value as a substitute for epinephrine . The review-
ers do not believe, therefore, that absence of epinephrine-like responses
in the ergotized or cocainized animal can be regarded as convincing
evidence of lack of sympathomimetic action on the part of other
substances.
b. Effects upon smooth musfle. In considering the work that has
been done upon this subject (pages 33-40) it was pointed out that
the effects of ephedrine upon uterus and bladder fundus appear to be
uniformly stimulant, though epinephrine may be depressant; that
the surviving small intestine may be stimulated or depressed by ephe-
52 K. K. CHEN AND CARL F. SCHMIDT
drine though invariably depressed by epinephrine. Apparently the
only smooth muscles that are uniformly relaxed in vitro by ephedrine
are found in the bronchi, the sphincter pupillae and the uterus of
the albino rat. While it is somewhat difficult to see why a substance
which acts directly upon smooth muscle fibers should stimulate some
and depress others, it is equally difficult to see why a substance which
owes its effects to sympathomimetic actions should so frequently lead
to contraction of structures that are relaxed by epinephrine.
Considering first the isolated small intestine, however, a reason for
this discrepancy is readily found in an action by ephedrine upon motor
ganglia as well as inhibitory endings. Chen and Schmidt (1924, fig. 5)
showed a tracing which illustrated the epinephrine-like effect of ephe-
drine after the ganglia had been paralyzed with nicotine. This proce-
dure has recently been repeated by one of the reviewers (S.) with pre-
parations made from the small intestines of cats, dogs, and rabbits, and
the results have been uniformly like the earlier ones. In no instance
did ephedrine fail to exert a typical sympathomimetic effect after
nicotine, while stimulation of strips from adjacent parts of the bowel
was frequently observed when ephedrine was applied before nicotine.
Reference has also been made (page 47) to the uniform absence of
stimulant effect by ephedrine upon plexus-free preparations of small
intestine. It appears, therefore, that the intestinal effects of ephe-
drine consist in a combined stimulation of ganglia (plexus of Auer-
bach), which causes increased motility, and of inhibitory sympathetic
endings. When the ganglionic action is excluded by means of nico-
tine or removal of the plexus, the sympathomimetic action is clearly
and uniformly manifested.
In the case of the uterus, the corresponding information is not
available. Ephedrine is almost invariably stimulant to isolated uteri,
whether epinephrine is stimulant or inhibitory, and this argues in
favor of the musculotropic or pituitrin type of effect. Ergotoxine
has been added to the solution in which the uterus was immersed,
by Nagel (1925), Kreitmair (1927), De Eds and Butt (1927), Reinitz
(1928), and Curtis (1929). This substance should paralyze motor
sympathetic nerve endings, and uteri so treated were uniformly
inhibited by epinephrine, but all observers except Curtis reported that
ergotoxine did not prevent the stimulant action of ephedrine: he
EPHEDRTNE AND BELATED SUBSTANCES S3
stated that by means of large doses of ergotoxine the effects of ephe-
drine could be prevented though never reversed. It may be, there-
fore, that the effects of ephedrine upon the isolated uterus are indeed
sympathomimetic, but are exerted mainly if not exclusively upon
motor parts of the .system, the inhibitory parts being affected much
less or not at all an analogy to the effects upon blood vessels.
The stimulant action of ephedrine upon the intestine being appar-
ently similar to that of nicotine (i.e., ganglionic), a similar action upon
the uterus may be regarded as a possibility. This has not been investi-
gated. It is not possible at present to make a plexus-free preparation
of uterine muscle. The effects of nicotine upon the uterus (virgin
organ of the cat) were found by Barger and Dale (1910) to be inhibi-
tory in vivo but stimulant in vitro. In current terminology, this
would imply that nicotine is sympathomimetic in vivo, musculotropic
in vitro. Barger and Dale, however, believed that the inhibitory effect
in vivo was due to stimulation of sympathetic ganglia which rapidly
lose their sensitivity when the uterus is excised. They did not explain
the stimulant action in vitro, but it can scarcely be called musculo-
tropic because nicotine does not stimulate ganglion-free smooth muscle
of the intestine (Gasser, 1926).
The situation appears to be rather obscure, and the reviewers
believe that the true explanation of the uterine effects of ephedrine
can be given only when more is known about the intrinsic innervation
of the organ.
The situation with respect to the urinary bladder muscle is much
the same. The only data are those of Macht (1929) and Liljestrand
(1927) (see page 40, above). These effects of ephedrine are like
those of pituitrin, unlike those of epinephrine. The results are
equivocal evidence for or against a musculotropic action by a drug that
appears to affect certain ganglia as well as endings, and to stimulate
motor sympathetic nerves more powerfully than inhibitory ones.
It has been claimed by Fujii (1925), Kreitmair (1927), Reinitz
(1928), and Marcu and Savulesco (1928) that ephedrine stimulates
both parasympathetic and sympathetic nervous systems, but the
evidence presented hi support of this contention is inconclusive.
Fujii (1925) believed that the constrictor action of ephedrine upon
perfused blood vessels of the frog was exerted through parasympathetic
54 Z. K. CHEN AND CARL F. SCHMIDT
nerve structures, since it was absent when atropine was added to the
perfusion fluid; however, it is well known that atropine has a vaso-
dilator action of its own hi such circumstances (Cushny, Textbook of
Pharmacology, 1928, p. 347). Fujii, as well as Reinitz (1928), found
that atropine prevented the stimulant action of ephedrine upon the
isolated uterus, but this has not been the case in the experience of the
reviewers. Kreitmair (1927) reported that the stimulant action of
ephedrine upon isolated intestine was prevented or abolished by
atropine, but this is denied by Reinitz (1928). M6hes and Kokas
(1929) claim that atropine partly prevents the depressant action of
ephedrine upon the perfused frog's heart, but this is opposed to the
results of Fujii (1925) and Kreitmair (1927).
Apparently there is no better agreement concerning the preferential
action of ephedrine, assuming that it acts upon both nervous systems.
Kreitmair (1927) believed that minimal doses affected only the
sympathetic, and that the parasympathetic was influenced only by
relatively high concentrations. Marcu and Savulesco (1928), how-
ever, claim that minimal quantities stimulate the parasympathetic
preferentially, while with large doses sympathetic stimulation domi-
nates the picture, the effects of intermediate dosages being antagonistic
and therefore inconstant or absent.
Further work is needed before this point can finally be settled. The
conflicting opinions indicate that ephedrine certainly has no con-
spicuous pilocarpine-like effects, and Reinitz (1928) claimed that it
actually has an atropine-like effect upon the intestine. There is no
reason therefore for employing ephedrine as a parasympathetic
stimulant.
As to the exact site of ephedrine actions, there is little information.
Chen and Schmidt (1924) pointed out that ephedrine was able to
dilate the pupil whose sympathetic (pupillo-dilator) innervation had
degenerated following extirpation of the ganglion, while cocaine was
ineffective. They concluded that the point of action of ephedrine was
apparently peripheral to that of cocaine, the absence of effect from the
latter indicating degeneration of the structures upon which it acted.
Marcu and Gheorghiu (1927) have recently shown that ephedrine is
able to increase the rate of a heart whose accelerator nerves have
degenerated following removal of the ganglia: this also points to an
EPHEDRINE AND BELATED SUBSTANCES 55
action upon structures peripheral to the finest nerve fibrils, which
degenerate when the ganglion is removed. On the other hand, there
is no good reason to attribute any of the peripheral effects of ephedrine
to direct action upon effector substance (muscle fibers, gland cells).
This makes the situation comparable to that encountered with epineph-
rine, and leads to the conclusion that ephedrine likewise acts upon
hypothetical myoneural junctions.
However, there is reason to believe that the myoneural junctions
affected by ephedrine are not the same as those affected by epineph-
rine, in the pupillo-dilator system at least. Reference has already
been made (page 34) to a few observations which indicate that
denervation does not sensitize the pupil to ephedrine, but rKTninishes
its effectiveness. Should this be confirmed, it would suggest that
some of the ephedrine receptors degenerate after denervation, as
all of those for cocaine appear to do. This would imply that the
point of action of ephedrine upon the pupil is at least partly central
to that of epinephrine, and partly peripheral to that of cocaine.
It has been suggested by several workers that many of the pe-
culiarities in the action of ephedrine could be explained on the basis
of an increased secretion of epinephrine by the suprarenal glands as a
result of absorption of ephedrine. This would account for the effects
of ephedrine upon metabolism, blood sugar, etc. and for epinephrine-
like effects upon small intestines in situ, not in vitro. The question
has a practical significance in connection with the treatment of Addi-
son's disease.
Evidence upon this point is somewhat contradictory. Nagel (1925)
reported that suprarenalectomy did not reduce, but seemed to augment
the pressor effectiveness of ephedrine. Chen and Schmidt (1926)
stated that removal or ligation of the suprarenal glands did not
diminish, the pressor effect of ephedrine. It seems dear, therefore,
that the circulatory effects of ephedrine are not due wholly to stimula-
tion of the suprarenal glands.
On the other side, Suzuki (1928) found that a given dose of ephedrine
produced a smaller and briefer rise in blood pressure in unanesthetized
rabbits whose splanchnic nerves had been cut or whose suprarenal
glands had been removed, than it did in normal controls. Section of
the splanchnics reduced the effectiveness of ephedrine more than
56 K. K. CHEN AND CARL F. SCHMIDT
suprarenalectomy did, which suggests that part of the influence of
ephedrine upon the suprarenals must be exerted through the nervous
system. Gradinesco and Marcu (1927) found that a small quantity
(0.1 to 0.2 cc. of a 1 per cent solution) of ephedrine, injected directly
into the suprarenal capsules of dogs anesthetized with chloroform,
caused a marked and sustained rise in blood pressure. To reproduce
the effect by intravenous injection of ephedrine, 7 to 10 tunes the
quantity was required. They reported also that removal of the
supra reiuils led to marked reduction in the pressor effectiveness of
ephedrine, which is opposed to the results reported by Nagel (1925)
ami by Chen and vSchmidt (1926). Houssay and Molinelli (1927)
employed a crosscd-circulation (suprarenalo-jugular anastomosis)
preparation in dogs. They reported that large doses (40 to SO mgm.
per kilogram) of ephedrine caused increased suprarenal output in six
out of ten attempts. The effect was abolished by section of the
splanchnic nerves, and was therefore presumably due to an action
ujjon the nervous system- - a conclusion which is like that of Suzuki
( 1928). It must be noted, however, that the doses of ephedrine used
by Suzuki (30 mum. per kilogram) and by Houssay and Molinelli
(40 to 50 mgm. per kilogram) are so close to the toxic level that
nervous effects are to be expected. Only the results of Gradinesco
and Marcu point to the possibility of a suprarenal stimulation by
small quantities of ephedrine, and these could scarcely be regarded as
small when they were injected directly into the gland.
It appears that ephedrine is probably capable of stimulating the
suprarenal glands, but whether the effect can be elicited by ordinary
doses or is exerted only by toxic quantities has not been determined.
It is certain that an action of this sort cannot account for all of the
effects of ephedrine, for some of these are elicited upon local application
(pupil), others are demonstrable in excised tissues (heart, perfused
blood vessels, isolated smooth muscle) . Clinical experience has shown
that ephedrine has no beneficial influence upon the course of Addison's
disease. However, since the pathological process is a progressive one
which ephedrine could not be expected to check, this does not prove
that the drug had not stimulated the residual normal tissue.
The above discussion concerning the mode of action of ephedrine
can be summarized as follows:
EPHEDMKE AND BELATED SUBSTANCES 57
There is no valid evidence that ephedrine is capable of directly
stimulating any smooth muscle, while there is some direct evidence
that it cannot do so (chromatophores of the squid, plexus-free and
nicotinized intestine, albino rat uterus).
There is reason to suspect that ephedrine stimulates motor sympa-
thetic nerves more powerfully than inhibitory ones when both are
present in the same tissue (blood vessels, perhaps uterus and bladder),
and possibly the inhibitory set is not affected at all by ephedrine; but
when the sympathetic innervation is purely inhibitory ephedrine seems
uniformly to stimulate it (bronchi, isolated sphincter pupillae, isolated
intestine nicotinized, plexus-free, sometimes intact).
Ephedrine appears to stimulate certain ganglia (cardiac accelerator,
plexus of Auerbach), but whether this is a general effect or is limited
to these localities has not been determined.
Its peripheral effects have not been shown definitely to involve the
parasympathetic system, unless the plexus of Auerbach is regarded
as a part of the latter. Ephedrine certainly has no conspicuous
pilocarpine-like actions, and its important effects are not prevented
by atropine.
There is no conclusive evidence that ordinary therapeutic doses of
ephedrine stimulate the suprarenal gland, or that any of the effects
of such doses are so caused.
The point of action of ephedrine upon the pupil appears to be central
to that of epinephrine, peripheral to that of cocaine, i.e., peripheral
to the finest anatomically demonstrable nerve fibers.
As to the precise mode of action, one can, in the present state of our
knowledge, only characterize it by one of two general, descriptive
terms sympathomimetic or musculotropic. The first, according to
the definition of Barger and Dale (1910), who introduced it, implies
that the effects of the drug are analogous to those of excitation of the
sympathetic nervous system by other agencies, such as electrical
stimulation. The second is currently used to designate a group of
drugs and poisons which stimulate smooth muscle indiscriminately
and irrespective of its innervation. The outstanding example of the
first group is epinephrine, while of the second pituitrin and barium
are representative. In the recent investigations of ephedrine it has
been tacitly assumed that epinephrine actions are the absolute
58 K. K. CHEN AND CAUL F. SCHMIDT
standard of sympathomimetic effects. But tlie originators of the
term (Barger and Dale, 1910) pointed out that in some respects the
effects of epinephrine are unlike those of electrical excitation of the
sympathetic as well as those of many sympathomimetic drugs,
notably in the pronounced tendency of epinephrine to produce inhibi-
tory effects upon blood vessels and uterus of the cat. It does not seem
to the reviewers that, with such observations on record, it is necessary
to restrict the group of sympathomimetic agents to those which
duplicate the actions of epinephrine in all respects.
Classification of ephedrine in one or the other of these categories is
at present rather arbitrary, for the choice depends upon the definition
of the terms. Since neither term is explanatory of the mode of reac-
tion of drug with tissue substance, but is merely descriptive of observed
or expected phenomena, the choice is of no great immediate impor-
tance. However, the reviewers believe that it is better at present to
regard ephedrine as sympathomimetic in all its peripheral effects than
to consider it as sympathomimetic in some localities, musculotropic in
others. This choice is based partly upon the burden of clinical evi-
dence, which justifies the retention of ephedrine as a drug with the
general usefulness of epinephrine, and partly upon the possibility of
future developments. If stimulation by ephedrine of structures that
are depressed by epinephrine is conclusive proof that ephedrine is
musculotropic, the matter is closed, and little or nothing has been
added by way of fundamental knowledge to utilize in investigation of
other substances. But if search is made for an explanation of these
discrepancies upon a sympathomunetic basis, it is reasonable to sup-
pose that something will be added to our knowledge concerning the
sympathetic innervation of various structures, and it is not incon-
ceivable that progress may be made toward an explanation of the
extraordinary predilection of many substances for the sympathetic
nervous system, or for certain parts of it.
It is quite possible that some of the effects of ephedrine are musculo-
tropic. The facts remain, however, that no valid evidence exists
that such is the case, that at least one of the supposedly musculotropic
actions can even now be shown not to be such (i.e., the stimulant
effect upon isolated intestine), and that the general picture of ephe-
drine actions is strikingly similar to that resulting from st.frmi1fl.firm
EPEEDRINE AND RELATED SUBSTANCES 59
of the sympathetic nervous system by other means. The reviewers
therefore believe it proper to await unequivocal demonstration of
musculotropic actions by ephedrine, and the exclusion of the possibility
of sympathetic stimulation as an explanation, before accepting the
view that any of the peripheral effects of ephedrine are not syrnpa-
thomimetic.
11. Absorption and excretion
Ephedrine is readily absorbed and produces systemic effects when
administered orally, subcutaneously, intramuscularly, subdurally,
intraperitoneally, or rectally in animals, and the same has been
shown to be true of men excepting for the subdural and intraperitoneal
routes, which have not been tried. The rate of absorption in men,
evidenced by the rise in blood pressure, is somewhat faster following
subcutaneous or intramuscular injection than following oral adminis-
tration, but the degree of effect is not significantly different (Miller,
1925); evidently absorption from the alimentary tract is complete.
The effects of intravenous injection are much briefer than those of
other modes of administration (Jansen). The readiness with which
ephedrine is absorbed represents an outstanding and usually ad-
vantageous difference from epinephrine; it may be due to a lack of
constrictor action of ephedrine upon finer blood vessels.
The fate of ephedrine in the body is still unknown, for there is no
reliable and sensitive method for detecting it in tissues or excreta. It
apparently passes through the liver unchanged but whether it is
destroyed in the body or eliminated, in unaltered or altered form, is
unknown, nor is anything known about the route of elimination.
12. Toxicity
a. Minimal lethal dose. Table 2 shows the toxicity of ephedrine
in different animals. The order of theM.L.D. by different methods
of administration is as follows: intravenous, intramuscular, intra-
peritoneal, subcutaneous, and oral. The drug is therefore most toxic
by intravenous injection and least toxic by mouth. In general, differ-
ent workers agree that ephedrine has a low toxicity and a wide margin
of safety. In dogs, for example, the optimal pressor dose intra-
venously is 1 to 10 mgm. per kilogram while the M.L.D. by the same
60
Z. K. CHEN AND CARL P. SCHMIDT
TABLE 2
Toxtcity of ephedrine in different animals
ANIMAL
ggrntTYBTNB
METHOD OV ADMINIS-
TRATION
M.LD.
AUXHOK
Squid (Loligo pealii) . . .
Froff '
Sulphate
Hydrochloride
Hydrocbloride
Subcutaneous
Subcutaneous
Subcutaneous
mgm per
kgm.
10*
400-500
440
Nadler
Amatsu and
Kubota
Fujii
Hamster . . . . .
Hydrochloride
Hydrochloride
Sulphate
TTydrochlorifle
Subcutaneous
Subcutaneous
Subcutaneous
Tn traperitoneal
600
540
530-690
350
Kreitmair
Pak and Read
Chen
Pak and Read
Hydrochloride
Hydrochloride
Subcutaneous
Subcutaneous
500
1,000
Fujii
ELreitmair
White mouse
Hydrochloride
Hydrochloride
Sulphate
Oral
Intravenous
In traperitoneal
3,000
200
400
Kreitmair
Kreitmair
Rowe
Rat
HyrlTochlorMe
Subcutaneous
320
Pak and Read
White rat
Sulphate
Intravenous
135-140
Chen
Guinea pig <
Rabbit
1 Hydrochloride
Sulphate
Hydrochloride
Hydrochloride
Subcutaneous
Subcutaneous
Subcutaneous
Subcutaneous
400
400-425
300-460
400-500
Kreitmair
Chen
Miura
Amatsu and
White rabbit
Hydrochloride
Hydrochloride
Hydrochloride
Sulphate
Sulphate
Intravenous
Intravenous
Intravenous
Oral
Subcu taneou fl
50
50
60
590
320-400
Kubota
Kreitmair
Pak and Read
Chen
Chen
Chen
Gray rabbit <
Sulphate
Sulphate
Sulphate
Hydrochloride
Intraperitoneal
Intramuscular
Intravenous
Subcutaneous
310-400
340
66-70
230
Chen
Chen
Chen
Pak and Read
Cat |
Dog <
Hydrochloride
Hydrochloride
Sulphate
Hydrochloride
"RydTochloride
Intravenous
Intravenous
Intravenous
Subcutaneous
Intravenous
80
60
75
220
70
Pak and Read
Kreitmair
Chen
Miura
Pak and Read
* Total dose.
Sulphate
Intravenous
70-75
Chen
EPHEDBJNE AND RELATED SUBSTANCES 61
route of administration is 70 to 75 mgm. per kilogram. It is interest-
ing to note the great deviation of the M.L.D. in mice obtained by
Kreitmair from those reported by Fujii and by Rowe. The difference
by subcutaneous injection is fully 100 per cent or more. One wonders
if these three workers experimented on the same species of animals.
The variations in the results, not more than 10 to 20 per cent among
other investigators, should not be considered significant if one bears
in mind the errors in the determination of toxicity. Such errors have
been critically analyzed by Trevan (Proc. Roy. Soc., 1927, B, ci, 483)
and by Burn (Methods of Biological Assay, London, 1928).
b. Toxic symptomatology. Miura (1887) briefly described the toxic
signs in animals with lethal doses of ephedrine. He observed general
depression, mydriasis, stoppage of the respiration and diastolic stand-
still of the heart in frogs. The signs of poisoning in mice, rabbits
and dogs, as stated by him, are mydriasis, elevation of temperature,
acceleration of the pulse and respiratory rates, fall of blood pressure,
clonic convulsions and death due to cardiac and respiratory failure.
Amatsu and Kubota (1913) reported about the same results. More
detailed investigations were carried out by Chen on frogs, rats, guinea
pigs, rabbits, cats and dogs. In his experience, cardiac collapse
occurs sooner than respiratory failure. Animals poisoned by sub-
lethal doses of ephedrine recover without complications. A full
account of poisoning symptoms in frogs, mice, guinea pigs, rabbits and
cats is also given by Kreitmair.
The picture in the squid, described by Nadler, may be worth men-
tioning. Ten milligrams of ephedrine given subcutaneously fre-
quently cause gangrene and necrosis at the site of injection, leaving
the muscles of the mantle exposed. The animal may, however, live
for hours. Oral administration and injection into the circulation via
the heart, in 5 to 10 mgm. dosage, produce a dark coloration. In
these cases the arms are extended and limp, and on stimulation they
go into a series of tonic contractions. The respiratory movements
are faster and heavier, gradually become slower and labored, and death
occurs.
c. Repeated administration. In a series of rabbits Chen gave daily
doses of ephedrine for several weeks intravenously, intramuscularly
and orally and reported that the drug produces no observable toxic
62 Z. K. CHEN AND CARL P. SCHMIDT
effects. These animals gained in weight as steadily as the controls.
Upon sacrifice, there were no gross or microscopic lesions in the visceral
organs. No tolerance is developed to the mydriatic or pressor action
of ephedrine by repeated administration, nor is there any change in the
dose required to cause death. Similar results were obtained in rats.
This work has recently been verified by Doty.
IV. CLINICAL APPLICATIONS
1. Methods of Administration and Dosage
For systemic effects, ephedrine can be given by mouth, by sub-
cutaneous or intramuscular injection, and only exceptionally by
intravenous administration. On occasion, the drug may be used per
rectum, as shown by Thomas and by Hess. For local application to
the nasal mucous membrane, concentrations varying from 1 to 5
per cent can be used. It may be in the form of a solution, pure or
mixed with other aromatic ingredients, a jelly or a snuff. As a
mydriatic, ephedrine is used in 5 to 10 per cent aqueous solutions.
As regards the dosage for internal administration, this is governed
entirely by the development of untoward symptoms. A small dose
for one individual may be a large one for another. From the
experience of early investigators, a single dose may be 50 to 100 mgm.
for an average adult. Hess advocates the use of 1 to 2 mgm.
per kilogram of body weight. This dose appears to be slightly too
large, especially for ambulatory patients, judging from the frequent
occurrence of side reactions. It has now been reduced to 25 to 50
mgm., and may be repeated as needed. It can be given three or four
times a day.
In children from 2 to 14 years of age, Munns and Aldrich use 12 to
50 mgm. of ephedrine by mouth. Anderson and Homan employ
J grain (15 mgm.) for those over 1 year of age and \ grain (7.5 mgm.)
for those under 1 year, the drug being given in water solution. Stewart
prescribes $ grain (10 mgm.) in children from 1 to 5 years, J to J grain
(15 to 30 mgm.) from 5 to 6 years, $ grain (7.5 mgm.) from 6 to 12
months, and -fa grain (5 mgm.) under 6 months of age. Such doses
are given with 20 minims of glycerine and enough chloroform water
to make a dram (4 cc.).
EPHEDEINE AND EELATED SUBSTANCES 63 -
2. Side effects
The untoward symptoms of ephedrine, given orally, subcutaneously
or intramuscularly, have been recorded by T. G. Miller, Rowntree
and Brown, Gaarde and Maytum, Pollak and Robitschek, MacDer-
mott, Hollingsworth, Thomas, Balyeat, BergerandEbster, Althausen
and Schumacher, Wu and Read, Anderson and Homan, Kesten,
Middleton and Chen, Wilmer, Gay and Herman, Bloedorn and
Dickens, Boston, Long, S6gard, Chopra, Dikshit and Pillai, Higgins,
and Stewart hi connection with their clinical investigations. The
development of such symptoms and signs depends upon the dosage but
more upon the stability of the nervous system, as emphasized by
Pollak and Rabitschek. Similarly, Gaarde and Maytum state that
the occurrence of the nervous smptoms bears a distinct relationship
to a neurotic tendency and the daily activity of the individual. The
same therapeutic dose, therefore, may produce only desirable effects
in one patient, and equally beneficial results but with some discomfort,
hi another. Meals sometimes aggravate the symptoms (Middleton
and Chen) . It is the best plan to test out the sensitivity of the patient
with small doses, say 10 mgm., and establish the maximal tolerated
dose. It is only by experience and judgment that these side reactions
can be reduced to a minimum.
Subjectively, the common symptoms are palpitations, trembling,
weakness, sweating, feeling of warmth, chilly sensation, nausea, and
vomiting, while those of less frequent and rare occurrence are nervous-
ness, headache, insomnia, dyspnea, a tired feeling, thirst, drowsiness,
precordial pain, feeling of distress in the precordium, flushing of the
skin, tingling and numbness of the extremities, anorexia, constipation,
quivering feeling, faintness and diuresis. Boston makes a special
report of difficulty in urination in 6 cases he observed. Berger and
Ebster give an account of a neurotic patient who had colic, followed
by diarrhea and anorexia, after the use of ephedrine, and of still
another who had such an increase of libido that he called ephedrine an
aphrodisiac. Higgins reports a case of chronic ephedrine poisoning
which simulated hyperthyroidism.
Objectively, the common signs are diaphoresis, tremor, extrasystoles
and tonal arrhythmia, while those of less frequent or rare occurrence
are tachycardia, restlessness, mydriasis, albuminuria, appearance of
64 K. K. CHEN AND CAILL E. SCHMIDT
red blood corpuscles and casts in the urine, and decompensation in
organic cardiac disorders. Anderson and Homan observed abdominal
distension, pain and discomfort, discharge from the nose and apparent
suppression of urine. T. G. Miller recorded a case of myocardial
degeneration in which ephedrine caused pulsus alternans. Four out
of 11 cases in the series of Middleton and Chen showed after ephedrine
extrasystoles of ventricular or auricular origin, as shown by electro-
cardiography. Another case developed a paroxysm of tachycardia
which lasted for a few minutes. Bloedorn and Dickens describe a
case of cardiac asthma, diagnosed as bronchial asthma, which resulted
in cardiac embarrassment, including pulsus alternans, marked tachy-
cardia and cardiac decompensation, following ephedrine therapy.
Such dangerous effects, however, do not appear to occur very fre-
quently, for in the series of Hess and of Gay and Herman there were
several patients with myocardial insufficiency but none experienced
any harmful effects. Pennetti observed, by means of electrocardio-
grams, that ephedrine increased the frequency of pre-existing extra-
systoles in 2 case's but produced no change in a case of A-V block of
vagal origin. The block in the last case disappeared after the adminis-
tration of atropine or epinephrine.
All the side effects occur singly or in groups of but a few, become
most pronounced when the systolic blood pressure is at its highest level,
and disappear as the pressure returns to normal. Some of the sub-
jective symptoms may be explained by the pharmacological action of
the drug. For example, palpitation is due to circulatory changes,
as borne out by objective observation, and the insomnia and tremors
present in some cases are due to stimulation of the central nervous
system. Leake, Loevenhart and Muehlberger attribute the headache
under ephedrine to the changes in pressure in the arteries or veins
within the skull. Occasionally, the untoward symptoms in some in-
dividuals disappear on repeated administration of ephedrine, showing
that these individuals become better accustomed to the drug. Alt-
hausen and Schumacher mention two such cases and HoUingsworth
another.
Investigators seem to agree that the prolonged use of ephedrine
does not have any cumulative harmful effects and does not result in
habit formation. Middleton and Chen reported a case that received a
EPHEDBJNE AND BELATED SUBSTANCES 65
total quantity of 10 grams of ephedrine sulphate in a period of 11 days
but showed no detectable pathological changes. Withdrawal did not
give that patient any discomfort or any craving for the drug. Wu
and Read mentioned a case in which ephedrine therapy (40 to 60
mgm. every 1 to 3 days) was continued for three years. Laboratory
examinations did not show any ill effects. Thomas and Balyeat,
and Collina also express the opinion that ephedrine is not a habit-
forming drug. In 5 out of 51 cases of asthma and hay fever, Althau-
sen and Schumacher noted a considerable diminution of action in the
relief of attacks, showing the increase in tolerance by repeated admin-
istration. It should also be borne in mind that the attacks may
not have been of equal severity and that severe cases are unfavor-
able for the action of ephedrine.
Contraindications are but few. In all cardiac disorders, especially
with signs of decompensation, ephedrine should be used with caution.
Slgard mentioned angina and hypertension as contraindications of the
use of ephedrine. However, recent work on spinal anesthesia shows
that it is permissible to use ephedrine in hypertension cases. Care
should also be taken in cases where there is a labile vagosympathetic
equHibrium, although there is not the same extent of hypersensitive-
ness to ephedrine as to epinephrine in Graves 3 disease (Cs6pai and
Fernbach). In late acute circulatory collapse, it is best not to give
ephedrine, since it may be a dangerous procedure, as shown by
Blalock hi experimental annuals.
Pitkin mentions two fatalities in spinal anesthesia which were
attributed to 50 mgm. of ephedrine, but his own toxicological studies
do not seem to support this statement. Sise knows of two similar
cases, not of his own; each patient was in very poor general condition,
received repeated doses of ephedrine, totaling about 150 mgm., be-
came cyanotic, fibrillated and, although the pressure was at or above
normal, died hi about 12 hours. In experimental animals, however,
death never occurs if the blood pressure is at its normal level.
V. THERAPEUTIC USES
1. In asthma
Following the publication of T. G. Miller, who first employed
ephedrine in the treatment of bronchial asthma, many other investi-
66 K. K. CHEN AND CARL P. SCHMIDT
gators have made similar reports concerning their experience with the
drug. It appears to be generally agreed now that ephedrine is a good
palliative remedy in the treatment of bronchial asthma. Its action is
weaker than that of epinephrine, and it is therefore only occasionally
efficacious in severe attacks of asthma. In mild and moderate cases
it may prevent the attack if it is given several hours beforehand, abort
the attack if it is administered during the prodromal period and some-
times stop the attack when it is used while the attack is in progress.
Its prophylactic action seems to be better than its antispasmodic
property. This is well illustrated by the work of Vallery-Radot and
Blamoutier, who showed that ephedrine was effective in 16 (69 per
cent) out of 23 cases when given prophylactically but in only 17
(43 per cent) out of 39 cases when given during the attack. Leopold
and Miller show that the best results are obtained in allergic and reflex
nasal cases, and comparativtely less satisfactory results are obtained in
the infectious type. Similarly, Gay an4 Herman note that the relief
from an asthmatic attack is most quickly obtained in patients whose
symptoms are due to a specific foreign protein, such as pollens, animal
emanations, orris root, feathers, with or without secondary bronchitis.
According to Thomas, a field for the use of ephedrine appears to lie in
its employment as often as necessary to prevent the occurrence of
paroxysms in asthmatic patients who are awaiting the completion of
skin testSj courses of vaccine administration, rhinological treatment,
radiotherapy or other methods from which more permanent benefit
is hoped for. This author adds, however, that patients who are about
to undergo sensitization tests should be cautioned not to seek relief in
ephedrine within a period of 12 hours before such tests are to be made ;
for the drug, like epinephrine, temporarily prevents the appearance
of positive reactions to specific tests for sensitiveness.
When desirable effects occur, ephedrine has certain advantages over
epinephrine from the therapeutical point of view. In the first place,
it can be given by mouth ; secondly, it can be employed as a preventive ;
thirdly, it has a more prolonged action, although its onset is not so
prompt ; and fourthly, it produces less side reactions. Some individuals
who are unable to take epinephrine are fortunately able to use ephe-
drine without untoward symptoms. In other words, a reaction from
epinephrine does not indicate that ephedrine likewise will have a
EPHEDJONE AND BELATED SUBSTANCES
67
TABLE 3
Results of ephedrine therapy in the treatment of asthma
T.G. Miller (1925).
T. G. Miller (1926) .
Leopold and T. G. Miller
(1927)
Thomas (1926) .
Thomas (1927) .
MacDermott
Pollak and Ro"bitschek
Hess .
Heller
Jansen
Kammerer and Dorrer. . .
Middleton and Chen . .
Piness and Miller ....
Althausen and Schumacher.
Wilmer
Wilkinson
Wu and Read.
Bibb . .
Balyeat
Rudolf and Graham
Jankowski
Collina . . .
Taylor.
NtntBEH Off CASES
7
36
59
20
Over 300
20
16
15
1
9
25
110
39
100
12
(Ward) 11
(Ambulatory) 90
2
Over 100
(Severe) 2
11
14
10
Benefit in 6; none in 1
Good results in 26, relief not
marked in 4; no improvement
in 6
Complete relief in 33; partial
relief in 17, no relief in 9
Relief in 17
Ephednne is a remarkably effi-
cient drug
Relief in most cases
Ephedrine replaces epinephrine
injections
Very good in part, good in part;
rarely insufficient success
Marked improvement (observa-
tion made on himself)
Favorable
Relief in 8; none in 1
Relief in 9; improvement in 8;
inconclusive in 8
24 severe cases did not obtain
relief
Complete relief in 21; partial
relief in 15
Relief in 75; relief in severe
attacks, 10
Excellent
9 responded well
Favorable
Perfect relief
Ephednne is of considerable
value in 65 per cent of the
cases
Ephedrine reduced epinephrine
injections in one, but had no
effect in the other
Ephedrine has a marked effect
Complete relief in 5, evident
improvement in 5; temporary
improvement in 2; no change
in 3
Prompt relief in every case
68
K. K. CHEN AND CARL P. SCHMIDT
Gay and Herman
Vallery-Radot and Blamoutier
McPhedran
Segard
Long
Munns and Aldrich.
Anderson and Homan.
Stewart
TABLE 3 Concluded
NUMBER OT CASES
100
49
12
(Children) 22
(Children) 5
29
Complete relief in 71; moderate
relief in 21, no relief in 8
In 23, ephedrine used prophy-
lactically, produced benefit in
16 but none in 7; in 39 ephe-
drine given during the attack,
gave relief to 17, but none to
22
Complete relief in 9; partial in 2
Total relief in mild cases
Effective in relief and prevention
Complete relief in 12; partial in
4; none in 6
Marked relief
Relief in over half
similar unpleasant effect. A combination of epinephrine and ephe-
drine has been found efficacious by some and objectionable by others.
On the whole, if the patient shows reactions to epinephrine alone, or
to both epinephrine and ephedrine, the injection of epinephrine in the
presence of ephedrine usually exaggerates the untoward symptoms
(Althausen and Schumacher, and Haintz) . If the patient can tolerate
both drugs well, there is no reason why epinephrine cannot be given
in addition to ephedrine if the latter fails to act.
Relief from ephedrine takes place in 20 to 30 minutes if it is given by
mouth but in 10 to 15 minutes if it is administered intramuscularly or
subcutaneously. The clinical improvement can sometimes be ob-
served objectively. It consists in diminution of cyanosis, increase
of vital capacity, decrease of rales, gradual disappearance of orthopnea,
and euphoria of the patient. Subjectively, the patient usually volun-
teers the information that he can breathe better and feels relieved.
The relief may be followed by coughing and expectoration (Heller).
Individuals who suffer regularly from daily or nightly paroxysms may
remain asthma-free for long periods of time by taking the drug once,
twice or three times every 24 hours. They can resume their daily
activities and pass comfortable nights. Withdrawal of the ephedrine
results in recurrence of asthmatic symptoms. Other persons are not
EPHEDJUNE AND RELATED SUBSTANCES 69
so fortunate, for the by-effects, occasionally met with, render its use
impracticable even though it relieves the bronchospasm.
In children afflicted with asthma the same beneficial results have
been obtained with the proper doses of ephedrine, as reported by
Munns and Aldrich and by Anderson and Homan.
The results of various workers, not only in this country but in
various parts of the world, are summarized in table 3. It will be seen
that beneficial results have been obtained in the majority of cases by
each physician. It is futile to compare the percentage of improve-
ment in different series since the essential factor is not the patient
or the drug but the severity of the asthmatic attack.
2. In hay fever
Gaarde and Maytum in 1926 reported their first series of 26 cases
of autumnad hay fever which were treated by the oral administration
of ephedrine. Thirteen of these patients obtained complete or almost
complete relief from symptoms by taking 60 mgm. doses 2 to 3 times
every 24 hours. The relief lasts 3 to 7 hours after each dose. Ex-
cessive nasal secretions stop, ocular symptoms disappear, and in every
way the patients are entirely comfortable. In 5 cases the result was
fair and partial relief was obtained for 2 to 3 hours after each dose.
In 8 cases the results were negative. In their next series, published
in 1927, they made a comparison of the effects of oral administration
with those of a 3 per cent nasal spray. In 24 patients who received
ephedrine by mouth, 13 (54 per cent) were completely or almost com-
pletelyrelieved for4hoursormore; 7 (29 per cent) werepartially relieved;
and 4 (16 per cent) were not relieved or they were not able to tolerate
the nervous symptoms. In a similar series of 25 cases which were
given ephedrine by a spray, 7 (28 per cent) were markedly relieved for
several hours; 12 (48 per cent) were partially relieved for several
hours or completely relieved for less than an hour; and 6 (24 per cent)
were not benefited. Ephedrine given in 3 per cent solution as a nasal
spray, therefore, appears to be less efficacious and the relief is of shorter
duration. However, the majority of patients feel that its use adds to
their comfort. The best results are obtained when the spray is used
early in the paroxysm. The effect of both the local and internal ad-
ministration seems to depend on the severity of the paroxysms and
70 K. K. CHEN AND CAKL P. SCHMIDT
the good results are obtained in the milder seizures. Untoward symp-
toms, when they occur, are attributable to the neurotic temperament
and nervous state of the patient. In analyzing their data of two suc-
cessive seasons, Graarde and Maytum conclude that ephedrine should
be given a definite place in the treatment of autumnal hay fever, and
they emphasize the fact that when good effects are obtained they are
temporary and symptomatic. Leopold and Miller observed complete
temporary relief in 63 per cent of 11 cases and prefer the oral route for
the administration of ephedrine. Encouraging results in the treatment
of hay fever with the new drug are also noted by Thomas, Balyeat,
Althausen and Schumacher, Wilkinson, and Ramirez. Piness and
Miller observed relief in only 1 out of 5 cases when ephedrine was
given by mouth, but in 18 out of 20 cases when the drug was used as a
spray. These results show that local application is more efficacious
than oral administration.
3. In bronchitis and emphysema
In 11 cases of senile emphysema, 1 with active and 6 with inactive
pulmonary tuberculosis and all having hypotension, Saxl reports
that ephedxine produced a striking improvement of the dyspnea in 8
but had no effect in 3. The blood pressure rose 15 to 30 mm. Eg for
several hours with 100 mgm. doses. According to him ephedrine has
the advantage over atropine in that it does not cause dryness of the
throat. These conclusions have been confirmed" by the study of a
larger series of cases by himself.
4. In whooping cough
Anderson and Homan were the first to try out ephedrine therapy in
pertussis. They noticed that the drug abolished the characteristic
signs of whooping cough in 18 out of 20 children. In all instances in
which improvement occurred, some cough remains but in mild form
and of a type associated with acute upper respiratory infections.
They believe that ephedrine is most useful during the second stage of
the disease. In a series of 35 children suffering from pertussis Stewart
observed that ephedrine relieves the coughing, the whooping and
vomiting in mild and moderate cases. In severe cases there is no
effect at all. He states, however, that the drug, combined with
EPHEDSJNE AND BELATED SUBSTANCES 7l
belladonna and ipecac, seems to have a beneficial effect. The progress
of the infection is not in any way influenced.
5. In spinal anesthesia
The blood pressure-raising property of ephedrine appears to be most
useful in spinal anesthesia. Rudolf and Graham studied 26 cases
under spinal anesthesia, in the surgical and gynecological wards of a
hospital, in which they administered ephedrine intravenously. Their
results are striking, especially with reference to the elevation of the
blood pressure. In their first few cases the blood pressure was allowed
to drop until it had apparently reached its lowest level and then 50 to
100 mgm. of the drug were given by vein. With but one exception
there quickly resulted an extraordinary and prolonged rise in blood
pressure, with a slower and stronger heart beat. This lasted for 1 to
1 hours. In their later cases they used smaller doses and gave the
ephedrine within 2 to 3 minutes after the anesthetic, so as to antic-
ipate the fall rather than combat it after it had developed. This
improved technique proved to be satisfactory and they had no case of
drastic fall in blood pressure or of vomiting, which occurs frequently
in spinal anesthesia. They also state that the drug can sometimes be
given with advantage before the spinal anesthetic where the blood
pressure is already too low. Ockerblad and Dillon have used ephe-
drine in 50 to 100 mgm. dosage, subcutaneously or orally, in a series of
250 cases and have been successful in restoring the right amount of
arterial tension necessary for surgical operations and the well being of
the patient. The fall in pressure must be anticipated if the best
results are to be obtained with ephedrine. In other words, once the
pressure falls as much as 50 per cent, the return to the normal level
even under comparatively large doses of the drug is slow and uncer-
tain. It is better to reinforce the vascular system with ephedrine
before the actual administration of the spinal anesthetic, to have the
blood pressure 20, 30 or more millimeters Hg above the normal for
that individual. The drug is repeated if there is a tendency to fall.
Chronic hypotension, which used to be a contraindication to spinal
anesthesia, is no longer a valid objection. Ephedrine relieves any
tendency toward retching and vomiting which, according to Ockerblad
and Dillon, is due to the preliminary hypodermic injection of morphine
72 K. Z. CHEN AND CARL F. SCHMIDT
and scopolamine. Pitkin uses 1 to 1.3 cc. of a solution containing
1 per cent of novocaine and 3 per cent of ephedrine to make a wheal at
the site of, and before, lumbar puncture. He is satisfied with the
pressor action of ephedrine and performs operations below the dia-
phragm. He states that the action of the drug can be relied on
for 2 to 3 hours and has contributed much to the safety of spinal
anesthesia. Pitkin and McCormack, and Cosgrove have tried the
drug in obstetrics where spinal anesthesia may be indicated, as in low
forceps extraction, episiotomy, perineorrhaphy, dilatation or incision
of the cervix, podalic version, craniotomy and extraction, vaginal
hysterectomy, etc. Ephedrine is used prophylactically as outlined
by Pitkin. Holder gives ephedrine subcutaneously IS minutes before
the administration of the spinal anesthetic and succeeds in keeping the
systolic blood pressure at a constant level, although somewhat below
the original. In 151 cases, approximately one-half received ephedrine
(50 to 100 mgm.) and the average drop of blood pressure was 12.8
mm. Hg. In the other half the average drop of pressure was 37.5
mm. Hg. Wehrheim reports his experience in over 300 cases of spinal
anesthesia with ephedrine (50 mgm.) injected subcutaneously 5 min-
utes before the spinal tap. To show the benefit of this procedure, he
states that the average drop in blood pressure in spinal anesthesia
without ephedrine is 10 to 30 mm. Hg within 15 minutes, but the
average drop in 30 consecutive medicated cases was nil. Sise con-
siders the repeated injection of ephedrine unnecessary and sometimes
dangerous if the blood pressure begins to drop in spite of the use of
ephedrine. Other measures, such as saline infusions with small doses
of epinephrine, should be resorted to. Other favorable reports of
spinal anesthesia with ephedrine have been made by Babcock, Wallace,
Jeck in kidney and ureter operations,' DeCourcy, Case who uses the
drug subcutaneously immediately after the spinal injection, Gosse,
Saklad, and Russell who injects ephedrine intramuscularly before the
spinal puncture.
6 . In hypotension
The use of ephedrine in the treatment of chronic or subacute hypo-
tension has, with some exceptions, not proved as promising as had been
hoped for. It has been tried in Addison's disease. Chen and Schmidt
EPBEDRINE AND BELATED SUBSTANCES 73
mentioned a single case in which ephedrine seemed to have a good
effect. T. G. Miller studied two cases of early Addison's disease and
found a rise of blood pressure and increase of basal metabolic rate fol-
lowing the administration of ephedrine, but both patients died from the
disease. Rowntree and Brown treated 14 cases of Addison's disease
and two of questionable Addison's disease with ephedrine. They also
demonstrated a definite rise of blood pressure and increase of metabolic
rate, but the rise was not accompanied by a marked feeling of well
being, significant increase in strength or relief from the gastric symp-
toms or circulatory asthenia. Only in one case of early Addison's
disease excellent clinical results were obtained. The feeling of weak-
ness and exhaustion disappeared and the patient felt buoyant, strong
and refreshed.
T. G. Miller tried ephedrine in a number of cases with essential or
chronic hypotension and observed that in some of them it produced
a temporary elevation of pressure, lasting from 3 to 6 hours after each
dose by mouth. The response in pressure increase was not as striking
as in certain other types of cases, and' sometimes a dose of 50 mgm.
had no effect whatever on the hypotension, yet most of the patients
expressed themselves as feeling stronger and more energetic under its
influence. Rowntree and Brown administered ephedrine in 9 cases of
nervous exhaustion and hypotension. Aside from the rise of blood
pressure for 3-6 hours and some increase of the basal metabolic
rate, no other evidence of clinical improvement was observed objec-
tively, although some of the patients were convinced that they felt
somewhat stronger. Pollak and Robitschek mentioned a case of
pneumonia in which daily doses of ephedrine raised the blood pressure
from a level below 100 mm. to 145 mm. Hg, although accompanied by
some untoward symptoms. Hess reported a series of cases with hypo-
tension, including pneumonia, bronchopneumonia, pulmonary tuber-
culosis, cardiac insufficiency and vasomotor weakness. Repeated
small doses of ephedrine produced favorable results . In the treatment
of paresis with malarial fever, the drug can maintain the blood pres-
sure at the normal level, as shown by three cases. He advocates the
combination of ephedrine with atropine in the treatment of bronchial
asthma and with digitalis or caffeine in cardiac insufficiency with low
pressure and chronic bronchitis. Middleton and Chen studied three
74 K. K. CHEN AND CARL F. SCHMIDT
patients who had hypotension two with asthma and one without
asthma with ephedrine at frequent intervals for a considerable length
of time, in the hope of elevating their blood pressure and maintaining
the higher pressure. The results in two were practically negative.
The slight elevation in the third was probably due to the improvement
of his asthmatic condition under ephedrine therapy. Wu and Read,
on the other hand, state that they obtain very satisfactory results
with ephedrine in cases of hypotension. Althausen and Shumacher
determined the value of ephedrine in 7 patients with chronic hypo-
tension. During an average period of 20 days the blood pressure was
raised by daily doses of the drug and three patients felt stronger while
four did not notice any change. Ghrist and Brown reported an
interesting case of postural hypotension with syncope, in which ephe-
drine raised and sustained the blood pressure and rendered the patient
free from symptoms. He has been able to go back to work without
further attacks by the daily use of the drug. These authors believe
that ephedrine may exercise a specific alleviative effect on the disease.
7. In shock
In acute circulatory collapse it is still a question how much good
ephedrine can do. The drug is not indicated in late stages of shock.
Chen in dogs observed that ephedrine restores the blood pressure in
hemorrhage and in experimental shock induced by histamine, peptone,
anaphylaxis or surgical manipulation, and that it fails to act when the
heart beat becomes impaired or respiration ceases, or the degree of
shock is too extensive, or when the hemorrhage exceeds 25 per cent of
the total blood volume. Blalock, also experimenting with dogs, con-
cluded that in less severe cases of shock ephedrine works better than
caffeine, strychnine, epinephrine and digitalis, but in severe cases it
seems to hasten death. Chen and Schmidt investigated its effect in
surgical shock in a single patient, with encouraging results. Miller
reported real improvement in two cases in profound shock. In one of
them an intravenous injection of 100 mgm. raised the blood pressure
from practically zero to 65 mm. Hg, although the patient finally died of
general peritonitis. Since then, he has tried the drug in a large num-
ber of cases of shock and hemorrhage, usually without beneficial
result, even though the drug was given intravenously (unpublished).
EPHEDBXNE AND BELATED SUBSTANCES 75
Pollak and Robitschek recorded a case of acute alcoholic poisoning in
which ephedrine caused a definite increase in blood pressure from an
almost imperceptible pulse. Similarly, in a patient dying of post-
operative peritonitis Rudolf and Graham administered 100 mgm. of
ephedrine intravenously. The systolic blood pressure rose from an
unrecordable level to 86 mm. Hg. within 2 minutes and later to 130
mm. Hg. The good effects lasted for some 45 minutes and then the
patient gradually sank and died some five hours later. Althausen and
Schumacher reported two cases in a state of surgical shock in which
ephedrine was given. One of them rapidly recovered and the other
died. Both were given blood transfusions simultaneously. Waters
(cited by Jackson) believes that the chances for a favorable result from
the action of ephedrine are much increased if it is given in the early
stages of traumatic or surgical shock. H. Schmidt advocates the use
of ephedrine as a prophylactic measure against vascular shock in local
anesthesia and surgical shock in major operations under chloroform,
spinal or avertin anesthesia. The action usually lasts longer than the
operation.
8. In Adams-Stokes' syndrome
In a single case of complete heart block T. G. Miller gave a subcu-
taneous injection of 100 mgm. of ephedrine : it caused an increase of the
ventricular rate from 38 to 55 per minute, of the auricular rate from
110 to 125 per minute, accompanied by a rise of blood pressure, as
shown by electrocardiograms. The shape of the P-wave and the
ventricular complexes was observed to alter from time to time.
Hollingsworth was the first to report a case of Adams-Stokes' syndrome
hi which the first dose of ephedrine (50 mgm.) by mouth stopped the
attacks within 30 minutes. The latter did not recur in 36 hours. On
taking the drug every morning the patient was completely freed from
symptoms and was able to resume her household duties. After three
weeks the drug was withheld but the attacks recurred in 48 hours. It
was therefore resumed. Stecher reported a similar case of complete
heart block with syncope and convulsions in which ephedrine gave
complete relief. The patient was given 30 mgm. doses three times
a day during the first week and 20 mgm. doses three times a day during
the next two weeks. The drug was then discontinued and the patient
76 K. K. CHEN AND CARL P. SCHMIDT
had no further attacks for 10 weeks afterwards, during which time
he was ambulatory.
9. As a nasal astringent
Dr. Alice H. Cook (cited by Fetterolf and Sponsler) was the first
to use ephedrine locally in the nose and throat. She found that a 10
per cent solution of ephedrine causes almost instant shrinkage of an
engorged nasal mucous membrane and that the action is more rapid and
complete than that of a 4 per cent solution of cocaine. This sub-
ject was investigated more thoroughly by Fetterolf and Sponsler who
used a 5 per cent solution in 17 patients and found it so effective
that they described ephedrine as a drug which, for use in the nose, has
all the advantages of epinephrine with perhaps none of its disadvant-
ages. Following the application to the anterior part of the lower
turbinate by means of a cotton brush, contraction begins in from a few
seconds to one minute. The maximum is established in from l to
5 minutes or in an average time, for their series, of 2f minutes. In
spite of a small area of application the turbinate in every case contracts
throughout its entire length. The general outline of the medial sur-
face changes from convex to concave. Contraction is so complete
and the mucosa becomes so thin and flat that it fits the bone as a glove
fits the finger. The color is altered to a paler hue and assumes a
gray tint at the maximum of the action. No white ischemia occurs, as
is often seen with epinephrine. Relaxation begins in 2 hours and 35
minutes and is complete in an average time of 3 hours and 17 minutes.
There is no sign of irritation of the mucous membrane, such as sneezing,
either on the same day or the following day. There is no secondary
congestion, as with epinephrine. Similar favorable results have been
obtained with weaker solutions (1 to 3 per cent) by Fiske, Proetz, and
others. Kennon advocates the use of ephedrine in (1) acute nasal
accessory sinus disease, (2) chronic nasal sinus disease where surgery
is contraindicated and as an adjunct to surgery, and (3) chronic*
accessory sinus disease in children where surgery should be used only
for the removal of toxic foci. Merkel states that a 3 per cent solution
of ephedrine is just as effective as a 5 per cent solution in rhinotherapy
and the drug can be applied by (1) spraying, which is best for children,
(2) topical application with cotton on a probe, and (3) introduction
EPHEDBINE AND RELATED SUBSTANCES 77
into the nose on cotton packs. Fifteen infants having definite evi-
dence of ethmoiditis were treated by this author in the following man-
ner: the nose was irrigated with a warm saline solution twice daily;
half an hour after the irrigation a 2 per cent solution of ephedrine was
sprayed on the nasal mucosa; and 5 minutes later 3 drops of a 5 per
cent solution of argyrol were placed in the nostril. Twelve patients at
least were benefited by such a regime. Ephedrine does not need to
be in contact with the nasal mucosa for more than a few seconds. A
pack left in situ for 3 minutes causes no more contraction than after
a shorter time. Daily use over a period of 10 days shows no change
in the rapidity or duration of the action. The drug brings about free
ventilation and drainage for a period of 3 to 6 hours. Merkel also tried
ephedrine in 3 cases of epistaxis and claimed to obtain good results.
Reaves, employing a mixture of 1 per cent of ephedrine and 0.5 per cent
of butyn, performs minor surgical operations on the nose. Gaarde
and Maytum reported that ephedrine given orally produces a stop-
page of excessive nasal secretions in cases of hay fever. They noticed
sneezing in some patients. Leopold and Miller observed actual
shrinkage of the nasal mucous membranes in similar cases by the same
method of administration. In experimental animals (dogs) , a contrac-
tion of the nasal mucosa and accessory sinuses following the intra-
venous injection or local application of ephedrine has been demon-
strated by Rudolf and Graham with Copeland's technique, by Jackson
with his own device and by King and Pak with Tschalussow's nasal
plethysmograph.
10. As a mydriatic
The first ophthalmological work with ephedrine was done by Miura
in 1887. He observed that a 6 to 7 per cent solution of ephedrine
produces mydriasis in most people in from 40 to 60 minutes. The use
of a 10 per cent solution in 18 patients did not cause a maximal dilata-
tion of the pupil but produced sufficient dilatation for the visualization
of the retina. During dilatation the light reflex is retained and the
accommodation is not paralyzed. There is no increase in intra-ocular
pressure, no irritation or inflammation follows its instillation and no ill
effects result from prolonged use. One patient receiving three treat-
ments daily for IS days showed no pathological changes. The dura-
78 Z. K. CHEN AND CARL F. SCHMIDT
tion of mydriasis varies from 5 to 20 hours. Children and aged people
are more susceptible than ydung adults. The diseased iris does not
seem to respond well. De Vriesse published practically identical
results in 1889. Inouje encountered a case in which the instillation of
ephedrine precipitated an acute attack of glaucoma. Groenouw re-
ported 100 cases he studied in which the following mixture was used:
ephedrine hydrochloride, 1 gram; homatropine hydrochloride, 0.01
gram; and water, 10 cc. Merck named this mixture Mydrin. The
mydriasis with this combination begins in 8^ minutes, reaches its max-
imum in 34 minutes and lasts for from 4 to 6 hours. The accommo-
dation is not interfered with by this solution. In strong light the
pupil contracts to 5.6 mm. in diameter. Similar favorable results
have been reported by Suker, Snell, Cattaneo and Stephenson. Mar-
moiton not long ago (1911) gave a re"sum6 of this work on ephedrine.
All these authors advocated the use of ephedrine in the exploration
of the fundus on account of the rapid action, absence of cycloplegia,
short duration of mydriasis and harmlessness of the drug. Since the
recent extensive study of ephedrine interest in its use in ophthalmology
has been revived. Middleton and Chen observed that a 10 per cent
solution of ephedrine, or the same concentration with the addition of
0.1 per cent of homatropine or of 0.1 per cent of atropine, may be used
locally as a mydriatic for routine ophthalmoscopic examinations.
Chen and Poth found that ephedrine is an efficient mydriatic for
Caucasians but is of little value in dilating the pupil of the Chinese
and of negroes. The investigation was made both in diffuse daylight
and under controlled illumination with accurate measurements.
The same difference in mydriatic action in these three races was
observed with cocaine and euphthalmine, which have hitherto been
used indiscriminately in clinics. The question seems not to be
entirely one of differentamounts of pigmentation, as rabbits of various
colors respond almost equally to ephedrine applied to the conjunctiva!
sac. Howard and Lee also reported that ephedrine is more effective
as a mydriatic in individuals with light irides than in those with dark.
Dittmann, on applying a 3 per cent solution on himself, experienced
conjunctivitis, increased tension and blurring of vision. Schoenberg,
on the other hand, concluded, from a study of several hundred patients,
that a 1 to 3 per cent solution of ephedrine is a valuable drug to produce
EPHEDBINE AND BELATED SUBSTANCES 79
mydriasis for ophthalmoscopic examination. The same author ob-
served that the effect of ephedrine on the human pupil is counteracted
by pilocarpine within 5 to 10 minutes. Similarly, Muller, after 2^
years' experience, considers it as a useful agent for diagnostic purposes.
This investigator administered ephedrine in several cases of chronic
glaucoma and found no change in the intra-ocular pressure. Re-
cently, Chen and Poth found that the dilated pupil in Caucasians
under the influence of ephedrine is made more stable to light if a small
amount of homatropine or euphthalmine is added. The mixtures
have a short duration of action and some (but only little) influence
upon the accommodation. As a result a better view of the eye ground
is obtained without inconveniencing the patient by blurring of vision.
The solutions are but little irritating. Some subjects experience a
burning sensation which lasts for about 30 to 60 seconds. In uveitis
and iritis, however, ephedrine, or its mixtures with other mydriatics,
fails to dilate the pupil.
11. As an antidote for narcotic drugs
C. F. Schmidt observed in experimental animals that ephedrine
possesses the power not only to increase the Oa supply of the brain by
its pressor action but also to stimulate the respiratory center directly.
He advocates the use of ephedrine and epinephrine in serious depres-
sion or failure of the respiration, such as following morphine, in prefer-
ence to the conventional respiratory stimulants, as caffeine, atropine,
strychnine or camphor. Similarly, Kreitmair found that in rabbits
and cats ephedrine, given intramuscularly or intravenously, not only
restores the respiration after its paralysis by scopolamine but also
raises the blood pressure. He suggests its clinical use in twilight sleep
with scopolamine and morphine, or scopolamine and eucodal (dihy-
droxycodeine hydrochloride). Subsequent reports seem to bear out
his point. In psychiatry Guttmann used hypodermically ampules
containing 1 mgm. of scopolamine and 25 mgm. of ephedrine in all cases
of senile dementia, arteriosclerosis and 2 excited cardiac psychoses.
During sleep these individuals had a quiet smooth breathing instead of
snoring. The addition of ephedrine apparently does not affect the
narcotic action of scopolamine. In surgery, Streissler reported 26
cases in which he injected subcutaneously morphine and ampules
80 K. K. CHEN AND GAEL P. SCHMIDT
containing 1 part of scopolamine and 25 parts of ephedrine to produce
analgesia and anesthesia. These drugs are given in divided dosage.
According to Streissler, 1\ hours before the operation the patient
should be given 10 mgm. of morphine and 1 mgm. of scopolamine with
25 mgm. of ephedrine. After 15 minutes 10 mgm. of morphine are
given and 15 minutes later 1 mgm. of scopolamine with 25 mgm. of
ephedrine is again injected. If sleep is not deep l hours before opera-
tion, 0.5 to 1 mgm. with ephedrine, which is an extra dose, should be
given. Finally, \ hour before operation, 10 mgm. of morphine, to-
gether with 1 mgm. of scopolamine plus ephedrine are injected. With
these medications the pain sensation disappears before tactile sensa-
tion. There is no anxiety, fear or resistance on the part of the patient
during induction of anesthesia. Many operations can be done under
this form of analgesia and anesthesia, such as amputations of the
breast, surgical treatment of the stomach or gall bladder, etc. In
young vigorous persons ether may be given during the operation, but
only as little as possible. The pulse rate is often unchanged but is
usually accelerated after the operation. Respiration is slowed but
not made stertorous. The blood pressure remains elevated for two
hours after the operation. The patient wakes up hi 4 to 6 hours with
complete amnesia and euphoria and without any struggling. Vomit-
ing does not occur. The pain in the wound is not so severe. There
were no postoperative complications that could be definitely attrib-
uted to the drugs. Lubitz, working at the same clinic, reported 14
more cases, using the same medication . Moro used this combination of
scopolamine, ephedrine and morphine in 32 urological cases, and OstrCil
for painless delivery. Similar results with the combination of eucodal,
scopolamine and ephedrine in surgical operations have been reported
by Dax and Weigand from 145 cases and by Wagner from several
hundred cases. Merck has patented the scopol am i n e-ephedrine com-
bination in England and Austria.
12. In dermatology
a. In urticaria. In view of the fact that ephedrine resembles epi-
nephrine it has been tried out clinically in allergic conditions other
than asthma and hay fever. T. G. Miller treated two cases of acute
urticaria with ephedrine given by mouth and recorded beneficial
EPHEDRINE AND RELATED SUBSTANCES 81
results. Kesten made a careful study with ephedrine in a large series.
She found that in 11 cases of chronic urticaria with angioneurotic
oedema, 7 were cured, 2 improved and 2 unaffected. Several patients
in this group had had urticaria almost continuously for years but be-
came free from symptoms after taking the drug and remained so for
some months after the medication had been discontinued. Results
are less favorable in cases without oedema. Of 6 patients with chronic
urticaria 2 had complete relief, 2 showed improvement and the remain-
ing 2 no change, following the oral use of ephedrine. In 3 cases of
papular urticaria, 2 of erythema multiforme and 2 of chronic eczema
there was practically no relief except for lessened itching. Similarly,
in a case of mild urticaria following the administration of serum but
with no other symptoms of serum sickness, ephedrine produced no re-
lief. Althausen and Schumacher reported that ephedrine gave
prompt relief from itching and brought about disappearance of the
lesions in a case of toxic erythema accompanied by pruritus, and
effected improvement in 2 cases of urticaria but gave no relief in 5
other cases of urticaria and 3 cases of angioneurotic oedema. Encour-
aging results were obtained by Thomas in a few cases, and by Munns
and Aldrich in a case of urticaria; by Berger and Ebster in a case and
by Wilkinson in 2 cases of chronic urticaria; by McPhedran in a case of
angioneurotic oedema; and by Sgard in a case of painful and purulent
polymorphous erythema.
b. In dermatitis medicamentosa. Perutz recommends the use of
ephedrine in anaphylactic reactions from turpentine. Stokes and
Mclntyre studied 68 cases which showed reactions towards arsphena-
mine injections. They found that in 57.5 per cent of them ephedrine
relieved such symptoms as nausea, headache, vertigo, dizziness, urti-
caria, pruritus, pain, choking, coughing and repeated nitritoid crises.
Besides, ephedrine reduced the fall of blood pressure from 28 to 6
mm. Hg.
c. In kprosy. The fact that epinephrine relieves the nerve pains
of lepers led Muir and Chatterji to use ephedrine for this purpose in
13 cases. They found that ephedrine does not interfere with the
simultaneous use of potassium iodide, and its action lasts for 12 to 24
hours. In their opinion, the beneficial effect is probably due to con-
traction of the arterioles of the nerve trunks, thereby relieving their
82 K. Z. CHEN AND CARL P. SCHMIDT
vascular engorgement. They admit that in certain cases ephedrine
does not give relief. Cochrane and Mittra reported 10 cases of leprosy
in which the lepra reactions, such as nerve pain, joint pain, swelling and
other manifestations, were controlled by ephedrine. They consider it
an extremely useful drug in relieving the distressing symptoms of
lepra reactions. The relief is usually complete. Ephedrine has no
action on the temperature, nor does it reduce the eruptions which
appear during reactions in skin cases. According to these authors, the
lepra reactions are allergic manifestations and ephedrine like epi-
nephrine, is able to alleviate allergic conditions.
13. In dysmenorrhea
Assuming that dysmenorrhea is due to local or general increase
of parasympathetic activity, Lang used ephedrine in 30 cases of
essential dysmenorrhea. There was not only complete freedom from
or diminution of pain, but also diminution of menstrual flow by one-
half to one-third. Ephedrine was given as soon as pain appeared,
usually 2 to 3 times a day. One patient experienced pain and a feeling
of cold in the legs. Palpitation and tremor were observed in other
cases. In one patient, repeated curettage did not produce any effect,
but the use of ephedrine actually yielded good results.
VI. ACTION OF SYNTHETIC EPHEDRINE AND COMPOUNDS OPTICALLY
ISOMERIC WITH OR RELATED TO EPHEDRINE
1. Synthetic or dl-ephedrine
No sooner was the natural or /-ephedrine introduced to medical
use than the synthetic or <#-ephedrine became a subject of study. It
is optically inactive and is marketed by Merck under the name of
Ephetonin. Kreitmair showed that qualitatively there is no difference
between the action of natural and synthetic ephedrines. Thus,
it has a prolonged pressor action, antispasmodic action, detoxifying
action against scopolamine or morphine, oxytocic action and effec-
tiveness by mouth. His results are in general confirmed by Chen and
by Pak and Read, although the last two authors believe that the
synthetic product is less sympathomimetic than the natural. Coelho
in chloralosed dogs observed with electrocardiograms the appearance of
EPEEDEINE AND RELATED SUBSTANCES 83
extrasystoles, changes in Q.R.S. and alteration in T waves, block, and
finally ventricular fibrillation, with various doses of synthetic ephe-
drine. As with the natural drug, Chen found relaxation of the isolated
rabbit's intestine, hyperglycemia in rabbits, mydriatic action in ani-
mals and in men, contraction of the nasal mucous membrane and acces-
sory sinuses and a decrease followed by an increase of the kidney
volume, with synthetic ephedrine. He also observed that there is a
diminution or loss of pressor action if it is injected intravenously after
a previous dose of itself or of natural ephedrine.
In men, Hess, Petow and Wittkower, Saxl, Berger, Ebster and Heuer,
and Nardelli reported a rise of systolic blood pressure by oral or rectal
administration or subcutaneous injection of synthetic ephedrine.
Berger, Ebster and Heuer, and Nardelli noted a primary leucopenia
and secondary leucocytosis following the subcutaneous injection of
synthetic ephedrine. Lublin showed that the synthetic product, when
given by mouth, like the natural, produces hyperglycemia and inhibits
the conversion of carbohydrates into fat. Cannavd obtained similar
results. Euler and Liljestrand showed that synthetic ephedrine in
men increases the 62 consumption and the minute cardiac output.
Synthetic ephedrine delays the emptying time of the stomach and
decreases the gastric acidity, as reported by Takacs. Fonseca and
Trincao state that oral ad-ministration diminishes but subcutaneous
injection increases the gastric acidity.
Quantitatively, Kreitmair in his preliminary communication con-
cluded that there was no difference between the natural and synthetic
ephedrines. Hess shared the same opinion for men by oral or rectal
administration. Petow and Wittkower, Saxl, and Berger, Ebster and
Heuer, on the other hand, seem to agree that synthetic ephedrine has a
weaker pressor action in men. Chen in 9 subjects found that the
changes in blood pressure by the oral use of synthetic ephedrine are
much less uniform than by that of natural ephedrine. Compared in-
directly in pithed cats against epinephrine, the average ratio, as found
by Chen, of the intensity of pressor action of synthetic ephedrine to
that of natural ephedrine with optimal doses is 1:1.33. Curtis,
using the same method, determined the ratio to be about 1:2. Schau-
mann, and Launoy and Nicolle arrived at the same conclusion. Pak
and Read, making direct comparisons in anesthetized dogs, gave the
84 K. K. CHEN AND CARL P. SCHMIDT
ratio of synthetic to natural ephedrine as 0.7:1 (or 1 : 1.43), which is
close to the one obtained by Chen. A quantitative difference can
also be shown in their mydriatic action. Under controlled illumina-
tion and with accurate measurements, Chen determined in Caucasians
the average ratio of the mydriatic action of synthetic ephedrine to that
of natural ephedrine to be 1 ; 1 .29. Regarding the toadcity, Kreitmair
found it to be the same in mice either by intravenous injection or by
oral administration. Chen recorded that synthetic and natural ephe-
drines, in the form of the hydrochlorides, given intravenously, both
have a M.L.D. of 60 mgm. per kilogram in white rabbits. Pak and
Read state that synthetic ephedrine is less toxic than natural ephedrine
in frogs, rats, rabbits and dogs ; the reverse is true for hamsters. King
and Pak studied in anesthetized dogs the ratio of the shrinkage of the
nasal mucous membrane produced by natural and synthetic ephe-
drines, respectively, and determined it to be 1 :0.8.
Clinically, synthetic ephedrine has been tried wherever natural
ephedrine is indicated. Petow and Wittkower treated 20 cases of
bronchial asthma by oral use of synthetic ephedrine. Their results
showed that in 12 cases the synthetic product rendered daily injections
of epinephrine and asthmolysin unnecessary, in 5 it effected transient
improvement without preventing severe attacks, but in the remaining
three there was no response to the drug. Fischer treated 1 1 asthmat-
ics with synthetic ephedrine and recorded improvement in 10. Ber-
ger and Ebster in an elaborate investigation recorded unquestionable
benefit from synthetic ephedrine in 10 cases of asthma and less signifi-
cant results in 2 severe cases of the same ailment. Neustadt studied
22 cases of bronchial asthma with synthetic ephedrine, and obtained
good results in 16. SSgard treated 70 cases of asthma with the same
drug and reported relief in 60 per cent, temporary or irregular improve-
ment in 30 per cent, but no effect in 10 per cent. Gay and Herman
(cited by Chen) used synthetic ephedrine in 16 cases of bronchial
asthma, recorded relief in 7, questionable relief in 1, and no relief in 8.
Favorable results in the treatment of asthma with the synthetic com-
pound have also been reported by Jankowski, Beck, Guttmann, and
Hamming. The majority of these investigators appear to agree that
synthetic ephedrine is useful, like the natural product, in the preven-
tion and arrest of mild and moderate attacks of asthma but less promis-
EPHEDRINE AND BELATED SUBSTANCES 85
ing in severe cases, and that it has a weaker action but produces less
untoward symptoms than natural ephedrine . The dosage of synthetic
ephedrine varies according to individual tolerance, but the average
dose lies between 25 and 150 mgm. per os.
Saxl treated 11 cases of emphysema with synthetic ephedrine, and
reported success in 8 but no effect in 3. Similar improvement was
observed by Berger and Ebster in 3 cases of chronic bronchitis with
emphysema, chronic bronchitis and bronchitis associated with pul-
monary tuberculosis. In hay fever Berger and Ebster, Kreitmair and
Nardelli advocated the oral use and local application of synthetic
ephedrine. Berger and Ebster observed relief of headaches in one
case of hemicrania with angioneurotic oedema, but no effect in a case of
chronic urticaria. Improvement of symptoms was reported by Frankel
in a severe case of urticaria, by Sack in 20 cases of eczema, and by
Nardelli in three cases of alimentary urticaria and two cases of
arsphenamine intolerance. Michalowsky was successful in relieving
malaise from roentgenological treatment, Poppe in controlling the
untoward symptoms of withdrawal of morphine in two addicts, and
Parade and Voit in arresting the attacks in a single case of Adams-
Stokes' syndrome. In practically every instance, synthetic ephedrine
was given by mouth. For acute infectious rhinitis, Berger and Ebster
used a 5 per cent solution of synthetic ephedrine as a spray. Slack
(cited by Chen) found that in 4 cases of hypertrophied turbinates and
3 cases of acute rhinitis, a topical application of the 5 per cent solution
produces a marked contraction of the turbinates. In a few other
cases of swollen turbinates, where natural and synthetic ephedrine
were used side by side in the same individuals, he was unable to
detect any significant difference between their constricting power.
Frankel described a case of vasomotor rhinitis in an opera singer, with
symptoms of sneezing, running of the eyes and dyspnea which were
controlled by the oral administration of synthetic ephedrine. Sattle
advocated the use of synthetic ephedrine in ophthalmology. Ac-
cording to him, a solution containing 5 per cent of synthetic ephedrine
and 0.3 per cent of homatropine produces good dilatation of the pupil.
2. Pseudoephedrine
The natural pseudoephedrine is dextro-rotatory and is obtained from
several species of Ephedra, including the ones yielding natural or I-
86 K. Z. CHEN AND CARL F. SCHMIDT
ephedrine. The mydriatic action of pseudoephedrine was first studied
by De Vriesse (1889). He observed that a 10 to 12 per cent solution
when applied locally to the eye of men produces, in from 30 to 35 min-
utes, mydriasis which lasts from 6 to 9 hours. There are no secondary
effects after a single instillation, nor after its prolonged use, and no
changes in intra-ocular pressure. Giinsburg (1891) in an extensive
study on animals and 120 patients presented evidence that the mydria-
sis produced by pseudoephedrine is caused by sympathetic stimulation.
Grahe (1895) observed a slight rise of blood pressure in curarized cats
after subcutaneous injection of the drug, and depression, block,
arrhythmia and stoppage of the frog's heart at diastole, following the
administration of pseudoephedrine. Fujii (1925) made a compara-
tive investigation of pseudoephedrine with ephedrine. He reported
that pseudoephedrine has a weaker pressor action in rabbits and a
weaker mydriatic action on the enucleated frog's eye. It dilates the
blood vessels in small doses but constricts them in large concentra-
tions, as shown by theperfusion of the frog's legs and the rabbit's ear.
Similarly, it relaxes the isolated rabbit's small intestines in small
concentrations but stimulates them in strong solutions. It contracts
the isolated rabbit's uterus in all concentrations. On the basis of these
data, Fujii concluded that pseudoephedrine, like ephedrine, stimulates
the sympathetic nerve endings but, unlike ephedrine, acts on smooth
muscles directly in small doses. The same view is held by Pak and
Read and by Chopra, Dikshit and Pillai. Chen made a similar com-
parative study, and reported that pseudoephedrine has a weaker pres-
sor action in dogs and in men, and a weaker mydriatic action in men.
Vasodilatation in frogs and toads was reported by Loo and Read.
Upon perfusion of the toad's heart, pseudoephedrine in the concentra-
tion of 1 : 20,000 causes a decrease in rate but an increase in amplitude.
Larger concentrations (1 :200) produce cessation of cardiac activity, as
shown by these workers. Pak and Read found that ergotoxine does
not invert, but cocaine abolishes, the pressor action of pseudoephe-
drine. Liljestrand observed that pseudoephedrine contracts the
isolated guinea pig's uterus and human uterus and that it has a
stimulating action on the fundus of the rabbit's urinary bladder
but no effect on the trigone.
Quantitatively, Chen, Wu and Henriksen recently compared indi-
EPHEDRINE AND BELATED SUBSTANCES 87
rectly in pithed cats the pressor action of pseudoephedrine and ephe-
drine, and found the average ratio of the intensity to be 1 : 5.1 7; that
is, ephedrine is about 5 times as strong as pseudoephedrine. Pak and
Read, by direct comparison in anesthetized dogs, concluded that
ephedrine is twice as strong as pseudoephedrine. Their method is
subject to criticism, as shown by Pittenger. King and Pak compared
the shrinkage of the nasal mucous membrane in anesthetized dogs with
ephedrine and pseudoephedrine and found the ratio to be 1 : 0.38. The
toxicity was compared by Fujii who found that pseudoephedrine is
less toxic in frogs but more toxic in mice. In white rabbits the
M.L.D. of pseudoephedrine hydrochloride is 75 mgm. and that of
ephedrine hydrochloride is 60 mgm. per kilogram of body weight, as
shown by Chen, Wu and Henriksen. Pak and Read reported that
pseudoephedrine is less toxic than ephedrine in frogs, rats, rabbits
and dogs; the reverse is true in hamsters.
Clinically, Howard and Lee tried out a 10 per cent solution of pseu-
doephedrine in their eye clinic and concluded that it is an uncertain
mydriatic and has no place in the treatment and examination of oph-
thalmic diseases. Since its action is much weaker than that of either
natural or synthetic ephedrine, it is not used in this branch of medicine,
although it has been advocated by Chopra, Dikshit and Pillai on the
basis of their experimental results.
3. Other optical isomers of ephedrine
Kreitmair showed that d-ephedrine is weaker in pressor action than
/-ephedrine. This has been confirmed by Chen, Schaumann, and
Launoy and Nicolle. Recently, Chen, Wu and Henriksen compared
the pharmacological activity of the six optical isomers of ephedrine,
courteously supplied by E. Merck of Darmstadt and Merck and Co.,
Rahway, N. J. The results are summarized in table 4. It will be
seen that the mydriatic action of /-ephedrine and d-pseudoephedrine is
greater than that of d-ephedrine and /-pseudoephedrine, respectively.
When indirectly compared for pressor action in pithed cats with epi-
nephrine, /-ephedrine is found to be about 3 times as strong as d-
ephedrine, and (/-pseudoephedrine 7 times as strong as /-pseudoephe-
drine. /-Ephedrine, the strongest isomer, is 35 times as powerful as
/-pseudoephedrine, the weakest isomer of the six. When given by
88
K. K. CHEN AND CARL P. SCHMIDT
mouth to men in the same quantity, d-ephedrine and /-pseudoephedrine
do not appear to raise the systolic blood pressure while the other four
isomers do. Of the two sets of isomers ^-ephedrine and J-pseudo-
ephedrine have the least toxicity.
TABLE 4
Pharmacological activity of the optical isomers of ephedrine
XFHEmUNE ISOMKB
/-
*-
<i-
<f/-Pseudo
^Pseudo
EATIO OT FKESSOX
ACTION IN AOTUALS
ERESSOK ACTION IN
HEN PIS OS
35.15
+
26 40
+
11 90
6 80
+
400
+
1.00
1LLJ) IS-WSOS
XABBITB
fflffli. jr kgm.
60
60
80
75
70
80
4. Compounds related to ephedrine
It has been shown that jS-phenylethylamine, CaH B - CH S - CH a -NH s ,
has a stronger pressor action than ephedrine (Chen, Alles) but is useless
when given by mouth. The M.L.D. of the hydrochloride of 0-
phenylethylamine in white rabbits, given subcutaneously, is 300 mgm.
per kilogram of body weight.
Phenylethanolamine, CBHs-CHOH-CHj-NHa, was first synthe-
sized by Kolshorn (Ber. deut. chem. Gesell., 1904, xxxvii, 2474),
later by Rosenmund (Ber. deut. chem. Gesell., 1913, xlvi, 1034),
and Mannich and Thiele (Arch. Pharm., 1915, ccliii, 181), and is cov-
ered by two German patents (D. R. P. 193, 631 and D. R. P. 244,321).
The pressor action of this compound was described by Barger and
Dale (Jour. Phys., 1910-11, xli, 19) and by Hirose. Alles recently
found that it has a blood pressure effect in rabbits that is initially
greater than and finally comparable with that of ephedrine, and a lower
toxicity in guinea pigs by subcutaneous injection. The same author
states that its tozicity is higher than that of ephedrine in rabbits by
intravenous injection, while Chen, Wu and Henriksen reported the
reverse in white rabbits. Tainter believes that the action of phenyl-
ethanolamine is on the smooth muscles directly. Miller and Piness
showed that this compound does not raise the blood pressure in men
EPHEDRINE AND RELATED SUBSTANCES 89
when taken by mouth and is useless in the treatment of asthma, but
its activity on the congested nasal mucous membrane is in every
respect comparable to that of ephedrine. Their results are in general
confirmed by Chen, Wu and Henriksen.
Nor-ephedrine, CeHs-CHOH-CHCHs-NHz, was obtained in a
racemic form by Rabe and Hallensleben (Ber. deut. chem. Gesell.,
1910, xliii, 2622), Calliess, Nagai, and Eberhard (Arch. Phann., 1917,
cclv, 140). Nagai patented his product under the name of Mydria-
tine in the United States (U. S. Pat. 1,356,877) and in Japan (Jap Pat.
27,056). Miura found that this compound (mydriatine) has a strong
mydriatic action in men. The pupil begins to dilate in 20 to 30 min-
utes and the mydriasis lasts for 24 to 36 hours. The accommodation
is not unpaired. Hirose first observed its pressor action in animals.
Amatsu and Kubota concluded that its action is quantitatively the
same as that of ephedrine. Their data show that the M.L.D of
mydriatine sulphate, given subcutaneously, is 0.4r-0.5 mgm. per gram
in frogs, and 400 to 500 mgm. per kilogram in rabbits. Chen, Wu and
Henriksen conclude from their study of ephedrine homologs and
isomers that primary amines are more powerful than their correspond-
ing methylated derivatives, and predicted that nor-ephedrine would
be stronger than J/-ephedrine. This has been found to be true. The
compound also raises the systolic blood pressure in men when given
by mouth in 50 mgm. dosage. Its M.L.D. intravenously in albino
rabbits is approximately 70 mgm. per kilogram of body weight.
Kanao succeeded in resolving the racemic mixtures of nor-ephedrine
into six optical isomers. According to Hirose (cited by Kanao), the
order of activity of these optical isomers is as follows:
Nor-^-pseudoephedrine > nor-dJ-ephedrine = nor-J-ephedrine
Nor-tZ-ephedrine < nor-/-eph.edrine
Nor-d-pseudoephedrine > nor-/-pseudoephedrine < nor-/-ephedrine
Nor-^pseudoephedrine also occurs in Ma Huang, as shown by Smith,
and confirmed by Nagai and Kanao. Chen, Wu and Henriksen
reported that nor-d-pseudoephedrine has a weaker action than /- or dl-
ephedrine, but a stronger action than ^-pseudoephedrine. It raises
the systolic blood pressure in men when given by mouth.
Tiffeneau, and TifFeneau, L6vy and Boyer synthesized three com-
90 K. K. CHEN AND CARL F. SCHMIDT
pounds of the general formula C^-CHOH-CHR-NHs, where R is
ethyl, propyl or phenyl. The ethyl compound, C 6 H B -CHOH--
CHC a H B -NH 2 , called nor-homoephedrine, has a prolonged pressor
action and a M.L.D. of 130 mgm. per kilogram in guinea pigs by
subcutaneous injection, and inhibits the movements of the isolated
dog's intestines, as shown by Tiffeneau. Its pressor action is weaker
than that of ephedrine (Chen, Wu and Henriksen) . The propyl and
phenyl derivatives have a depressor action, as reported by Tiffeneau,
Levy and Boyer.
Hyde, Browning and Adams synthesized a series of compounds of
the general formula CflH B -CHOH- CHR'-NHR", where R' is hydro-
gen, methyl, or -propyl, and R" is methyl, ethyl, -propyl, iso-
propylj w-butyl or w-amyl. Most of these substances, including two
prepared by Manske in which R' is methyl and R" is oxyethyl or
benzyl were studied pharmacologically and compared with ephedrine
by Chen, Wu and Henriksen . They are weaker than ephedrine . The
general conclusion drawn by these workers was that with increase in
the number of C-atoms in R' and R" the cardiac depressant action
increases, the toxicity rises and the pressor action becomes a depressor
action when R 7 or R" is equal to a propyl or higher alkyl group.
ELanao prepared a similar series of compounds of the general formula
C fl H B -CHOH-CHCH 3 -NHR, where R is ethyl, wo-amyl, heptyl,
benzyl, 0-hydroxybenzyl, 0-vanillyl, vanillyl, piperonyl, w,-dihy-
droxybenzyl, furfuryl or citryl. He states that the hydrochloride of
the citryl derivative has a strong local anesthetic action.
/-Methylephedrine, a tertiary amine isolated from Ma Huang by
Smith, was proved to be much less active than ephedrine, a secondary
amine, by Chen, Wu and Henriksen. The same conclusion was
reached by Curtis with a series of tertiary amines related to ephedrine
of the general formula CeHe-CHOH-CHCHa-NR'R'', where R' is
methyl or ethyl, and R" is methyl, ethyl, oxyethyl, -propyl, iso-
propyl or butyl. Some of these compounds, however, produce dilata-
tion of the bronchi equal to that of ephedrine. The tertiary amine of
the formula C fl H 6 -CHOH-CHC2HB-N(C 4 H 8 ) 2 , prepared by Hyde,
Browning and Adams, has a depressor action, as shown by Chen,
Wu and Henriksen.
Nagai synthesized the following two substances with the idea that
EPHEDRINE AND RELATED SUBSTANCES 91
they might possess the anesthetic property of cocaine and the styptic
action of epinephrine:
C.H. CH CHCHa N(CjHn)t CsHj CH CHCH, NHC S H,
O CO-CeHs O-CO-CeHs
Attocain A Allocain S
His process has been patented in Canada (Can. Pat. 177,019), Japan
(Jap. Pat. 32,476) and the United States (U. S. Pat. 1,399,312).
Kubota studied allocain S and found it to have a local anesthetic
property but that it produces a primary fall of blood pressure in
animals. The substance causes local irritation and necrosis so that its
clinical use does not seem justifiable.
Beaufour prepared w-methoxymethylephedrine, CaH B -CHOH-CH-
(CH 2 - OCHs) -N(CH 8 )2, and found it to have a local anesthetic action.
Brauchli and Cloetta reported that diallylephedrine, C e H B -CH-
(OC 3 H 6 ) CHCH 8 NCH 3 (C 8 H 6 ), has a depressor action.
Emde and Runne synthesized a-isoephedrine, C 6 H 5 -CHNHCH8--
CHOH-CHs. This compound is of interest because ephedrine for
some time was considered to have the same structural formula.
Dulire made synthetically several ethers of phenylpropanolamine,
and studied their pharmacological action.
Tyramine, H0<^ y>CH a CH 2 NH 2 , was proven to have a stronger
pressor action than ephedrine but to be useless when given by mouth
in men, as shown by Chen and Meek. Sympatol, H0<^ ^>CHOH- -
CHNHCHa, which has recently been studied as a possible substitute
for ephedrine by Ehrismann, Lasch, and Ehrismann and MalofF, has,
on the other hand, a weaker pressor action than ephedrine, as observed
by Chen, Wu and Henriksen. In view of the fact that the presence of
an OH group at the ^-position usually intensifies the action, and the
introduction of a methyl group on the a-C-atom from the N-atom
prolongs the action, Chen, Wu and Henriksen suggested the synthesis
of the compound H0<( )>CHOH CHCHs NH 2 , which was soon
achieved by Hartung of Sharp and Dohme, Baltimore. It has in
fact a prolonged and stronger pressor action, and is much less toxic,
than either dl- or /-ephedrine in animals, but it has not been demon-
92 K. K. CHEN AND CARL F. SCHMIDT
strated that it produces systemic effects when given by mouth in men.
Further study is needed here.
Tiffeneau, Levy and Boyer synthesized ^-methoxy-norhomoephe-
drine, CHsO^ ^>CHOH CHCaH s - NH a , and found it to possess a
greater pressor action than nor-homoephedrine. Kohler prepared p-
methoxyephedrine, CHaO^ ^>CHOH CHCHs NHCHs, and m-
methoxy-^-oxyephedrine, HO<^ ^>CHOH CHCHj NHCH g , and
CHsO
found them to have no pressor action in rabbits.
It is universally agreed that epinephrine H0<^ ]>CHOH CHj -
HO
NHCHs, has a strong but fleeting action, while ephedrine has a
weaker but more prolonged action. The latter produces systemic
effects when given by mouth. 0-Dihydroxyphenylethanolamine,
HO<^ ^>CHOH CH a NH 8 , also has a stronger pressor action than
HO
ephedrine, as shown by Hirose.
The compound HQ<( ^>CHOH CHCHg NH a , is mentioned in
HO
the German patent literature (D.R.P. 254,438, 256,750, 269,327)
and has been studied pharmacologically by Tiffeneau (1920). The
latter found that an Z-isomer resolved from its racemic mixture has 60
to 75 per cent of the activity of /-epinephrine, but he did not study the
duration of its action nor its absorption from the gastrointestinal tract.
It seems desirable to compare its action with that of ephedrine.
Kanao recently synthesized three series of compounds having the
general formulae:
CHsNHR 1 CHOH-CH,-NHR CHOH-CHCH 8 -NHR
O-COCH,
O-COCHj 0-COCHi
where R 1 is methyl, ethyl or propyl, R a is methyl, heptyl, benzyl,
piperonyl, diacetoxybenzyl, acetovanillyl or f urfuryl and R 8 is methyl,
EPHEDEINE AND RELATED SUBSTANCES 93
heptyl, benzyl or diacetoxybenzyl. The physiological activity of these
substances has not been reported.
From the above account it appears that there is no difficulty in
synthesizing compounds related to ephedrine that are stronger
pharmacologically in animals, especially by making primary amines
and introducing 1 or 2 OH groups on the benzene ring. A prolonged
action may also be imparted to them by introducing a methyl group
on the a-C-atom from the N-atom. The absorbability from the
gastrointestinal tract seems to be a peculiar feature of ephedrine, and
this has made ephedrine particularly useful clinically because the drug
can be given by mouth. Among the synthetic compounds, ^/-ephe-
drine and <f/-norephedrine resemble natural ephedrine most closely
and deserve a clinical trial. Some other compounds have a strong
contracting power on the congested nasal mucous membrane in men,
and a comparative study may yield profitable results.
vn. SUMMARY
The following very brief summary is made from the practical point
of view.
1. Ephedrine is the chief active principle occurring in the Asiatic
species of Ephedra. The other constituents that are present in
the Chinese species are pseudoephedrine, nor-<2-pseudoephedrine,
/-methylephedrine, and d-methylpseudoephedrine.
2. Ephedrine is a stable compound. Its solutions are not decom-
posed on exposure to air, light or heat, or by long standing.
3. Ephedrine has been successfully synthesized by various methods.
4. In mammals, ephedrine in suitable doses raises the blood pressure,
increases cardiac activity, dilates the pupil, relieves broncho-spasm,
contracts the uterus, more frequently inhibits than stimulates the
gastrointestinal tract. These effects can be explained by the stimu-
lation of the myoneural junctions of the sympathetic fibers. In cer-
tain instances, there is an additional stimulation of the ganglia. It
has been claimed by some investigators that it acts on the smooth
muscles.
5 . In animals, ephedrine does not have a marked effect on any of the
body secretions.
94 Z. K. CKEN AND GAEL F. SCHMIDT
6. There is an increase in the formed elements of the blood and
hyperglycemia, following the administration of a suitable quantity of
ephedrine.
7. Ephedrine increases slightly the basal metabolic rate and the
oxygen consumption.
8. Ephedrine may stimulate the central nervous system.
9. Ephedrine is easily absorbed and has a low toxicity.
10. In clinical use, ephedrine can be applied locally and given
by mouth or by injection. Individuals who do not have a vago-
sympathetic equilibrium may experience untoward symptoms.
11. Ephedrine has been used with success in the treatment of bron-
chial asthma, hay fever, whooping cough, bronchitis, postural hypo-
tension and Adams-Stokes' syndrome, in combating the fall of blood
pressure in spinal anesthesia, in antagonizing the action of narcotic
drugs, in shrinking the congested nasal mucous membrane, and in
dilating the pupil for ophthalmic examination. Its value in dermatol-
ogy, shock and dysmenorrhea is promising.
12. Compared with epinephrine, ephedrine has a less intense but
more prolonged action.
13. Of the many synthetic compounds, dZ-ephedrine and dl-noi-
ephedrine deserve more extensive clinical trials.
This review is intended to be as concise as possible. Naturally
the authors could not discuss many valuable papers as fully as they
desired. The literature consists of all those articles available on or
before November 1, 1929.
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L I B R A R Y
EPHEDKINE AND RELATED SUBSTACX 99
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Department of Commerce, Chemical Division, Bureau of Foreign and Domestic Com-
merce, Washington; World Trade Notes on Chemicals and Allied Products.
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~S 1
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INDEX
Absorption, 59, 94
Action, mode of, 46
Adams-Stokes 1 syndrome, use in, 75, 94
Addison's disease, 43, 44, 55, 56, 72
Administration, methods of, 62, 94
Adrenaline, see epinephrine
Alkaloids other than ephedrine in Ma
Huang, 14, 93
AUocain A, 91
Allocam S, 91
Arsphenamine reactions, use in, 81
Asthma, pressor action in, 22
treated with synthetic ephedrine, 84
use in, 65, 94
Asthmatol, 6, 11
Atropine, 23, 24, 25, 27, 34, 35, 38, 41, 47,
54, 57, 64, 70, 73, 78, 79
Bile, effect on, 41
Bladder, urinary, action on, 40, 53
Blood cells, influence on, 42, 94
Blood pressure, diminished effect on by
repeated injections, 19
effect upon, 17, 21, 93
Blood sugar, influence on, 43, 94
Blood vessels, action on, 29, 31
Bronchi, action on, 40, 93
Bronchitis and emphysema, use in, 70, 94
Capillaries, action on, 31, 32
Cardiac insufficiency, 64, 65, 73
Cardiac output, effect on, 26
Central nervous system, action on, 17, 45,
46, 64, 94
Chemical properties, 12, 13
Cocaine, effect on pressor action, 50, 86
Commercial development, recent, 11
Contraindications, 65
Council on Pharmacy and Chemistry,
A. M. A., 7, 8
Crabs' hearts, action on, 24
Crop muscle of pigeon, action on, 35
Diallylephedrine, 91
o-Dihydroxyphenylethanolamine, 92
Dosage, 62
Dysmenorrhea, use in, 82, 94
Electrocardiogram, effect on, 26, 28, 64, 75
Ephedra, habitat, 7, 8
species of, 4, 7
species of, containing ephedrine, 8
Ephedrine hydrochloride, 12
export of, 11
Ephedrine sulphate, 12
Ephetonin, 15, 82
Epinephrine, 3, 4, 6, 7, 13, 15, 16, 17, 18, 19,
20, 21, 22, 24, 25, 26, 29, 30, 31, 32,
33, 34, 35, 36, 37, 38, 39, 40, 44, 46,
47, 48, 49, 50, 51, 52, 53, 55, 57, 58,
64, 65, 66, 68, 74, 76, 79, 80, 81, 82,
83,84,87,92,94
combined with ephedrine, 21, 68
vs. ephednne, 18, 55, 59, 66, 76, 94
Ergotamine, see ergotozLae
Ergotozine, effect on pressor action, 48,
52,86
Excretion, 59
Formula of ephedrine, 13
Frog's heart, action on, 23
Gastric secretion, effect on, 41
Graves' disease, 22, 65
Habit formation, 65
Hay fever, use in, 69, 94
Heart, action on, 23, 27, 46, 93
Hippuris, 4
History, 4
Hodgkm's disease, 43, 44
Hypotension, use in, 72, 94
Insulin, effect on pressor action, 51
Intestinal secretion, effect on, 41
119
120
INDEX
Intestine, isolated, action on, 37
large, action on, 37
small, action on, 36
small, plexus free, action on, 47
Isoephedrine, IS
ce-Isoephedrine, 91
Isolation of ephedrine, 5, 7, 9
Isomerism, 13
Leprosy, use in, 81
Lufinus albus, seedlings of, action on, 16
Lymph, effect on, 42
Ma Huang, 4, 5, 7, 8, 14, 41, 89, 90
assay for ephedrine, 10
export of, 11
identification of, 8
price of, 12
Mammalian heart, action on, 25, 27
Metabolism, influence on, 44, 94
^>-Methoxyephedrine, 92
co-Methoxymethylephedrine, 91
^-Methoxy-norhoraoephedrine, 92
m-Methoxy--oxyephedrine, 92
Z-Methyl-ephedrine, 14, 90, 93
Methylmydriatine, 14
d-Methyl-pseudoephedrine, 14, 93
Minimal lethal dose, 59
Motor nerve, action on, 45
Musculotropic action, 17, 47, 48, 49, 50, 52,
57
Mydriatic action in different races, 78
Mydriatine, 89
Mydrin, 78
Myoneural junctions, action on, 55, 93
Myzedema, 22
Nasal plethysmography, 77
Nicotine, 34, 37, 52, 53
Nor-ephedrine, 89, 93, 94
Nor-homoephedrine, 90
Nor-^-pseudoephedrine, 14, 89, 93
Nose, use in, 62, 69, 76, 94
(Esophagus, effect on, 35
Ophthalmology, use in, 6, 62, 77, 94
Optical isomers of ephedrine, action of, 87
Parasympathetic system, action on, 53
Pentsao Kang Mu, 4, 41
Phenylethanolamine, 88
0-Phenylethylamine, 88
Phenylpropanolamine, ethers of, 91
Physical properties, 12, 93
Plexus of Auerbach, stimulation of, 52, 57
Pneumonia, use in, 73
Pseudoephedrine, 11, 14, 17, 23, 24, 40, 85,
93
action of, 86
vs. ephedrine, 86
Pulse rate, effect on, 25, 27
Pupil, action on, 33, 93
denervated, diminished response in, 34
Related compounds of ephedrine, 88
Repeated administration in animals, 61
Respiration, action on, 32
Respiratory depression and failure, use in,
79
Salivery secretion,, effect on, 40
Scopolamine combined with ephedrine, 79
Sea crab (Palaemon), action on, 16
Sensory d[erve, action on, 46
Serum albumin and globulin, effect on, 44
Shock, use in, 74, 94
Smooth muscle, action on, 33, 51, 93
Snail's heart (Helix pomatia), action on, 24
Spinal anesthesia, use in 71, 94
Squid (Loligo peatii), action on, 16, 45, 61
Stellate ganglia, action on, 25, 29, 57
Stomach, action on, 35
Suprarenal gland, stimulation, 55, 57
Sweat glands, effect on, 41
Sympathomimetic action, 3, 4, 15, 46, 47,
48, 50, 52, 57
Sympatol, 91
Symptoms, toxic, in animals, 61
untoward, 63, 94
Synthesis, 14, 93
Synthetic ephedrij^e, action of, 82
clinical use of, 84, 93, 94
vs. natural, 83
Toad's heart, action on, 24
Tolerance, development of, 62, 65
INDEX
121
Toxicity, 59, 94
Turpentine reactions, use in, 81
Turtle's heart, action on, 24
Tyramine, SO, 91
Ureter, action on, 39
Urine, effect on, 42, 64
Urticaria, use in, 80
Uterus, action on, 39, 93
Venous pressure, effect on, 23
Voluntary muscle, action on, 46
Whooping cough, use in, 70, 94
Yield of ephedrine, 9
seasonal variation, 10
Yohimbine, effect on pressor action, 50
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