Medicine Monographs MEDICINE reviews that MONOGRAPHS are comprehensive adequately discuss a disease, certain

aspects of a disease, or subjects that allow a better comprehension of disease processes. MEDICINE MONOGRAPHS will enable the teacher, the clinician, and the laboratory worker to have available, in convenient and readable form, critical digests of the recent views on general medicine, neurology and pediatrics. MEDICINE in MONOGRAPHS originally appeared MEDICINE, a quarterly periodical edited by

David L. EdsaU, Harvard Medical School; Associate Editor, Alan M. Chesney, Johns Hopkins Hospital. EPHEDRINE AND SUBSTANCES MEDICINE MONOGRAPHS VOLUME E BY K. K. CHEN Department of Pharmacology Johns Hopktns Umverstty AND CARL F. SCHMIDT Department of Pharmacology Untverstty of Pennsylvania BAILLIIiRE, 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 TINDALL AND COX P A N D XVII H E D R I N E SUBSTANCES R E L A T E D RELATED

of Pennsylvania CONTENTS L Introduction 2 Historical 4 II. 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-ihtestinal 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 43 b. Effects upon smooth, muscle 51 11. Absorption and excretion 59 12. Tojricity 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 availa BLE L. EdsaU P H N D R E L T SUBSTANCES X V E P H E D R N E ANDRELATEDSUBSTANCES K. K. C H E N Hopktns Umverstty R L F D T S C H M untverstty BAILLIITINDALLANDCOX

 1930 1930 E P H E D R I N E KK EH.D. Carl F. l 2 4 7 1 7 2 9 9 9 C 11 D 12 E 13 F 14 14 15 1 16 2 17 17 23 C 29 3 32 4 33 33 ihtestinal 35 C 39 D 39 E 40 5 40 40 41 C 41

D 41 E 41 F 41 42 42 6 42 42 43 1 2 K. K. 7 44 44 44 C 44 8 45 9 45 voluritary 10 46 43 51 11 59 12 tojricity 59 59 61 C 61 62 1 62 2 63 65 1 65 2 69 3 70 4 70 5 71 6 72 7 74 8 - 75 9 76 10 77

11 79 12 80 80 81 C 81 13 82 82 1 TW- 82 2 4 85 3 87 4 88 VTI 93 94 I. INTRODUCTION The rise of ephedrine from obscurity to its present state of widespread popularity, within less than five years, involves a variety of features of unusual interest. Much of the initial enthusiasm for the EPHEDRHSTE 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 possibilities 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 experimentsa circumstance which illustrates the readiness with which an initial misconception may be propagated and may influence the subsequent fate of a new remedy. 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. pated uses The result has been not only the discovery of unanticifor the drug butof greater ultimate importancea The

renewal of interest in the problem of the relation of chemical composition 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). from ideal in certain respects. 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. therapeutics since epinephrine was discovered, it has certainly been the object of more investigation than any other. In spite of this, the literature is full of disagreements and unjustified assumptions with respect to the fundamental features in the action of the drug, though the_ clinical results are quite uniform in indicating that it produces effects t h a t is inevitable that workers with other substances of this" sort will be confronted with the same difficulties. These can be obviated, to some 4e K. K. CHEN AND CAUL P. SCHMIDT extent at least, if it is generally realized that a drug can be sympathomimetic, 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 M a Huang, has been used by native physicians for some 5000 years. one of the drugs which is said t o h a v e been tasted by the Emperor I t was are of the same nature as those of epmeghrine. It For if ephedrine In the search for other remedies of this I t is now quite certain t h a t ephedrine, in spite of its present popularity, is far

is not the only agent of this sort to have been introduced into

Shen Nung, who placed it in the "medium class." Pentsao Kang M u , Shih-Cheng Li. the Chinese I t is mentioned in the 1596 by dispensatory, written in

According to this authority M a Huang is of value as An English

a circulatory stimulant, diaphoretic, antipyretic, sedative in cough, and it is an ingredient of m a n y famous prescriptions. paper by Hagerty and W o o . Plants similar to, if n o t identical with Ma Huang have been employed as medicines since remote antiquity in other parts of the world. Thus, it is said (Berendes) t h a t Greek physicians employed plants of the same genus (Ephedra) as M a Huang, and that the Hippuris of The top of Dioscorides (about 50 A.D.) w a s E. fragiUs var. graeca. to produce diuresis and t o were reputed to be useful in t h e treatment of cough, orthopnea, and internal rupture (Berendes). In Russia Ephedras have been in medical use since olden times. vulgaris, In the 19th century decoctions of E. were regarded as a specific remedy for syphilis and gout, the latter virtue being attributed to t h e twigs and roots of the plant. A peasant named Bechtin (1891) reported very striking results with decoctions of E. vulgaris in patients with rheumatism. In India the dried Sassetsky and Lewaschew, however, were of E. pachyclada, or E. intermedia, unable to confirm these results (Grahe). branches Kusmitsch effected such marvelous The sap and disorders. with cures candied fruits were used in t h e treatment of respiratory decoctions of Ephedra together with milk and cure dysentery, and both root and top translation of the ancient Chinese records can be found in the

this plant was used as a n astringent; taken with wine it was said

butter, were recommended in t h e treatment of rheumatism and

t h a t he won a wide reputation, and

EPHEDRINE AND BELATED SUBSTANCES 5 are thought to possess medicinal value, but they are chiefly used in religious (Parsi) ceremonials. I t is also said that this plant, mixed intoxication. with milk and honey and allowed to ferment, was the "soma" of the Vedas, which was used to induce an exhilarating 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 and gonorrhoea, and were used as local applications as well as by internal administration. The Coahuila Indians made a cooling beverage from E. nevadetisis, and the Panamint Indians made bread from the ground roasted seeds of the same plant. E. The Indians and Spaniards and In used decoctions of E. californica as a tonic and blood purifier, trifurca was regarded as an excellent remedy for nephritis. various purposes. E. antisyphilitica, E. caUfornica, and E. nevadensis were regarded as valuable in the treatment of syphilis

Mexico, E. aspera is still used occasionally in the treatment of pneumonia, and in Zacatecas E. pedunculate is highly esteemed as a remedy for pleurisy and pneumonia. It appears, therefore, that the Ephedras have long been utilized as empirical remedies in many discontiguous parts of the world. the whole, they seem to have enjoyed a reputation for two different sorts of usefulnessfirst, 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 M a 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 medicaincluding Ma Huangwas 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 On

impure substance. (1887). in 1888.

After his death the study was continued by Nagai,

with the assistance of Y. Hori, who obtained the alkaloid in pure form The same compound was obtained in Germany b y E . Merck The name ephedrine was first applied to this substance by

6 K. K. CHEN AND CARL P SCHMIDT . Nagaij though the name had already been coined in 1875 by Loew for the tannin which he had prepared from E. antisyphiUtica. ployed it, viz., to designate an alkaloidal active principle of Husmg and other Ephedras. Nagai's ephedrine was subjected to physiological investigations by Miura (1887). drug. This study disclosed the toxic effects of large doses upon the circulation and demonstrated the mydriatic action of the As a result it was introduced to Western medicine as a new Apparently it was mydriatic, but its vogue was limited and brief. substance. I t 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 undertaken the Japanese investigators Amatsu and Kubota (1917) demonstrated the essentially sympathomimetic (epinephrine-like) effects of ephedrine, and other workersHirose, and Toalso 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 condition that is relieved by epinephrinenamely, asthmathat an the the ephedrine-contaming preparation was put on the market in Mukden under the name of Asthmatol. No publication was made of and when the results obtained with this product question of Ma The name ephedrine is now used only in the sense in which Nagai em-

not utilized for other purposes and was regarded as a very toxic

therapeutic

possibilities

of

ephedrine

was

reopened

in

1923

this

development was unknown to the Western world (and to the authors). I t is proper, however, that the Japanese scientists should be given due credit for having been the first to appreciate the usefulness of ephedrine 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 EPHEDRINE AND RELATED SUBSTANCES concerning native actions. drugs which might Among others, Ma Huang was 7 be expected mentioned, to possess real a small and

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 experiments 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 Clinical trial of the drug was limited by the As soon as a substance as ephedrine.

small quantity of ephedrine available at the time.

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 subsequently 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. PHARMACOGNOSY AND CHEMISTRY

 EPHEDRHSTE 3 30 possi bilities unantici pated COM t THERA peutics

 the_ epmeghrine I T CON 4E K. K. sympa thomimetic M 5000 I T I T M U pentsao dispensatory 1596 M W O O EM ployed Berendes M Hippuris E. fragiUs VAR dioscorides 50 graeca ; Berendes Ephedras 19 SAP Kusmitsch Bechtin

1891 sassetsky Lewaschew Grahe E. pachyclada 5 ceremonials T E. antisyphiliticaE. caUfornica E nevadensis E. nevadetisis Panamint E. trifurca ASPERA E. pedunculate Ephedras M M G. 18 5

 Y. 1887 1888 6 K. K. nagaij 1875 antisyphiUtica EM- ployed Husmg Ephedras 1887 I T 12 Amatsu 1917 strated TION contaming Asthmatol 1923 t

 EPHE drine 7 1923 ments LG 1926 sequently H.

1.

Botany (family

Ephedrine occurs in certain plants of the genus Ephedra

Ephedraceae) which includes a large number of species (35, according to Engler and Prantl, 1926; 45, according to the Index Kewensis, 18951920). These are distributed throughout the temperate and sub-

tropical regions of Europe, Asia, and America.

They are found in an

area extending from the middle Amur region through central Asia, including its deserts and covering China and Arabia, to the Mediterranean and even to the Canary Islands (Engler and Prantl), as well as 8 K. K. (TFTF.N AND CARL F. SCHMIDT Siberia, Hungary, the Carpathian Mountains, the Western Alps, and Western France. I n the Americas they grow along the Rocky Mountains 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 ephedrine-bearing plants are found in the Tai-hung Mountains, which are the site of the Great Wall in Chihli Province. Shansi, Shensi, Kansu, associates, 1928). Honan, and Hupeh They also occur in Provinces (Read and

They are also found in Northern Chosen (Korea) In India and Tibet they occur

and in Akita Prefecture in J a p a n .

along the Himalaya Mountains (Chopra and associates). The actual identification of M a Huang has been somewhat uncertain. I t was formerly classified as E. vulgaris var. helvetica (Nagai; Botanical Nomenclature, etc.), b u t this name appears to be obsolete. Cowdry (1922) identified M a H u a n g as E. equisetina, the name recognized b y the Council on Phannacy and Chemistry of the American Medical Association for the plant from which ephedrine is obtained. Holmes (1926) suggested that M a Huang is E. intermedia var. tibetica, while Stapf pany. (1927) gave a provisional new name of E. and this is

sinica to specimens submitted by Read and by Parke, Davis & ComLiu and Read (1929) identified another species, . distaekya, which is found in Western Chihli and is also known as M a Huang. This statement needs confirmation. tained, is E. sinica been shown recently b y or intermedia, and E. intermedia var. helvetica. Their results have Chopra a n d his coworkers (1928), that ephedrine also occurs in the I n d i a n species, E. vulgaris, E. pachyclada or E. equisetina At present it appears that Ma ephedrine is obI t has (Smalland Short). Huang, from which most of t h e present supply of

been confirmed by Read and F e n g (1928). present, These are the principal natural sources of ephedrine at Europe, in Northern China and in J a p a n . examined but they contained no alkaloid, or only the isomeric pseudoephedrine, which is distinctly less useful than ephedrine. species E. trifurca, E. nevadensis, E. californica, by Nielson, McCausland, and Spruth, and found to contain no alkaloid. Terry obtained the same negative result with E. nevadensis. EPHEDRINE AND BELATED SUBSTANCES and Groff reported the of E. californica ttystaJJinV.aetive substance could be isolated. by De Eds and Butt or by Read and Feng. pseudoephedrine 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 (Nielson and McCausland, 1928). 2. Properties of a. Isolation. ephedrine having the solubility reactions of a Ephedrine, in E. alata, collected American Ephedras Black and Kelly found only in Morocco. None of the Their results were not substantiated and E. nevadensis, 9 substances^irrieXEracts no though presence of pressor Clark and E. viridis were examined T h e American Other Ephedras have been

though ephedrine is also found in plants growing in Southern

have been shown to contain ephedrine, and

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. means of chloroform The akaloid is extracted from them by Upon removal of the solvent the or ether.

residue is neutralized with dilute HC1 or H2SO4, thus forming the corresponding 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 Generally results, even with the same plant, as shown in table 1.

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 cent or more is ephedrine. E. intermedia 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 alkalinization of the percolate before extraction with chloroform or ether, and em10 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. studied the variations in yield of ephedrine from different parts of the plant a n d a t different seasons of the year (Feng and Read, 1928). They find The old Chinese custom of collecting the plant in the autumn appears to be based upon sound observation. TABLE 1 Assay of Ephedras reported by different workers Ma Huang Ma Huang season the male plant contains more alkaloid than therefore During the flowering the female, the progressive increase in total ephedrine content from spring to the maximum being attained just before the frosts. autumn, They have also Chinese plants: of this 80 per pachyclada and The Indian species E.

var. tibetica have a distinctly lower ephedrine content

Ma Huang Ma Huang Ma Huang Ma Huang E. Equisetina B. Sinica E. vulgaris E. vulgaris E pachyclada E. pachyclada E. intermedia var. Tibetica TOTAX AXXALoms, PER CENT OT CRUDE DKTTG 0 31-0 40 0 02-0 09 0 30 0.40-0 86 0 20-0 90 0 64-1 43 1 75 1 32 1 02-1 27 1.65-1 70 1 8 1 15 0.25-0 60 H-.fH KuBTEnr. PIE. CENT OS im. TOTAL 85-90 80-85 50 70-80 30-36 30-40 Chen

Masucci and Suto Schoetzon and Needham Neilson, McCausland 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. alkaloid content is practically equal in plants of both sexes. investigators find (in E. equisetina) less ephedrine than the internodes, and that the root, berries, seeds, and woody stalks contain none at all. Ephedra. T h e special tissue of the plant stem which is concerned in manufacturing or storing ephedrine has not been determined. EPKEDRINE 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. China. Ephedrine has been upon the market for more than 30 years. has It The recent popularity of ephedrine has led to the development of a considerable industry in Nothing is known about the manner in which it is synthesized by the plant or Similar conclusions were reached b y Chopra and his associates'with respect to Indian species of With respect to t h e distribution of alkaloid in different parts of the plant, these that the nodes contain much After the fruiting season the

been

listed

in

E.

Merck's

Index

since

1896.

Japanese

manu-

facturers (Dainihon Seiyaku Kabushiki Kaisha, of Osaka, later succeeded 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, Woodard, Assistant Shanghai, Ma Trade since the drug was scarcely According to Mr. G. States at Ma exclusively through of the United used at all except for chemical investigations. Commissioner exported Huang was almost Read

German firms for the past 30 years.

(1928) states that

Huang was probably never exported from Tientsin prior to August, 1926, but from this time the trade developed rapidly. 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. 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 Products of Peiping Union Medical College, was exported Tientsin as follows: in $3,688. Ma Huang 1926, 12$ pounds, valued has also been exported Chemical through (The figures for 1926 and 1927 By the end of 1926 the exports from Tientsin alone, and to the United States

at U. S. $3,612; Shanghai and

in 1927,23 pounds and $7,490; in 1928 (to December 1) 20 pounds and from 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, Osaka and ephedrine-containing and plants are also and exported from Tokyo, Japan, from Karachi

Rawalpindi, India.

The world supply of these plants appears to have

12 K. K. CHEN AND CARL F. SCHMIDT satisfied t h e demand during 1927, and is now greater, for the average price of M a 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. I n contrast with the two concernsone 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, b y two in Germany, by three in China, by four Japanese companies, and by two in India. others of which the writers are unaware. d. Physical colorless and odorless crystals appear as needles or recrystallization. The alkaloid and is These melt [a], of in soluble at The specific rotation, ether, paper. water, rosettes on standing or and7.5. petroleum litmus 34r-40C. and boil above 200C. chloroform, alcohol, and chemical characteristics. The alkaloid ephedrine is deposited from an ether solution as an oily substance, but There may be

the base is between6 being strongly Peterson,

ether,

the solutions

alkaline to

T h e crystallography of

ephedrine has been investigated by 1928). Geppert inA peculiar

Schwankte, and Walcott (quoted by

vestigated its effects upon the surface tension of water. is shaken with chloroform: this was Chen (1925) for ephedrine base. For laboratory and clinical uses the hydrochloride and

reaction of ephedrine is the formation of the hydrochloride when it pointed out by Peterson (1928),

and is responsible for the high melting point incorrectly reported by 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, 243C. []" - 2 9 to - 3 0 , containing 21.8 to 23.1 per cent of S C V ", soluble in water and hot alcohol, insoluble in ether, chloroform, and paraffine oil. ether, and paraffine oil. The sulphate occurs as fine, white, odorless crystals, melting at 240-

1 35 Prantl1926 45 Kewensis1895 1920 ranean Prantl 8 K K.TFTF.N n tains Ephedras EPHE drine ONAN 1928 J A P A N M TAIN I T E. VAR; cowdry1922 M uang Phannacy 1926 M tibetica Stapf1927 COMpany 1929 distaekya M OBtained E. Smalland I T 1928 EPHE drine ndian E.E. pachyclada

 F E N G1928 J A P A N Ephedras T H E. trifurcaE. nevadensis McCauslandSpruth E. nevadensis 9 groff ^ irrieXEracts E. E. nevadensis ttystaJJinV.aetive EDS Ephedras E.E. distachya McCausland1928 2 60 ammonum akaloid I T 1

 1 80 E. pachyclada tibetica EM10 K. K. phasize andat 1928 1 Ephedras pachyclada pachyclada tibetica TOTAX AXXA LOM CENT

DKTTG 0 31-0 40 0 02-0 09 0 30 0.40-0 86 0 20-0 90 0 64-1 43 1 75 1 32 1 2 1 27 1.65-1 70 18 1 15 0.25-0 60 H .fH KuBTEnr PIE CENT IM 85-90 80-85 50 70-80 30-36 30-40 masucci Suto schoetzon Needham McCausland sprunt Dikshit Dikshit Dikshit 5 LOID

 associates'with T facturing EPKEDRINE 11 C EPHE drine 30 I T E 1896 facturersSeiyaku Dainihon ceeded Asthmatol 1924 G. M 30 1928 8 1926 2000 1926 224058 17753 1927 622060 64840 1928 11 1003700 69300 1926 1927 ; 1928

 1926 12 $3612 ; 1927,23 7490 1928 12 1 20 3688 M A 12 K. K. 1927 M 1927 U 10.43 100 1928 6.91 n 1924 8 D 34R-40C 200C [A] 6 7.5 Schwankte1928 Geppert vestigated Peterson1928 1925 214-220 [A] - 33 -35.5; 17.317.7

 240-243C [] - 2 9 - 3 0 21.8 23.1 Solutions of ephedrine or its salts react with few of the alkaloidal reagents. (1927) With Mayer's reagent there is a turbidity or white preTsiang and Brown reactions when characteristic micro-crystalline cipitate, according to the degree of concentration. described EPHEDBINE AND RELATED SUBSTANCES 13 ephedrine is treated with Millon's reagent, gold chloride, chloride, or Kraut's reagent. platinic 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 b y E. Schmidt, Nagai, E. R. Miller, Flaecher, Calliess, Emde, and others. Probably the most important property is its stability: Thus, a ephedrine solutions are not decomposed by exposure to light, air, or heat, and age apparently does not affect their activity. 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 customa r y 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 isomeristn. The chemical constitution of ephedrine The empirical has been studied by Ladenburg and Oelschlagel, Nagai, E. Merck, E . Schmidt, E. R. Miller, Rabe, Ogata, and others. structural formula as CeHg-CHOH-CHCHs-NHCHs, or /3-phenyl-jS-hydroxya-methyl-ethyl-methyl amine, or l-phenyl-2-methylaminopropanol-l, o r a-hydroxy-)9-methylamino-propyl benzene: formula has been definitely established as C 10 Hi B ON, the

CHOH-CHJ-NHCHJ CHOH-CHCHi-NHCHa 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 and section); they are designated 1-, d-, mixtures. and dZ-ephedrines, d-, l- }

<#-pseudoephedrines, the dl forms being optically inactive racemic Only two occur in nature, namely Z-ephedrine, which is the ephedrine now in use, and ^-pseudoephedrine, which is also found in Ma Huang, and which is the pseudoephedrine first isolated by Merck from European Ephedra, removed. and recently prepared by Chou and PseudoRead (1926) from Ma Huang extracts from which ephedrine had been This is the pseudoephedrine of current literature. 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). Emde (1928) has obtained eviThe literature dealing with the isomerism of these alkaloids was reviewed by Chen and Kao (1926). dence that the -OH and NHCHs groups are distant from each other in the ephedrine molecule but close together in the pseudoephedrine molecule. / . Other alkaloids occurring in Ma Huang. alkaloids have been isolated from M a Huang. (1928) confirmed these findings, Smith (1927, 1928) obtained Nagai and Kanao Z-rnethyl-ephedrine and nor-rf-pseudoephedrine. alkaloid, namely, ^-methyl-pseudoephedrine. In addition to ephedrine and pseudoephedrine, three other related (but not isomeric)

and succeeded in isolating a third I t 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 ephedrine. He and his associates later methods. succeeded in the synthesis by (1927). different His process was patented in England

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 However, the case when an optically active substance is synthesized. EPHEDKINE AND BELATED SUBSTANCES 15 according to Ogata (1919), Nagai succeeded in 1918 in resolving his product into Z- and d-ephedrines. Recently, Nagai (1927) has stated that he was able to synthesize two racemic ephedrines, one melting a t 40, the other at 70, and in separating each into its d- and /-components by means of tartaric acid: the pair obtained from the mixture melting at 70 he called isoephedrines (identical with pseudoephedrines). also Spath and Gohring (1920) described their complete success Eberhard (1915) Kanao (1927) E. Merck in in the synthesis and separation of all six isomers. succeeded in synthesizing racemic ephedrine.

reported the success of his attempts to synthesize and separate the six isomers, confirming the results of Sp2.th and Gohring. the name of Ephetonin; Germany and England. Eleil (1929) have has recently placed synthetic racemic ephedrine on the market, under the process of preparation is patented achieved new syntheses of Manske and Johnson (1929) and Skita and ephedrine.

recently

Fourneau and Nicolitch, Manske and Johnson, and Neuberg, Jacobson and Wagner employed chemical agents other than tartaric acid in the resolution of racemic ephedrine. I t is obvious that the final confirmation of the deduced structure of ephedrinenamely, synthesis of the substancehas been repeatedly. are supplying only natural ephedrine. m . PHARMACOLOGICAL 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 the synthetic and at the time of writing American furnished At present the natural product is more widely used than manufacturers

that of epinephrine.

This belief has been strengthened by subsequent to be amply justified. actions of However, of the

clinical experience, and appears sympathomimetic effectsi.e., and

when the actions of ephedrine are compared with the pattern the epinephrinein

laboratory, differences are perhaps more frequent than analogies, there has recently been a tendency on the part of several investigators to emphasize the differences as indicative of an absence of any sympathomimetic effect on the part of ephedrine. pected, of course, that two different 16 K. 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. importance are not sympathomimetic, and there is considerable evidence t h a t they are. in which the effects of ephedrine are identical with those of epinephrine, and there are several instances in which the two substances have of life Macht (1929), opposite actions upon the same structure or function. 1. Action on lower forms Very little work has been done along these lines. substances upon living plant organisms found that ephedrine was much less toxic than epinephrine to the seedlings of Lupinus concentration of 1 in 5,000 of ephedrine having a phyto-toxic index of 75 per cent. plants This is in accord with other observations of the same author, indicating that a drug of animal origin is more toxic to Albus, a On the other hand, there is scarcely any respect On the whole, there appears to be no conclusive evidence that the actions of ephedrine that are of therapeutic It is scarcely to be exclosely substances, however

who has made a systematic study of the toxic effects of various

t h a n one of vegetable origin. in

In the

sea crab, Pdaemon,

kept

1 to 1000 solution of ephedrine, a Nadler squid injected system. in two respects, however. reported interesting results

temperature of 36 induces heat from experiments and with the

narcosis in 30 minutes (Frohlich and Kreidl, 1921). (Loligo pealii). He found that epinephrine of the ephedrine,

subcutaneously, produced local blanching, which was supchromatophore The effect of ephedrine differed from that of epinephrine First, the blanching was much slower in its

posedly due to inhibition of smooth muscle

appearance when ephedrine was used, though it lasted 8 hours or more instead of 10 minutes, which was the duration of the epinephrine effect. diffuse generalized reddish coloration excepting at of the drug. caused the the injected area; this coloration was also produced by intravascular or oral administration Since excitement or irritation of the animal likewise same color change, it was ascribed to stimulation by Second, the animals injected with ephedrine showed a

ephedrine of the central nervous system of the animal; epinephrine EPHEDEINE AND RELATED SUBSTANCES 17 apparently had no such effect. 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. chloride. These were parathyroid and barium anterior pituitary extracts, posterior pituitary extract, and These results indicate that the

The last two are known to stimulate smooth muscle fibers

directly, irrespective of their innervation (i.e., they are musculotropic), and the effects in 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 life, of the fundamental nature of the action of ephedrine. and not pituitrin-like (musculotropic). 2. Actions on the circulation These are probably the most striking effects of ephedrine in common laboratory animals, and it is somewhat strange that were not investigated until comparatively recent times. several decades ago. a. The effect upon tory depressant. blood pressure. The doses used The first workthat of Miura by him were excessive (fatal) Grahe (1887)led to the conclusion that ephedrine is essentially a circulaones, and cardiac depression evidently dominated the picture. upon subcutaneous or intravenous injection of ephedrine or pseudoephedrine, but his published tracings show barely detectable effects. found that subsequent injections led to a fall in pressure. first demonstration of the characteristic pressor effect of ephedrine was that of Hirose (1915), who injected the drug intravenously in anesthetized rabbits. by Mayer cipitate 1927 EPHEDBINE 13 TION 1892 Amatsu and Kubota (1917) confirmed these results, and added the observation that the rise in pressure was not prevented He also The been, the present status of ephedrine might have been attained the they The conclusion was that the action of ephedrine is epinephrine-Uke (sympathomimetic)

If they had

(1895) reported a slight rise of blood pressure of curarized dogs

 400 1 40 FlaecherCalliess 1923 12 23 14,1929 pithed witzmann1927 dibromphenolindophenol naphtholdichlorindophenol E isomeristn Oelschlagel ER C 10 CeHg-CHOH-CHCHs NHCHs/ 3 - -JS- A-- L--2-methylaminopropanol-L O R A-9- CHOH- NHCHJ CHOH CHCHi-NHCHa 14 K. K. 1 - D DZ-DL-} DL <-pseudoephedrines Z - ^- 1926 118

[] + 50 Calliess1926 19261928 dence - OH -NHCHs / M 1927 1928 Z rnethyl NOR-RF- Kanao 1928 ^- I T E. Schmidt fourneau1904 EPHE drine 1927 1911 Methylmydriatine EPHEDKINE 15 1919 1918 Z-D-1927 4070 D-/ COM 70 isoephedrines pseudoephe drines SPATH1920 1915 kanao1927

6 Sp2.th Ephetonin manske 1929 Skita eleil1929 fourneau Nicolitch Manske I T Schmidt1924 sympa thomimetic pected 16 K. K. T T H

1 macht1929 CON 5000 1 75 T H n Pdaemon 1 1000 36 30 Kreidl1921 pealii SUPposedly 8 10 ; EPHEDEINE 17 musculotropic

 UKE -musculotropic 2 1887 grahe 1895 curarized 1915 amatsu 1917 18 K. K. CHEN AND CARL F. SCHMIDT destruction of the medulla or b y paralytic doses of chloral hydrate. Chen and Schmidt (1924) dogs, and emphasized ephedrine, the diminution, blood pressure when taken b y m o u t h . contributed to the subject, a n d the principal features in the circulatory actions of ephedrine are well established. Ephedrine causes a rise in blood pressure of anesthetized dogs when Since then many workers have demonstrated similar effects in cats disappearance, or reversal of the and t h e relatively long duration of the effect of effect

upon repeated injections, a n d the ability of ephedrine to raise

injected intravenously in dosage of 0.005 to 30 mgm. per kilogram, but the greatest effect is produced b y doses of 1 to 10 mgm. per kilogram: 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. ephedrine per kilogram, by vein, was found b y 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 mim'Tnum pressor dose, injected intravenously, was found to be 0.05 mgm. per kilogram in rabbits, while l / 5 0 t h of this quantity was effective in cats. Large quantities of ephedrine jected intravenously in dogs, (40 to 65 mgm. per kilogram) incause only a fall in blood pressure Kreitmair I n unanesthetized dogs, 5 to 10 mgm. of

(Chen and Meek, 1926): these are close to the fatal dose. vein causes a fall in blood pressure in cats. doses. When the pressor effect of

(1927) states that 10 mgm. or more per kilogram injected into a This is the type of effect

observed by Miura (1887), who apparently did not try smaller ephedrine is compared with that of are apparent.

epinephrine, several outstanding points of difference

First, the effect of epinephrine is much more intense but much less prolonged than that of ephedrine: under optimal conditions, employing 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 commonly 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 t h a t the pressor response can be employed in assaying epinephrine preparations (United States Pharmacopoeia, EPHEDRTJNE 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 quantity injected (Chen and Schmidt, 1924); they may be less from large doses than, from smaller ones. injection of epinephrine blood pressure frequently falls from the peak of the pressor effect to a subnormal level, rising slowly to normal; this is not true of ephedrine, following which pressure simply falls very gradually to normal (Kreitmair, 1927). Fourth, when epinephrine injections each; are repeated the same degree of effect will be obtained from 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 repeatedly (Rowe, 1927; Rudolf and Graham, 1927; Kreitmair, 1927; Pittinger, 1928; Launoy and Nicolle, 1928) in cats, dogs, and rabbits, anesthetized or pithed. between the circulatory effects of ephedrine and epinephrine, and the observations 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 kilogram), 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 (i.e., a step-like mgm. per kilogram) may show cumulative effects intervals (Chen, 1926), and if time is allowed for pressure to recover Its explanation involves factors which are also responsible for most, if not all, of the other differences Third, following an intravenous

with ephedrine, however, the first dose is by far the most effective

rise in pressure to a sustained high level) if injected at close

between injections each may sometimesthough by no means always produce the same pressor effect. injections of ephedrine is that maximal pressor effects are soon developed, and and Meek, 1926) that the "receptors" with which ephedrine may be fewer in number, or more easily saturated, 20 K. K. CHEN AND CAEL P. SCHMIDT epinephrine, which would account for the absence of progressive effects as the dose of ephedrine is increased above the optimum level. seems probable the case with epinephrine and if the ephedrine receptors are saturated early the lack of progressive effect from repeated injections of ephedrine is accounted for. tions have been made. When the quantities of ephedrine are small Such explanation appears to harmonize with this saturation would not be accomplished until a number of injecexperimental 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 depressionan effect which is well known and will be considered in the following section. with minimal doses and is apparently due to stimulation of vasodilator nerve endings (Dale: Journ. Physiol., 1906, xxxiv, 163): with ephedrine, 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 I t is wholly unlike the depressor action of epinephrine, which can be demonstrated that the greater persistence of ephedrine depends upon a more stable union with receptor substance than is It actions combines those of than that additional quantities of the drug are then incapable of I t has been suggested (Chen producing further stimulant effects. The explanation advanced (Chen

and Schmidt, 1924) for the decreasing effectiveness of repeated

produce a vasodilator effect comparable with that of a

epinephrine.

The fact that the pressor effect of epinephrine is often followed by 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 in ephedrine, or is very much less conspicuous than is the case with epinephrine. noted also that the pressor action of ephedrine is more affected by the condition 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). only a few injections of ephedrine (Chen, 1925). fall than to rise in blood pressurea contingency that is not encountered with epinephrine. EPHEDRINE AND BELATED SUBSTANCES 21 I n 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 producmg further effects once these have been saturated; second, by the depressant action of ephedrine upon the heartan effect that is masked by the pressor effect until the latter has become maximal, or unless overwhelming quantities are injected. Epinephrine is not subject to these limitations to anything This suggests that a mixture like the same degree as ephedrine. Under such circumstances increasing the dose of ephedrine would be more likely to lead to Deep anesthesia and consequent hypotension also increase the probability of fall in pressure after I t may be

of the two drugs might possess the virtues of boththe intensity of epinephrine and the persistence of ephedrinewhile TnimTnizing their

respective disadvantagesthe found to be the case.

evanescence of epinephrine and

the

danger of cardiac depression by ephedrine.

This has actually been

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. Dolesshall (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 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. o u t of 84 individuals given a dose of 50 to 125 mgm. of ephedrine orally or by subcutaneous injection. altered, while in 6 it fell. In 7 cases pressure was not Similar results (1926), The rise in pressure varied from a few The first study was that of Miller (1925), who reported rise in pressure in 70 ephedrine sensitizes sympathetic nerve endings just as thyroxin sensitizes the Csepai and

millimeters to 65, and its duration was 6 to 8 hours. (1926), Rudolf Kesten and Graham (1927), Hess

were reported by Rowntree and Brown (1926), Pollak and Robitschak (1926), Jansen (1927), Middleton and Chen (1927), Althausen and Schu-

macher (1927), Wu and Read (1927), Csepai and Fernbach (1928), 22 K. K. CHEN AND CARL F. SCHMIDT Radoslav and Stoicesco (1927), and Pennetti (1928). mgm. of ephedrine hydrochloride. The results of Rowntree and Brown (1926), and of Hess (1926), indicate that blood pressure can be maintained at an elevated level for several days by means of daily administration of ephedrine. All observers agree that ephedrine is Anderson and H o m a n (1927) observed a rise in pressure in children given 15

effectively absorbed following oral administration, and Hess (1926) has shown that rise in blood pressure also occurs following rectal administration of ephedrine, in dosage of 2 mgm. per kilogram, fluid. as by other suppository, in milk, or dissolved in the proctoclysis Jansen (1926). The effects are more marked than Intra-

venous injection was first tried by Miller (1925), subsequently those of

routes of administration, but last only 15 to 30 minutes (Jansen). T h e influence of disease upon the pressor effect man has been studied by several workers. (1926) In of ephedrine in Graves' disease, in from

which there is conspicuous sensitization to epinephrine, Pollak and Robitschek no sensitization to ephedrine in Graves 5 disease. (1926) In asthma, Thomas (1926) found no rise in pressure following However, studies and MacDennot reported unusually marked pressor effects ephedrine, but Cs6pai and Fernbach (1928) concluded that there is

oral administration of ephedrine, and a similar statement was made in a n earlier review by Chen and Schmidt (1926). andMiddleton and Chen (1927) have shown that ephedrine raises blood pressure in asthmatic patients, possibly less frequently than in normals, b u t to as high a level and for as long a time. tried ephedrine in a single case of myxedema and found a fall in blood pressure from 210 to 145 mm. of mercury. T h e effect of repeated doses of ephedrine, taken by mouth, upon the blood pressure of human beings has been mvestigated 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 maintaining it at an abnormally high level as long as the drug Pennetti (1928) of larger series of cases by Althausen and Schumacher (1927)

is given regularly. obtained by intravenous injections of small doses (0.02 to 0.05 mgm. per EPHEDBINE A2STD RELATED SUBSTANCES 23 kilogram) at short intervals in anesthetized dogs, and appear to indicate 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). T h e effect of ephedrine upon venous pressure was studied by Chen and Meek (1926) in two dogs, one of which was atropinized. pressure. b. The action on the heart. 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 atropine, 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) irrigated with ephedrine. Subsequent investigations have confirmed the conclusion that ephedrine is essentially depressant to the frog's heart, while to overcome the depressant effect of ephedrine. Chen and Schmidt (1924) found only depression of the frog's heart The first investigations of the physiological effects of ephedrine disclosed its power of depressing the In each, a slight fall in venous pressure coincided with the rise in arterial These results are therefore similar to those

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 acceleration 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 rh'minished, 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 CAB! F. SCHMIDT rarely 10 4 ephedrine hydrochloride; rate was not affected, and higher concentrations were purely depressant, 1 in 100 causing arrest that could be combated b y means of perfusion with 1 in 10 4 dilution of epinephrine, with calcium, or with histamine, but was not reversible upon simple perfusion with pure Ringer's solution, and was not affected by atropine. ephedrine. Boyer Gomes da Costa (1927) reported stimulant effects of dilute (1927) found only depression when any effect was evident. solutions of ephedrine upon the perfused frog's heart, but Levy and Gradinesco (1927) also found that epinephrine is able to restore the beat to the frog's heart arrested by perfusion with exceeded 10 per cent. Kreitmair (1927) noted increase in amplitude of the frog's heart perfused by Straub's method with 1 in

M6hes and Kokas (1929) likewise observed depression of the frog's heart perfused with a 1 in 50,000 dilution of ephedrine, and believed t h a t 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. the heart of the snail (Helix pomatia) 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 contraction, with periodic variations. of crabs (Maia squinado, 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 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 depression 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. EPHEDRINE AN3> REXATE^^SgiESrANCES 25 The action of ephedrineon %^^mt^0^mU^M was kivestigated by Chen and Schmidt (1924) swfi. fey C & M b & - M e & (*926)> Pulse rate in the intact unajjestlietized dog Isi-ustialiy ^owed, oecasionally no effect whatever. Apparently a stronger solution of ephedrine was not used, so that one can conclude only that Bain (1929) perfused the hearts pogurus, and Carcinus Cancer L6vy and Boyer (1927) studied and found systolic

accelerated, intra-

when

epbe$&in& is^ i$$eete^/<siijKratajiiecai^

or

venously; in the w$?tlse$&e& an$ml $fi$eEfttfoB; i s c^wraealy observed following KLtmvje&Q^5 lnjsetio& of less tibm-,% gram, though afiber^safg^ieses (1 toffl Bagm. p e r fcfio^ commonly seep.i rise in blood pressure, the stewing being greater io aaimitfa whose cenidkoh inhibitory centers are not depressed by anesthesia. This explanation is, however, called into question by the receeat experiments of Peraietti (1928), who found that section of the vagi or injection of a^opine 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, in dosage of 1 to 20 mgm. per kilogram, causes acceleration of the heart. T h e strength of the beats of mflTnrnaiian hearts has also been found t o be increased by ephedrine. the contractions of part of the right ventricle (myocardiograph) and found t h e m markedly increased by atropine-like or effect upon ephedrine. The effect nerves, was not prewas fully vented by section of the vagus nerves or by atropine, was not due to an cardio-inhibitory and comparable with that of electrical stimulation of the accelerator nerve of injection of epinephrine. They also showed that ephedrine caused increase in rate and amplitude of ventricular not tion. shared by epinephrine (Chen and Meek, 1926). contractions Intravenous Chen and Schmidt (1924) recorded Atropme 3p^ele^,|i|)olishes or bradycardiay which is tbfc&to be^ |x^rde4#tst a-reflex eSect of the

when applied locally to the stellate gangliaa feature in action that is injection of ephedrine caused still further acceleration and augmentaLarge quantities of ephedrine (40 to 55 mgm. per kilogram by vein) are apt to cause acute cardiac depression (Chen and Meek, 1926). T h e 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 Nicolle (1928) on rabbits.

Chopra, Dikshit, and Pillai (1929) found increase in auricular contractions in cats given 2 mgm. injections, the ventricles being unaffected, while with 5 mgm. both auricles and ventricles were depressed. 26 K. K. CHEN AND CARL P SCHMIDT . I t has been shown by La Barre (1928) that ephedrine does not lead to ventricular of the fibrillation effect of in cats under chloroform anesthesia; in of this respect ephedrine differs from epinephrine. Studies ephedrine upon the cardiac output 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 increase 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 unanesthetized 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. that those obtained by other methods. I t should be noted opposed to results obtained by this procedure are frequently

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 method (Halsey, Reynolds, and Blackberg, 1927). are satisfactorily Until such discrepancies explained it is impossible to evaluate the results cardiac depressants, appear as cardiac stimulants according to the results obtained by this

obtained with respect to ephedrine. Electrocardiograph^ 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 verted, or occasionally augmented. flattened, inMassive doses (40 to 75 mgm. studies made by Chen and Meek (1926) in unanesthetized and anesthetized animals, showed that small

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, bradyEPHEDRENE 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, found that epinephrine 1926). was Similar results were obtained to revive a heart by by Chopra, Dikshit, and Pillai (1929), and by Pennetti (1928); the latter able arrested ephedrine. The effects of ephedrine upon the human heart have received considerable study. after the oral or The effect upon pulse rate was observed by Chen and subcutaneous administration of ephedrine. Miller Schmidt (1924) in a small series of cases, all of whom showed a slowing (1925), in a much larger series, found slowing of the pulse during

rise in blood pressure in the majority, but in 16 of his 84 subjects pulse and Brown (1926) noted acceleration of the pulse as frequently as slowing, and Middleton and Chen (1927) observed that acceleration was produced more frequently than slowing. In the experience of Hess (1926) and of Rudolf and Graham (1927), a decrease in pulse rate was the more frequent these series pulse rate was unaffected. 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. apparently not been investigated, but it may be inferred that bradycardia following 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 sounds became louder. ephedrine. before and the heart The influence of atropine upon the cardiac effects of ephedrine in man has On the whole, the effect of result of ephedrine, but in the cases of Jensen (1926) acceleration was the more frequent. In some cases in all rate was accelerated by ephedrine. Pulse rate and blood pressure returned to normal at about the same time. Rowntree

These observations furnish an explanation of

the palpitation which is commonly complained of by patients receiving Miller (1925) has also called attention to the occasional to the intensification of existing appearance of systolic murmurs in patients who had normal sounds ephedrine was given, and

systolic murmurs by ephedrine. or in all these areas. of

These murmurs may be heard at the

apex alone, at the base alone (in either aortic or pulmonary area), He suggested that they might be the result

distention of the cardiac chambers leading to the relative stenosis of aortic or pulmonary orifices, or to relative insufficiency of the mitral valve. Electrocardiographs 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 following ephedrine. in whom systolic blood pressure fell 30 mm. Pennetti (1928) studied the electrocardiograms Five of these showed perfectly

of 8 subjects with normal cardiovascular systems upon subcutaneous injection of 50 mgm. of ephedrine. normal tracings after the drug was-given, while in three there was some changedecrease or increasein height of the R wave and prolongation 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 likewise well marked in the case of the Tnfl.Tirvma.1ism 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 ephedrine the stimulant effect is increased little or not at all, or may be replaced by a depressant effect. 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. of perfusion experiments. Ephedrine produces vasoconstriction. This was first demonstrated in 1917 by Amatsu and Kubota by means They observed constriction of vessels of with a concentration of 1 in 10,000 of were frogs' legs upon perfusion The ability of ephedrine to

ephedrine hydrochloride; the vessels of the ear of the rabbit striction was also noted in the perfused spleen, and kidney of the dog. y vessels of the

constricted by solutions ranging from 1 in 2,000 to 1 in 20,000; conintestine, Their results have been confirmed b

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 Me"hes and Kokas (1929) on the frog, by Loo and Read (1928) on the toad, the latter finding a 1 in 20,000 solution effective. than these results would indicate. Other workers, while agreeing (1927) found that ephedrine is a vasoconstrictor, found it a much less powerful one Thus, Kreitmair

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. attention to the acidity of ephedrine solutions as a probable factor in the result obtained by Chen and Schmidt (1924). 30 K. Z. CHEN AND CAB! 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 epinephrine augmented the constrictor action of ephedrine, and that repeated 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 of the vascular system. decrease in volume of the kidney only, and this decrease was followed by increase to a level far above normal. the leg. Chen and Meek (1926) obtained similar results; they also reRudolf and Graham decreased, (1927) indicating reported corded volume of the spleen and found it usually decreased during the rise in blood pressure produced by ephedrine. slightly increased at first, but subsequently (1927) noted that the volumes of intestines and leg of the dog were delayed vasoconstriction. Gradinesco and Marcu Increase in volume as blood pressure rose was usually observed in the intestines and invariably in Chen and Schmidt (1924) additional information concerning its relative effectiveness upon different parts reported that intravenous injection of ephedrine in dogs caused immediate He calls

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 viviperfused 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 vasoconstrictor that is much less powerful and uniform in its effects than epinephrine. Yet it appears that the vasoconstrictor action of ephedrine, 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 Kubota (1917), and by Chen and Schmidt (1924), who found ephedrine effective in raising the blood pressure of fl.nJTnfl.1s whose central nervous systems were destroyed or paralyzed. 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 b y Heymans (1928), who employed crossed-circulation ephedrine still raised blood pressure after exclusion of cardiac and effects. But since plethysmographic experiments have vasoconstriction is evident only in certain organs (kidney, is not exerted in the same degree upon all blood vesselsa conclusion that is equally applicable to epinephrine. Concerning the part of the vascular bed that is affected by ephedrine, little information is available. Kreitmair (1927) reported t h a t a 1 per cent solution of ephedrine, locally applied to the web or tongue of a frog, causes constriction of arterioles and obliteration of capillaries. 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 splanchnic that spleen) shown experiments to exclude the central nervous system; the former found that The same conclusion

as blood pressure rises following ephedrine it is clear that the effect

ephedrine until a sufficient cardiac depression. not

quantity had been given to depress the

heart, when the observed effects could be attributed wholly to H. C. Hou (personal communication) obtained practiI t appears, therefore, that ephedrine has parts

cally the same result.

the intense constrictor action upon the extremely peripheral epinephrine.

of the vascular bed that is so conspicuous a feature in the case of 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. vessels of the rabbit's Chen and Schmidt (1924) found perfused by Langendorff's that ephedrine, like epinephrine, increased the outflow from the coronary heart method. Schmidt (1928) reported increase in venous outflow from the brains of dogs and cats given pressor doses of ephedrine, as well as epinephrine, but pituitrin had the same sort of effect. 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. other. Marcu (1926) applied a plethysmograph to one arm and a cuff for sphygmomanometry to the 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 constriction 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 animals. Rowntree and Brown (1926) studied the effects of mtradermal The reaction injection of 10 per cent ephedrine in saline solution. The effects upon

was a small red central area surrounded by a patchy white border

of irregular outline and inconstant frequent. tral area, appearance; reflex erythema was This confirms the Epinephrine, similaly injected, caused a small white censurrounded by a zone of erythema.

results obtained by observation of the effects of ephedrine on capillaries of the frog in indicating that ephedrine has little or no constrictor effect upon capillaries. 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 respiratory center, resembling caffeine in its effects. 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 common result. somewhat variable in detail but stimulation is a In intact a-m'-mais The ability of ephedrine to constrict the vessels of the nasal mucous membrane of man when the drug

Fujii (1925) found that the respiration of urethanized rabbits was increased in rate and decreased in depth by ephedrine in dosage of 10 mgm. per kilogram. Kreitmair (1927), using cats anesthetized with methane and ether, found that 5 mgm. of ephedrine per kilogram caused increase in depth of respiration, rate being unaffected. EPHEDBHSTE 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 breathing, of though occasionally rate was increased in markedly. combating Schmidt any extreme (1929) found that ephedrine was more regularly effective than the conventional respiratory stimulants respiratory depression due to morphine. Toxic or lethal

doses of animals

ephedrine always produce acceleration of respiratory rate immediately before final failure of breathing, in intact or anesthetized large extent to acute circulatory depression. (Miura, 1887; Chen, 1926; Kreitmair, 1927); this may be due to a

The action of ephedrine upon the respiratory center seems to consist 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. therefore 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 however, two agents are compared upon smooth muscle in general opposite to those of epinephrine. Since the latter are due, in so far as is known at present, wholly to stimulation of the sympathetic innervation 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 intensities that are different from those of epinephrine. a. Pupil. Ephedrine produces mydriasis when applied locally to This was first the conjunctiva or when absorbed into the circulation. The result of ephedrine action is

it is soon evident that the effects of ephedrine are sometimes

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. of ephedrine. They found that the light and accommodation the pupil dilated b y reflexes were not abolished by the drug; that electrical stimulation of the oculomotor nerve caused contraction of ephedrine; 34 K. E. CHEN AND CAKL 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 physostigmine, as well as nicotine; that atropine did not These earliest workers left little to be added to the analysis of this feature in the action

cause further effect.

mydriasis after ephedrine had produced its

complete and does

They concluded (1889) that ephedrine mydriasis is due to

stimulation of the sympathetic pupillo-dilator mechanism constrictors.

not involve paralysis of the parasympathetic (oculomotor) pupilloThe 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 Koppanyi (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. rine and The latter was able to show that ephedrinelike epinephcocainecauses increase in tone of the dilator muscle, This

decrease in that of the sphincter; the stimulant effect upon the dilator was augmented by increasing the alkalinity of the solution. may explain the result obtained by Munch (1928), confirmed by Swanson, Thompson and Rose (1929), that ephedrine base is a more powerful mydriatic in the cat than is the alkaloidal sulphate or hydrochloride. Chen and Schmidt (1924) confirmed the results of Miura, adding the observation that ephedrine does not cause loosening of corneal epithelium. 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 epinephrine, 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 previously: epinephrine, locally applied to both eyes or injected intravenously, 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 pupil. It is and Schmidt (1924), cocaine dilated only the normal 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 removal of inhibitory influences exerted by the ganglion upon the peripheral receptors with which epinephrine reacts, latter do not degenerate under such conditions. assuming that the On this basis, it

obvious that denervation does not sensitize the pupil to the effect

would be necessary to conclude that cocaine acts upon receptors all of which degenerate following removal of the ganglion, and that ephedrine, the effects of which are weakened but not abolished by such removal, acts partly upon epinephrine-like ones. b. Gastro-intestmal innervation of tract. In contrast with the effects of epinephephedrine appear to be rine, which are uniformly like those of stimulation of the sympathetic this system, the effects of irregular and uncertain. The effects upon the oesophagus were studied by To (1921), using the isolated organ of the frog. effect when given together with atropine or papaverine. The crop muscles of the pigeon were found by Hanzlik and B u t t (1928) to be thrown into contraction by ephedrine in dosage of 10 to 20 mgm. per kilogram; the effect involved both circular and longitudinal He found that ephedrine relaxed its tone in concentration of 1 in 2,000, and exerted a potentiating cocaine-like receptors and partly upon

musculature, lasted 5 to 10 minutes, and was not prevented by atropine, 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. fall in intragastric Pollak the barium meal into the duodenum, to 1 minute after the subject had swallowed 20 drops of 10 per cent solution of ephedrine. state that epinephrine caused a similar effect, which, they believe, may have been due to direct excitation of the musculature or to reflex stimulation consequent upon irritation of the mucous membrane. was swallowed ephedrine they observed transitory contraction of the stomach, 0.02 to 0.05 mgm. had no effect, while 0.1 mgm. caused inhibition of contractions for about 10 minutes; upon intravenous injection of 20 mgm. of Marcu and Savuiesco (1928) recorded gastric motility by means of a balloon which and connected to a water manometer; upon intravenous injection of 1 cc. of a 1 in 500,000 solution (0.002 mgm.) of They and M'Crea and Macdonald (1928) found that anesthetized cats. The effects of investigated. studies: they ephedrine, like epinephrine, inhibited gastric peristalsis and caused pressure of ephedrine upon the human Robitschek stomach have also been roentgenologic

(1926) made

observed an increase in gastric peristalsis, leading to expulsion of

ephedrine, there was marked and prolonged inhibition of gastric movements, with a stimulant tion . after-effect. T h e effects upon the small intestine in situ have received less attenUsing unanesthetized dogs with fistulae of the ileum, Kinnaman and Plant (1927) found that ephedrine, injected intravenously, uniformly caused immediate relaxation and inhibition of motility, followed by a stimulant effect that became more marked as the dose was increased. stimulation, 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. I n 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. colonic fistulae, and Schmidt (unpublished), using two such dogs, saw distinct decrease in tone and prolonged inhibition of motility following intramuscular injection 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 of 2 mgm. of ephedrine per kilogram, if active movements were present before the drug was given; if not there Kinnaman and Plant (1927) found this to be the case in unanesthetized dogs with With 0.5 to 1 mgm. per kilogram inhibition was marked, lasted 30 minutes to 2 hours, and was followed by only slight

muscle, surviving in a warm saline solution, the results are much less uniform, some workers only stimulation. rabbits, and the same result was obtained by To (1921), by Fujii (1925), and by Chen and Schmidt (1924) in rabbits. The last-named investigators 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 (plexus of Auerbach). these results. Subsequent workers have failed to ganglia confirm effect (1927) finding that ephedrine is only depressant, observing others reporting depression and stimulation, still others

Thus, Amatsu and Kubota (1917) found ephedrine

to be essentially depressant to isolated intestine of cats and

Nagel (1925) found ephedrine to be purely stimulant Kreitmair

to the isolated intestine of the rabbit and cat; the inhibitory of epinephrine could be overcome by ephedrine. 38 K. K. CHEN AND CABL P. SCHMIDT

found the isolated intestine of the cat to be relaxed by low concentrations (1:1,000,000 to 1:100,000) of ephedrine, but slightly stimulated by a stronger one (1:6,000); the latter effect could be prevented completely by atropine. Reinitz (1928) reported that isolated rabbit ephedrine; of to intestine was sometimes inhibited, often stimulated, sometimes inhibited and then stimulated, by the same concentration of lant response. isolated rabbit 1:50,000) of M6hes and intestine Kokas weak (1929) reported concentrations he stated that atropine had no significant influence upon the stimustimulation (1:150,000 by

ephedrine,

relaxation with a stronger

one (1:10,000). Lim and but rabbit Halsey De Eds, of

Rudolf and Graham (1927) found only slight and transitory depressant effects by ephedrine upon isolated rabbit intestine. Chen (1928) noted only stimulation with intact circulation, upon the addition of ephedrine. Rosenthal, and Voegtlin (1928) reported pure stimulation intestine exposed to a 1:5,000 solution of cat intestine, isolated

of ephedrine, and

(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. and guinea-pigs was antagonized by ephedrine. I t 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. (page 52). 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. explanation, the effects Whatever the upon the gastro-intestinal tract in situ are A probable explanation for this will be presented later I t should be pointed out here that the effects of Thienes (1929) reported that epinephrine depression of isolated large intestines of cats, rabbits, dogs, rats

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 a few experiments of Chen and Schmidt by isolated tissue excepting ephedrine. 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 a Schmidt (1924) found that the isolated rabbit uterus was uniformly stimulated by ephedrine, with only one exceptionthe uterus of recently delivered rabbit. Stimulation was the only effect of ephe-

(1924), who found that the dog's uterus in situ was stimulated To (1921) reported that the isolated uterus of the

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 frequently relaxes the non-pregnant guinea-pig uterus. rine upon various uteri. epinephrine upon the isolated rabbit uterus, but larger quantities reduce it. In general, the action of ephedrine upon the isolated uterus is characteristically a stimulant one, and bears no constant relation to the action of epinephrine. upon the intact uterus in situ has not been determined, for no experiments have as yet epinephrine. d. Urinary contractions of both circular and longitudinal muscle was increased by ephedrine, and that it was occasionally possible, by means of ephedrine, to restore contractions after they had been arrested by sodium glycocholate; the effects of epinephrine were qualitatively the same b u t it was a much more powerful stimulant than ephedrine. have been confirmed by Roth on the dog's ureter. 40 K. K. CHEN AND CARL F. SCHMIDT Macht (1929) studied the effects of ephedrine upon the trigonal and fundus portions of the urinary bladders of rabbits, cats and rats. I t has been shown repeatedly that epinephrine causes contraction of the trigone and relaxation of the fundus. traction of both portions. Liljestrand results with the rabbit's bladder. e. Bronchi. One of the most useful therapeutic actions of ephedrine is its ability to relieve or to prevent the paroxysms of Ephedrine caused conthe same (1927) obtained His results tract. Hofbauer (1928) tested the effect of ephedrine upon the isolated ureter of the pig: he found that the rate of been made with animals whose uteri are relaxed by Whether the same is true of the effects Reinitz (1928) reported In fact Thienes very small (1929) found that ephedrine prevented the inhibitory effect of epinephthat quantities of ephedrine augment the (stimulant) effect of

asthma. Animal experimentation has shown from the start that various poisons. spasmodic contraction by means of pilocarpine, muscarine, or peptone. also found by ephedrine, even in such low concentration as 1 in 80,000. 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 generally when 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. first Grahe in 1895 studied has no the action effect of ephedrine and pseudoephedrine on the submaxillary flow in a dog and found that the intravenous injection while repeated injections gradually diminish the flow. animals, ephedrine in a dosage of 1 to 2 mgm. per kilogram produces inconsistent EPKEDBINE AND RELATED SUBSTANCES results. Occasionally it increases the 41 submaxillary flow, and this Chen and Schmidt, and Chen investiIn anesthetized only exceptional is bronchodilatation It is by ephedrine. assumed It that is agreed that ephedrine may fail to relax bronchial spasm effective. generally They These that isolated bronchial muscle of the cow was relaxed Amatsu and Kubota (1917) were the first to demonstrate this effect in rabbits whose bronchi had been thrown into ephedrine, like epinephrine, is able to relax bronchial spasm induced by

epinephrine

gated the same question in a series of dogs.

occurs in spite of atropinization, but in the majority of cases it has

no effect.

Larger doses (25 mgm. per kilogram or more) dogs may cause profuse salivation. When

in nona dose

anesthetized

slightly below the M.L.D. is administered, the increase in salivary flow is a constant feature. b. Gastric secretion. Heidenhain pouches. Ephedrine injected subcutaneously unmistakably inThere is no difference between the Heidenhain In anesthetized dogs with a cannula in the In non-anesthetized (1928) reported dogs that creases the gastric secretion both in volume and in acidity, although to only a small extent. c. Pancreatic secretion. and Pavlov preparations. pancreatic duct ephedrine, given intravenously, does not change the pancreatic secretion, as shown by Chen. gave negative results. d. Intestinal injection of ephedrine, as reported by Chen. e. Bile. I n acute experiments with anesthetized dogs, there is no ephedrine injected intraThe same can be said for non-anesthetized fl.subcudemonstrable alteration of bile flow after venously (Chen). nima.1s with a pancreatic biliary fistula when ephedrine is injected taneously. Kreitmair, using larger doses (50 to 100 mgm. per dog), The increase in volume continues for more than secretion. with a pancreatic fistula, subcutaneous injections of ephedrine also Fonseca and Trincao ephedrine caused decrease in pancreatic secretion. Dogs with Thiry-Vella fistula do not show any response in their intestinal secretions to the subcutaneous Chen in Lim's laboratory studied the action of ephedrine on the gastric secretion in dogs with Pavlov or

found an increase of bile flow from the biliary fistula, with a reduction of the dry matter. three days. / . Sweat. Chen and Schmidt determined the sweat secretion of an ephedrine Kreitmair arrived at the same conclusion. ephedrine occasionally produces anesthetized cat and could not detect any increase after was injected into the paw. In the use of Ma Huang, firmly believed in by the Chinese and described b y men a therapeutic diaphoresis. dose of

I t is interesting to note that perspiration caused by

Li Shih-Cheng in his Pentsao Kang Mu, although not experimentally proved in animals, has been clinically confirmed in many reports. 42 K. Z. CHEN AND CARL P. SCHMIDT g. Lymph. With the cooperation of M. Kayumi, Chen and Schmidt I t regularly causes an increase the studied the influence of ephedrine on lymph flow, collected from the thoracic duct of anesthetized dogs. intravenous injection. h. Urine. Schmidt. but In anesthetized dogs the urine flow appears to follow There is suppression during the primary vasoconstriction, the secondary dilatation. After repeated Intact rabbits which receive the plethysmograph of the kidney volume, as observed by Chen and an increase during in lymph, which reaches its maximum about 15 minutes after

doses the urine is invariably suppressed.

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 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. level. Hess reported leucocytosis after ephedrine, reaching its maximum at the same time as the blood pressure attams its highest Marcu and Petresco studied the blood changes in men on of the glomerular functional units. Kreitmair observed diuresis on himself after the ingestion of 50 mgm. of ephedrine,

intravenous injection of ephedrine. and 40 minutes.

A dose of 20 mgm. increases the

leucocytes within the first five minutes, lasting for more than one hour The leucocytosis consists chiefly of lymphocytosis. corresponding The maximum is attained in about 40 minThe red blood corpuscles are also increased, with a increase in hemoglobin. utes.

Ephedrine in a dosage of 60 mgm., given intravenously, pro-

EPKEDRINE AND BELATED SUBSTANCES 43 duces a leucocytosis and erythrocytosis which lasts for two hours or longer. These changes, the authors believe, indicate a concentration Pathological conditions apparently modify this reaction. of the blood.

Thus, Marcu and Petresco observed with a dose of 20 mgm. intravenously 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. leucocytosis in chloralosed dogs. 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 administration of yohimbine, which paralyzes the contractors of the spleen, abolishes such a response. b. Blood chemistry. were inconclusive. Chen and Schmidt studied the effect of epheTheir results by by Negative or doubtful results were obtained rabbits, drine on the blood sugar in two anesthetized dogs. T. G. Miller in men, by Hess in men, by Kreitmair in men. The maximal increase in the platelets is Binet, Arnaudet, Fournier and Kaplan observed an increase in platelets in addition to erythrocytosis and

Rudolf and Graham in diabetics, by Tu in men, and by Haintz in Hyperglycemia may be produced in animals by doses larger Thus, Nagel determined the hyperglycemic intravenously. (intravenously occurs they than the pressor ones.

dose in rabbits to be 25 mgm. per kilogram, injected Wilson found it to be 10 to 15 mgm. per kilogram venously) in rabbits.

or subcutaneously) in dogs, and 20 to 30 mgm. per kilogram (intraAccording to Nitzescu, hyperglycemia digestion but is absent when in dogs when they are in full

are previously starved. per kilogram,

The doses he The

used were 0.5 to 3.0 mgm. simultaneous administrahyperglycemia A limited

given intravenously.

tion of glucose and ephedrine does not increase the produced by glucose alone but lengthens its duration.

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 b y Doses of 5 to 90 mgm. produce a diphasic The intravenous injection.

reactiona primary hyperglycemia followed by hypoglycemia. 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 Unlike albumins and globulins occurred in both healthy individuals and in a case of Addison's disease and another of Hodgkin's disease. serum (Pfeiffer and Standenath). 7. Action on metabolism a. Metabolic rate. taneously. T. G. Miller reported an increase in metabolic rate in 4 cases with 100 to 125 mgm. of ephedrine injected subcuRowntree and Brown also studied the calorigenic effects In 3 of ephedrine, given by mouth, in several diseased conditions. in two but a decrease in the third. 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 In a case of obesity showed a decrease of 11 points with SO mgm., but with 100 mgm. there was an increase of 13 points in 3 hours. pituitary tumor there was a demonstrable increase of the basal metabolic rate In a case of questionable epinephrine, ephedrine does not raise the peptidase titer of the rabbit's

cases of Addison's disease there was an increase in metabolic rate

after

50 mgm. of ephedrine had been given.

In rabbits, Duli&re

observed only inconsistent changes in metabolism after the administration of ephedrine. b. Gaseous exchange. Pilcher and CO 2 time the R.Q. becomes less than 1. According to Lublin, this means the In rabbits, DuliSre coninhibition of fat formation by ephedrine. tion of ephedrine. c. Body temperature. With toxic doses Miura in 1887 reported an Like epinephrine 45 elevation of temperature in dogs, rabbits and mice. EPHEDRINE AND BELATED SUBSTANCES to fall. Harrison, Schmidt (1928) demonstrated that ephedrine Wilson, also and Halsey, Reynolds or and Blackberg increases both cerebral Oa consumption and COa liberation.

observed an increase in O2 consumption with a tendency of the alveolar After giving fructose glucose, the R.Q. is always greater than 1, but if ephedrine and fructose are given at the same

stantly observed a decrease of R.Q. following the intravenous injec-

and jS-tetrahydronaphthylamine, 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. 20 mgm. per kilogram. Notwithstanding, Suzuki recently reported a slight fall in rectal temperature in rabbits, either normal, adrenalectomized or with the splanchnic nerves sectioned, using a dose of 30 mgm. per kilogram, given intravenously. 8. Action on the central nervous system Airila Ephedrine appears to stimulate the central nervous system. by an intravenous injection of ephedrine (10 to 20 mgm.). The dose for the production of this response is

in 1913 showed that chloralized rabbits can be awakened temporarily 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 Oral administration and injecdark blood-red within half an hour, the color persisting for twelve to twenty hours or more, as observed by Nadler. coloration. tion into the circulation via the heart likewise produce this central nervous system.

The author attributes this change to stimulation of the In men moderate doses of ephedrine

sometimes cause tremor, nausea, and insomnia, which in all probability is due to stimulation of the central nervous system. center. C. F . Schmidt that obtained evidence that ephedrine directly stimulates the respiratory In anesthetized dogs, Johnson and Luckhardt found ephedrine in large doses, injected 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 outlasts the rise of blood pressure. 9. Action on the peripheral nerves and voluntary Read and Lin. muscles The action of ephedrine on the motor nerves has been studied b y They conclude that ephedrine potentiates the action By the addition of 0.005 of novocaine on the frog's sciatic nerve. time 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 and potassium sulphate. Amatsu and Kubota (1917) studied the effect of ephedrine on the frog's gastrocnemius muscle. irregular 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) theradivided the actions of ephedrine into three categories: the They found that a 0.1 per cent solution raises the threshold of stimulation (electric) and produces a mixture of similar proportions and strengths of novocaine, epinephrine intravenously or subcutaneously,

causes a marked increase in the reflex excitability of the spinal

per cent of ephedrine to a 1 per cent solution of novocaine the

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. 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, ephedrine particularly upon the respiratory center. comparable 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 limitations 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. 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 a sympathomimetic substance. 47 ephedrine to those of epinephrine, and concluded that ephedrine is These effects include mydriasis with inhibition and preservation of light and accommodation reflexes, broncho-dilatation, cardiac acceleration and augmentation, vasoconstriction, of gastro-intestinal motility (in many cases), hyperglycemia, The earliest The action of The second and third types

upon the brain cells has not been analyzed, but it appears to be

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 sympathomimetic 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, irrespective of sympathetic innervation. De Eds (1927), De Eds and than theoretical importance, Butt Those who have concluded that (1927), Pak and Read (1928), justified ephedrine acts at least partly upon muscle fibers include Nagel (1925), M6h.es and Kokas (1929), and Halsey (1928). The question has more

for if this conclusion is fully

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. of Nadler (1927), which has culotropic. established. 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. Pharmacol. Exper. Therap., 1926, xxvii, 395). the reviewers (S.) recently tested 12 such preparations with 48 K. 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. support These results lend no ephedrine. In no case was there any trace of stimulation, and depression was more This apparently has not One of been used to test the musculotropic power of ephedrine. already been discussed (page 16). He concluded that ephedrine is essentially sympathomimetic, not musHowever, the organism used by him is relatively complex, and the exact mechanism of the responses studied has not been The only pertinent investigation of the action of ephedrine upon a lower form of life is that

to the conception suggest rather

that

ephedrine is musculotropic. direct action of

In fact upon

they smooth

that

the

ephedrine

muscle is a depressant one, since ephedrine was more uniformly inhibitory than epinephrine. Another suitable test-object would be blood vessels which are not conspicuously affected by epinephrine, such as those of the coronary, cerebral, statement of Chen and Schmidt (1924) that coronary outflow from perfused mammalian heart was augmented, never ephedrine. increased. However, pituitrin regularly causes very marked reduction in coronary flow in such preparations. If the latter is regarded as a repreFurther coronary, sentative example of the effect of musculotropic agents, the result with ephedrine indicates that the latter is not musculotropic. information concerning the actions of ephedrine upon cerebral, and pulmonary vessels is highly desirable. The contention that 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. decisive. a. Circulatory 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. quanOther things being equal, a given responses. The fact that ergotoxine (ergotamine) leads to a reversal of the blood pressure effect of epinephrine has led None of the evidence so far obtained by these procedures appears to be ephedrine is capable of exerting stimulant effects upon smooth muscle fibers irrespective of their innervation the by decreased, and pulmonary areas. The only available information concerning the action of ephedrine upon such structures is the

This is far from conclusive evidence upon the point at

issue, since rate and force of cardiac contractions were also

tity of the agent being tested should cause a fall in pressure ergotoxine if it is sympathomimetic, while if its effects are unaltered by ergotoxine it must be musculotropic. EPKEDRINE AND BELATED SUBSTANCES 49

after

Among those who have tested the influence of ergotoxine upon the pressor response to ephedrine are Nagel (1925), Kreitmair De Eds and Butt (1927), Chen (1928), and Curtis (1929). (1927), 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. his success to the use of smaller quantities of ephedrine and larger doses of ergotoxine than had been used by his predecessors. is confirmed, however, it appears proper to conclude that while ergotoxine may diminish or even prevent the pressor effect of ephedrine, an actual reversal, similar to that of epinephrine, is not the characteristic 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 epinephrine the reverse is true. I t is well known that ergotoxine, in Until this Curtis attributed

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). latter system that ephedrine exerts much of its influence upon blood pressure. Consequently one need not expect the pressor effect of ephedrine to I t is through the

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. raised by Chen (1928) and by Curtis (1928). Second, it must be remembered that the epinephrine reversal by means of believe that ephedrine possesses such an action. produce only a rise in blood pressure, and as the effects of ephedrine wear 50 K. Z. CHEN AND CAM. 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. ephedrine upon blood vessels are dominantly if are conspicuous (Dale, 1906). not exclusively motor situation is (constrictor), while in the case of epinephrine inhibitory (dilator) actions The present therefore that practically identical with that encountered by Barger and Dale (1910) in their investigation of sympathorrrimetic bases. They found ergotoxine reduced but did not reverse the pressor effect of aminoaceto-catechol or d^amino-ethanol-catechol, while it led to complete reversal of epinephrine. The difference was attributed to a greater predominance of inhibitory (vasodilator) actions on the part of the latter substances, though the effects of methyl am in o-catechol or dZThere is no decisive evidence upon this point, but these observations suggest strongly that the effects of For, as has already been pointed out (page 20), the smallest effective doses of ephedrine ergotoxine presupposes a powerful stimulant action by epinephrine upon vasodilator nerves, but there is no reason to These objections to the conclusions derived from the ergotoxine experiments have been

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 yoTn'mbine, which Raymond-Hamet apply also to (1927) found the effects of 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 musculotropic. De Eds (1927) and Pak and Read (1928) found that cocaine Chen (1928) was unable also reduced the pressor effect of ephedrine.

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. the pressor ephedrine. These results have been interpreted as evidence that ephedrine is not sympathomimetic, but musculotropic, in its circulatory effects. EPHEDBINE AND RELATED SUBSTANCES 51 Yet, as far as the reviewers are aware, no evidence has been presented might that cocaine augments the effectiveness of sympathetic nerve excitation by anything but epinephrine, and this particular effect sympathetic stimulation per se. musculotropic action. In fact Tainter has recently reported (XIII International Physiological Congress) that cocaine neither increases nor decreases the effectiveness of barium and pituitrin. of the assumption that test, If one grants the validity any agent, to be sympathomim etic, must well be a drug synergism, peculiar to epinephrine, with no relation to Nor is there any evidence that reduction of pressor effectiveness by cocaine is an index of effect of epinephrine, may However, Tainter augments abolish that of (1929) has recently shown that cocaine, in dosage which reduce or

duplicate all of the peculiar effects of epinephrine, the cocaine

like the ergotoxine one, indicates that ephedrine is neither sympathomimetic nor musculotropic. Another agent which modifies the circulatory response to epinephrine much more than that to ephedrine is insulin. of epinephrine, but not that of ephedrine. ephedrine are in some way different 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 substance 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 reviewers 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 muscle. been done upon this subject be uniformly stimulant, though epinephrine may be depressant; that the surviving small intestine may be stimulated or depressed by ephe52 K. K. CHEN AND CARL F. SCHMIDT drine though invariably depressed by epinephrine. 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 Apparently the only smooth muscles that are uniformly relaxed in vitro by In considering the work that has that (pages 33-40) it was pointed out from Cs6pai and effect Pinter-Kovats (1927) found that insulin prevents the pressor

The significance of this those of epinephrine, is

observation, apart from an indication that the circulatory effects of

the effects of ephedrine upon uterus and bladder fundus appear to

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) This proceshowed a tracing which illustrated the epinephrine-like effect of ephedrine after the ganglia had been paralyzed with nicotine. dure has recently been repeated by one of the reviewers (S.) with preparations made from the small intestines of cats, dogs, and rabbits, and the results have been uniformly Eke the earlier ones. instance did ephedrine fail to exert a typical sympathomimetic effect 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. I t appears, therefore, that the intestinal effects of ephedrine consist in a combined stimulation of ganglia (plexus of Auerbach), which causes increased motility, and of inhibitory sympathetic endings. When the ganglionic action is excluded by means of nicotine 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, Ergotoxine whether epinephrine is stimulant or inhibitory, and this argues in favor of the musculotropic or pituitrin type of effect. 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). sympathetic nerve This substance should paralyze motor and uteri so treated were uniformly endings, after nicotine, while stimulation of strips from adjacent parts of the In no

inhibited by epinephrine, but all observers except Curtis reported that ergotoxine did not prevent the stimulant action of ephedrine: he 53 EPHEDRTNE AND BELATED SUBSTANCES ephedrine could be prevented though never reversed. indeed I t may be, therefore, that the effects of ephedrine upon the isolated uterus are

stated that by means of large doses of ergotoxine the effects of

sympathomimetic, but are

exerted

mainly if not

exclusively upon

motor parts of the .system, the inhibitory parts being affected much less or not at allan analogy to the effects upon blood vessels. The stimulant action of ephedrine upon the intestine being apparently similar to that of nicotine (i.e., ganglionic), a similar action upon the uterus may be regarded as a possibility. gated. preparation of uterine muscle. The effects of nicotine upon the uterus (virgin In current terminology, this organ of the cat) were found by Barger and Dale (1910) to be inhibitory in vivo but stimulant in vitro. in vitro. would imply that nicotine is sympathomimetic in vivo, musculotropic Barger and Dale, however, believed that the inhibitory effect They did not explain in vivo was due to stimulation of sympathetic ganglia which rapidly lose their sensitivity when the uterus is excised. the stimulant action in vitro, but it can scarcely be called musculotropic 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. (1927) (see those of The only data are those of Macht (1929) and page 40, above). These effects of of pituitrin, unlike those epinephrine. Liljestrand are ephedrine are like The results This has not been investiI t is not possible at present to make a plexus-free

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. I t has been claimed by Fujii both parasympathetic evidence presented Fujii and (1925), Kreitmair nervous (1927), Reinitz the (1928), and Marcu and Savulesco (1928) that ephedrine stimulates sympathetic of this systems, but is in support contention inconclusive.

(1925) believed that the constrictor action of ephedrine upon

perfused blood vessels of the frog was exerted through parasympathetic 54 Z. K. CHEN AND CAUL 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 vasodilator action of its own in 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 isolated intestine was prevented or abolished by M6hes and Kokas ephedrine upon

atropine, but this is denied by Reinitz (1928).

(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), however, claim that minimal quantities stimulate the parasympathetic preferentially, while with large doses sympathetic stimulation dominates 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. conflicting opinions indicate that ephedrine The certainly has no conThere is no

spicuous pilocarpine-like effects, and Reinitz (1928) claimed that it actually has an atropine-like effect upon the intestine. reason therefore for employing ephedrine as a 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. the latter indicating degeneration of the structures upon which it acted. They concluded that the point of action of ephedrine was apparently peripheral to that of cocaine, the absence of effect from parasympathetic

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 action upon structures peripheral to the 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 epinephrine, 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 epinephrine, in the pupillo-dilator system at least. been made diminishes its effectiveness. some of Should this be confirmed, degenerate it would suggest after that as the the ephedrine receptors denervation, (page 34) to a Reference has already that few observations which indicate degenerate when the ganglion is removed. 55 finest nerve fibrils, which On the other hand,

denervation does not sensitize the pupil to ephedrine, but

all of those for cocaine appear to do. central

This would imply that

point of action of ephedrine upon the pupil is at least partly to that of epinephrine, and partly peripheral to that of cocaine. I t has been suggested by several workers that many of the peculiarities in the action of ephedrine could be explained on the basis of an increased secretion of epmephrine by the suprarenal glands as a result of absorption of ephedrine. effects of ephedrine upon metabolism, blood sugar, etc. and for epinephrinelike effects upon small intestines in situ, not in vitro. son's disease. The question has a practical significance in connection with the treatment of AddiThis would account for the

Evidence upon this point is somewhat contradictory. the pressor effectiveness stated that therefore, of ephedrine. Chen and

Nagel (1925) Schmidt glands (1926) not

reported that suprarenalectomy did not reduce, but seemed to augment removal or ligation of the suprarenal did

diminish, the pressor effect of ephedrine.

I t seems clear,

that the circulatory effects of ephedrine are not due wholly to stimulation 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. 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. directly into the suprarenal capsules of dogs anesthetized with chloroform, To caused a marked and sustained rise in blood pressure. reproduce the effect quantity by intravenous injection of ephedrine, 7 to 10 times the required. They reported also that removal of the reduction in the pressor effectiveness of Houssay and Molinelli (1927) anastomosis) was Gradinesco and Marcu (1927) found that a small quantity (0.1 to 0.2 cc. of a 1 per cent solution) of ephedrine, injected Section

suprarentils led to marked ami by Chen and a

ephedrine, which is opposed to the results reported by Nagel (1925) vSchmidt (1926). employed 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 crossed-circulation (suprarenalo-jugular

preparation in dogs.

They reported that large doses (40 to SO

used by Suzuki (30 mum. per kilogram) (40 to 50 mgm. per kilogram) nervous effects are to be expected. and by Houssay and Molinelli Only the results of Gradinesco stimulation by are so close to the toxic level that

and Marcu point to the possibility of a suprarenal as

small quantities of ephedrine, and these could scarcely be regarded 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, blood vessels, isolated smooth muscle). Addison's disease. one which ephedrine could not be expected to check, this does not prove that the drug had not stimulated the residual normal tissue. T h e above discussion concerning the mode of action of ephedrine can be summarized as follows: EPHEDIUKE AND BELATED SUBSTANCES 57 directly and There is no valid evidence that ephedrine is capable of However, since the pathological process is a progressive perfused Clinical experience has shown

that ephedrine has no beneficial influence upon the course of

stimulating any smooth muscle, while there is some direct evidence that it cannot do so (chromatophores of the squid, plexus-free nicotinized intestine, albino rat uterus). There is reason to suspect that ephedrine stimulates motor sympathetic nerves more powerfully bladder), and possibly the inhibitory set is not affected at all by ephedrine; b u t than inhibitory ones when both are present in the same tissue (blood vessels, perhaps uterus and

when the sympathetic innervation is purely inhibitory ephedrine seems uniformly to stimulate it (bronchi, isolated sphincter pupillae, isolated intestinenicotinized, 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. by atropine. There is no conclusive evidence that ordinary therapeutic doses of ephedrine stimulate the suprarenal gland, or that any of the 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 termssympathomimetic or musculotropic. general, descriptive The first, according to effects Ephedrine certainly has no conspicuous prevented pilocarpine-like actions, and its important effects are not

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 stimulation. other agencies, such as electrical The second is currently used to designate a group of The outstanding example of the

drugs and poisons which stimulate smooth muscle indiscriminately and irrespective of its innervation. are representative. been tacitly first group is epinephrine, while of the second pituitrin and barium In the recent investigations of ephedrine it has that epinephrine effects. actions are the absolute the assumed

58 K. K. CHEN AND CAUL F. SCHMIDT standard of sympathomimetic But the originators of 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 inhibitory 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. reaction of drug with tissue substance, but is merely descriptive of observed or expected phenomena, the choice is of no great immediate importance. 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 evidence, 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. these discrepancies upon a sympatiomimetic basis, it is reasonable to suppose that something will be added to our knowledge concerning the sympathetic innervation of various structures, and it is not inconceivable 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. I t is quite possible that some of the effects of ephedrine are musculotropic. 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 ephedrine actions is strikingly similar to that resulting from stimulation EPHEDRINE AND RELATED SUBSTANCES 59 of the sympathetic nervous system by other means. The reviewers But if search is made for an explanation of However, the reviewers believe that it is better at present Since neither term is explanatory of the mode of

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 sympathomimetic. 11. Absorption administered and excretion subcutaneously, rectally in intramuscularly, and the subdurally, been Ephedrine is readily absorbed and produces systemic effects when orally, or intraperitoneally, animals, same has

shown to be true of men excepting for the subdural and intraperitoneal routes, which have not been tried. following subcutaneous or intramuscular injection than following oral administration, 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). ephedrine is absorbed represents The readiness with which and usually adan outstanding The rate of absorption in men, evidenced by the rise in blood pressure, is somewhat faster

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 is unknown, nor is anything known about 12. Toxicity lethal dose. Table 2 shows the toxicity of ephedrine methods intraThe order of theM.L.D. by different a. Minimal the route of elimination. the liver unchanged but whether it is destroyed in the body or eliminated, in unaltered or altered form,

in different animals. of administration toxic

is as follows: intravenous, intramuscular,

peritoneal, subcutaneous, and oral.

The drug is therefore most In general, differpressor dose intra-

by intravenous injection and least toxic by mouth. of safety. In dogs, for example, the optimal

ent workers agree that ephedrine has a low toxicity and a wide margin venously is 1 to 10 mgm. per kilogram while the M.L.D. by the same

60 Z. K. CHEN AND CARL P SCHMIDT . Squid (Loligo j>ealii). Frog. Hamster. Mouse.. White mouse. Rat White rat... Guinea pig.. Rabbit. White rabbit. Gray rabbit Cat Dog Total dose. TABLE 2 Toxicity of ephedrine in different animals Sulphate Hydrochloride Hydrocbloride Hydrochloride Hydrochloride Sulphate Hydrochloride Hydrochloride Hydrochloride Hydrochloride Hydrochbride Sulphate Hydrochloride Sulphate Hydrochbride Sulphate Hydrochloride Hydrochloride Hydrochbride Hydrochbride Hydrochbride

Sulphate Sulphate Sulphate Sulphate Sulphate Hydrochloride Hydrochbride Hydrochloride Sulphate Hydrochloride Hydrochloride Sulphate METHOD O3 ADMINISTRATION Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Intraperitoneal Subcutaneous Subcutaneous Oral Intravenous Intraperitoneal Subcutaneous Intravenous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Intravenous Intravenous Intravenous Oral Subcutaneous Intraperitoneal

Intramuscular Intravenous Subcutaneous Intravenous Intravenous Intravenous Subcutaneous Intravenous Intravenous H.LD. mgm per kgm. 10* 400-500 440 600 540 530-690 350 500 1,000 3,000 200 400 320 135-140 400 400-425 300-460 400-500 50 50 60 590 320-400 310-400 340 66-70

230 80 60 75 220 70 70-75 AUTHOK Nadler Amatsu Kubota Fujii Kreitmair Pak and Read Chen Pak and Read Fujii Kreitmair Kreitmair Kreitmair Rowe Pak and Read Chen Kreitmair Chen Miura Amatsu Kubota Kreitmair Pak and Read Chen Chen Chen Chen Chen Chen Pak and Read Pak and Read and

Kreitmair Chen Miura Pak and Read Chen and EPHEDBINE AND BELATED SUBSTANCES 61 I t is interestby The difference One wonders route of administration is 70 to 75 mgm. per kilogram. Kreitmair from those reported by Fujii and by Rowe. by subcutaneous injection is fully 100 per cent or more. 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, d, 483) and by Burn (Methods of Biological Assay, London, 1928). b. Toxic symptomatology. general depression, mydriasis, stoppage of the respiration and diastolic standstill of the heart in frogs. 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. pigs, rabbits, cats lethal doses of and dogs. In his experience, without cardiac More detailed investigations were carried out by Chen on frogs, rats, guinea collapse subA full occurs sooner than respiratory failure. ephedrine recover Animals poisoned by complications. The signs of poisoning in mice, rabbits and dogs, as stated by him, are mydriasis, elevation of Miura (1887) briefly described the toxic H e observed signs in animals with lethal doses of ephedrine.

ing to note the great deviation of the M.L.D. in mice obtained

if these three workers experimented on the same species of

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. for hours. The animal may, however, live In Oral administration and injection into the circulation via

the heart, in 5 to 10 mgm. dosage, produce a dark coloration. these cases the arms are extended and limp, and on stimulation they go into a series of tonic contractions. occurs. c. Repeated administration. The respiratory

movements

are faster and heavier, gradually become slower and labored, and death In a series of rabbits Chen gave daily intramuscularly

doses of ephedrine for several weeks intravenously, 62 K. K. CHEN AND CARL P. SCHMIDT effects. controls.

and orally and reported that the drug produces no observable toxic These anfma.k gained in weight as steadily as the

Upon sacrifice, there were no gross or microscopic lesions in the visceral organs. No tolerance is developed to the mydriatic or pressor action Similar results were obtained in of ephedrine by repeated administration, nor is there any change in the dose required to cause death. rats. This work has recently been verified by Doty. IV. CLINICAL APPLICATIONS 1. Methods of Administration cutaneous or intramuscular and Dosage injection, and only exceptionally by For systemic effects, ephedrine can be given by mouth, by subintravenous administration. On occasion, the drug may be used per For local application to 1 to 5 concentrations varying from

rectum, as shown by Thomas and by Hess. the nasal mucous membrane, per cent can be used. or mixed with other aromatic ingredients, a

I t may be in the form of a solution, pure 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. for one individual may be a large one for A small dose From the another.

experience of early investigators, a single dose may be 50 to 100 mgm.

for

an

average adult.

Hess advocates

the use of

1 to

mgm.

per kilogram of body weight. occurrence of side reactions. four times a day.

This dose appears to be slightly too I t has now been reduced to 25 to 50 I t can be given three or

large, especially for ambulatory patients, judging from the frequent mgm., and may be repeated as needed.

In children from 2 to 14 years of age, Munns and Aldrich use 12 to 50 mgm. of 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, 1 to J grain (15 to 30 mgm.) from 5 to 6 years, grain (7.5 mgm.) from 6 to 12 months, and & grain (5 mgm.) under 6 months of age. doses are given with 20 minims of glycerine and enough chloroform water to make a dram (4 c c ) . EPHEDEINE AND EELATED SUBSTANCES 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, MacDermott, Hollingsworth, Thomas, Balyeat, BergerandEbster, Althausen and Schumacher, Middleton and Wu and Read, Anderson and and Homan, Kesten, and The by Chen, Wihner, Gay Herman, Bloedorn 63 Such ephedrine by mouth. Anderson and Homan employ i grain (15 mgm.) for those over 1 year of age and $ grain (7.5

Dickens, Boston, Long, S6gard, Chopra, Dikshit and Pillai, Higgins, and Stewart in connection with their clinical investigations. development of such symptoms and signs depends upon the dosage but more upon the stability of the nervous system, as emphasized Pollak and Rabitschek. Similarly, Gaarde and Maytum state that The

the occurrence of the nervous smptoms bears a distinct relationship to a neurotic tendency and the daily activity of the individual. same therapeutic dose, therefore, may produce only desirable effects in one patient, and equally beneficial results but with some discomfort, in another. and Chen). Meals sometimes aggravate the symptoms (Middleton 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 nervousness, 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 Berger and still report of difficulty in urination in 6 cases he observed. by diarrhea and anorexia, after aphrodisiac.

Ebster give an account of a neurotic patient who had colic, followed the use of ephedrine, and of another who had such an increase of libido that he called ephedrine an 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. suppression of urine. Anderson and Homan observed abdominal distension, pain and discomfort, discharge from the nose and apparent T. G. Miller recorded a case of myocardial Four out degeneration in which ephedxine caused pulsus alternans.

of 11 cases in the series of Middleton and Chen showed after ephedrine extrasystoles of ventricular or auricular origin, as shown by electrocardiography. 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 tachycardia and cardiac decompensation, following ephedrine therapy. freSuch dangerous effects, however, do not appear to occur very

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 electrocardiograms, that ephedrine increased the frequency of pre-existing extrasystoles 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 administration 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. subjective 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 Occasionally, the untoward symptoms in some inAltunder ephedrine to the changes in pressure in the arteries or veins within the skull. dividuals disappear on repeated administration of ephedrine, showing that these individuals become better accustomed to the drug. 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 EPHEDBINE 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 Wu give that patient any discomfort or any craving for the drug. mgm. every 1 to 3 days) was continued for three years. Laboratory examinations did not show any ill effects. forming drug. the Thomas and Balyeat, and Collina also express the opinion that ephedrine is not a habitIn 5 out of 51 cases of asthma and hay fever, Althausen and Schumacher noted a considerable diminution of action in hausen and Schumacher mention two such cases and Hollingsworth Some of the

and Read mentioned a case in which ephedrine therapy (40 to 60

relief of attacks, showing the increase in tolerance by repeated administration. It should also be borne in mind t h a t the attacks may not have been of equal severity and that severe cases are able for the action of ephedrine. Contraindications are but few. caution. Se"gard mentioned angina and hypertension as contraindications of the use of ephedrine. However, recent work on spinal anesthesia shows Care that it is permissible to use ephedrine in hypertension cases. should also be taken in cases where there is a labile vagosympathetic equilibrium, although there is not the same extent of hypersensitiveness to ephedrine as to epinephrine in Graves 3 disease (Cs6pai and Fernbach). In late acute circulatory collapse, it is best not to give be a dangerous procedure, in spinal anesthesia as shown which by ephedrine, since it may Pitkin mentions 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., became cyanotic, nbrillated and, although the pressure was at or above normal, died in about 12 hours. V. THERAPEUTIC USES 1. In asthma of T. G. Miller, who first employed Following the publication In experimental animals, however, death never occurs if the blood pressure is at its normal level. two In all cardiac disorders, especially with signs of decompensation, ephedrine should be used with unfavor-

Blalock in experimental animals. fatalities were attributed to 50 mgm. of ephedrine, but his own toxicological

ephedrine in the treatment of bronchial asthma, many other investi66 K. K. CHEN AND CARL P. SCHMIDT gators have made similar reports concerning their experience with the

drug. good

I t appears to be generally agreed now that ephedrine is a Its action is

palliative remedy in the treatment of bronchial asthma. occasionally efficacious in severe attacks of asthma. cases

"weaker than that of epinephrine, and it is therefore only In mild and moderate

it may prevent the attack if it is given several hours beforehand, abort the attack if it is administered during the prodromal period and sometimes stop the attack when it is used while the attack is in progress. Its prophylactic action seems to be better property. cent) than its antispasmodic This is well illustrated by the work of Vallery-Radot and only 17

Blamoutier, who showed that ephedrine was effective in 16 (69 per out of 23 cases when given prophylactically but in (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 comparativfely 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. 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, This author adds, however, that patients who are about to undergo sensitization tests should be cautioned not to seek relief

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. ephedrine without untoward symptoms. In other words, a reaction from epinephrine does not indicate that ephedrine likewise will have a EPHEDRINE AND BELATED SUBSTANCES 67 TABLE 3 Results of ephedrine therapy in the treatment of asthma AUXHOU T. G. Miller (1925). T. G. Miller (1926) . Leopold and T. (1927) Thomas (1926) . Thomas (1927) . MacDermott Pollak and Ro"bitschek Hess . Heller Jansen Kammerer and Dorrer.. . Middleton and Chen Piness and Miller Wilmer Wilkinson Wu and Read Bibb Balyeat Rudolf and Graham Jankowski Collina .. Taylor... NTTHBEH Off CASES 7 36 .... Althausen and Schumacher. G. Miller Some individuals who are unable to take epinephrine are fortunately able to use

BT7.gTTT.Ta Benefit in 6; none in 1 Good results in 26, relief not marked in 4; no improvement in 6 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 Complete relief in 33; partial relief in 17, no relief in 9 Relief in 17 Ephednne is a remarkably efficient 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 riimqdf) Favorable Relief m 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 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 TABLE 3-Concluded NUMBER 01 CASES 100 49 12 ? ? (Children) 22 is of considerable value in 65 per cent of the

(Children) 29 XZSTTLTS

Complete relief in 71; moderate relief in 21, no relief in 8 In 23, ephedrine used prophylactically, produced benefit in 16 but none in 7; in 39 ephedrine 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 McPhedran Segard Long Munns and Aldrich.., Anderson and Homan Stewart , similar unpleasant effect. 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). 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 If the patient can tolerate both drugs well, there is no reason why epinephrine cannot be A combination of epinephrine and ephedrine has been found efficacious by some and objectionable by

subcutaneously.

The

clinical improvement

can sometimes be ob-

served objectively.

I t consists in diminution of cyanosis, increase Subjectively, the patient usually volun-

of vital capacity, decrease of rales, gradual disappearance of orthopnea, and euphoria of the patient. 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. activities and pass comfortable nights. EPHEDETNE AND RELATED SUBSTANCES 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 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. seen that beneficial results have been obtained in the majority of cases by each physician. I t is futile to compare the percentage of improvement 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 autumnal hay fever which were treated by the oral administration of ephedrine. 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. In 5 cases the result Excessive nasal secretions stop, ocular symptoms disappear, and in every way the patients are entirely comfortable. was Thirteen of these patients obtained complete or I t will be by They can resume their daily Withdrawal of the ephedrine Other persons are not 69

results in recurrence of asthmatic symptoms.

so fortunate, for the by-effects, occasionally met with, render its

fair and partial relief was obtained for 2 to 3 hours after each dose. In 8 cases the results were negative. published in 1927, they made a comparison of the effects of oral administration with those of a 3 per cent nasal spray. received ephedrine by mouth, 13 (54 per cent) were completely or almost completelyrelieved 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. for several hours; 12 (48 per cent) were partially relieved for cent) were not benefited. nasal spray, therefore, appears to be less efficacious and the relief is of shorter duration. used early in the paroxysm. The effect of both the local and internal administration seems to depend on the severity of the paroxysms and 70 K. K. CHEN AND CARL P. SCHMIDT the good results are obtained in the milder seizures. and nervous state of the patient. successive 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 Untoward symptoms, when they occur, are attributable to the neurotic temperament I n analyzing their data of two However, the majority of patients feel that its use adds to The best results are obtained when the spray is their comfort. Ephedrine given in 3 per cent solution as a several hours or completely relieved for less than an hour; and 6 (24 per In a similar series of 25 cases which were given ephedrine by a spray, 7 (28 per cent) were markedly relieved In 24 patients who In their next series,

are temporary and symptomatic. Leopold and Miller observed complete Encouraging results in the treatment Piness and temporary relief in 63 per cent of 11 cases and prefer the oral route for the administration of ephedrine. of hay fever with the new drug are also noted by Thomas, Balyeat, Althausen and Schumacher, Wilkinson, and Ramirez. 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. 3. In These results show that local application is more efficacious bronchitis and emphysema all having hypotension, Saxl reports than oral administration. I n 11 cases of senile emphysema, 1 with active and 6 with inactive pulmonary 8 but had no effect in 3. for several hours with 100 mgm. doses. 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. in which improvement occurred, some cough remains but in mild form and of a of the disease. Stewart observed effect at that all. ephedrine relieves the He states, however, coughing, the whooping the drug, combined and with vomiting in mild and moderate cases. In severe cases there is no In a series of 35 children suffering from pertussis type associated with acute upper respiratory infections. They believe that ephedrine is most useful during the second stage They noticed that the drug abolished the characteristic In all instances signs of whooping cough in 18 out of 20 children. According to him ephedrine The blood pressure rose 15 to 30 mm. Hg tuberculosis and that ephedrine produced a striking improvement of the dyspnea in

that

EPHEDSINE AND BELATED SUBSTANCES

7l The progress

belladonna and ipecac, seems to have a beneficial effect. of the infection is not in any way influenced. 5. In spinal anesthesia Rudolf and

The blood pressure-raising property of ephedrine appears to be most useful in spinal anesthesia. a hospital, in which they administered ephedrine intravenously. blood pressure. 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 This lasted for 1 there quickly resulted an extraordinary and prolonged rise in blood pressure, with a slower and stronger heart beat. to 1 hours. the ephedrine within 2 to 3 minutes after the anesthetic, so as to anticipate the fall rather of drastic fall in blood pressure or of vomiting, which occurs frequently in spinal anesthesia. be given with advantage before the spinal anesthetic where the blood pressure is already too low. Ockerblad and Dillon have used ephedrine 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 The fall in pressure must be anticipated if the best results are to be obtained with ephedrine. In other words, once They also state that the drug can sometimes than combat it after it had developed. This improved technique proved to be satisfactory and they had no case In their later cases they used smaller doses and gave In their first few cases the blood pressure was Their results are striking, especially with reference to the elevation of the Graham studied 26 cases under spinal anesthesia, in the surgical and gynecological wards of

pressure falls as much as 50 per cent, the return to the normal level even under comparatively large doses of the drugis slow and uncertain. the blood pressure 20, 30 or more milli-meters Hg above the normal for that individual. The drug is repeated if there is a tendency to fall. Ephedrine relieves any Chronic hypotension, which used to be a contraindication to spinal anesthesia, is no longer a valid objection. tendency toward retching and vomiting which, according to Ockerblad and Dillon, is due to the preliminary hypodermic injection of morphine 72 K. K. CHEN AND CARL F. SCHMIDT and scopolamine. Pitkin uses 1 to 1.3 cc. of a solution containing He is satisfied with the 1 per cent of novocaine and 3 per cent of ephedrine to make a wheal at the site of, and before, lumbar puncture. phragm. pressor action of ephedrine and performs operations below the diaHe states that the action of the drug can be relied on Pitkin and McCormack, and Cosgrove have tried the for 2 to 3 hours and has contributed much to the safety of spinal anesthesia. drug in obstetrics where spinal anesthesia may be indicated, as in low forceps extraction, episiotomy, perineorrhaphy, dilatation or incision of the cervix, podalic version, hysterectomy, etc. by Pitkin. craniotomy and extraction, vaginal Ephedrine is used prophylactically as outlined It is better to reinforce the vascular system with ephedrine before the actual administration of the spinal anesthetic, to have

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. mm. Hg. mm. Hg. In 151 cases, approximately one-half received ephedrine (50 to 100 mgm.) and the average drop of blood pressure was 12.8 In the other half the average drop of pressure was 37.5 Wehrheim reports his experience in over 300 cases of spinal To show the benefit of this procedure,

anesthesia with ephedrine (50 mgm.) injected subcutaneously 5 minutes before the spinal tap. 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. 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, spinal puncture. 6. In hypotension The use of ephedrine in the treatment of chronic or subacute hypotension has, with some exceptions, not proved as promising as had been hoped for. I t has been tried in Addison's disease. Chen and Schmidt EPHEDRINE AND BELATED SUBSTANCES 73 mentioned a single case in which ephedrine seemed to have a goo, d 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 following the administration of ephedrine, but both patients died from the disease. Rowntree and Brown treated 14 cases of Addison's disease They also and two of questionable Addison's disease with ephedrine. Gosse, Saklad, and Russell who injects ephedrine intramuscularly before the Other measures, such as saline infusions with small

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 symptoms or circulatory asthenia. Only in one case of early Addison's The feeling of weakdisease excellent clinical results were obtained. 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. mgm. had no effect whatever on the hypotension, yet most of the The response in pressure increase was not as striking as in certain other types of cases, and" sometimes a dose of 50

ness and exhaustion disappeared and the patient felt buoyant, strong

patients expressed themselves as feeling stronger and more energetic under its influence. Rowntree and Brown administered ephedrine in 9 cases of Aside from the rise of blood of the basal metabolic nervous exhaustion and hypotension.

pressure for 3-6 hours and some increase

rate, no other evidence of clinical improvement was observed objectively, although some of the patients were convinced t h a t they felt somewhat stronger. Pollak and Robitschek mentioned a case of by pneumonia in which daily doses of ephedrine raised the blood pressure from a level below 100 mm. to 145 mm. Hg, although accompanied some untoward symptoms. Hess reported a series of cases with hypoand vasomotor weakness. Repeated

tension, including pneumonia, bronchopneumonia, pulmonary tuberculosis, cardiac insufficiency small doses of ephedrine produced favorable results. sure at the normal level, as shown by three cases. 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 hypotensiontwo with asthma and one without asthmawith 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. Wu and Read, The slight elevation in the third was probably due to the improvement of his asthmatic condition under ephedrine therapy. with ephedrine in cases of hypotension. tension. four on the other hand, state that they obtain very satisfactory results Althausen and Shumacher determined the value of ephedrine in 7 patients with chronic hypoDuring an average period of 20 days the blood pressure was Ghrist and Brown reported an raised by daily doses of the drug and three patients felt stronger while did not notice any change. interesting case of postural hypotension with syncope, in which ephedrine raised and sustained the blood pressure and rendered the patient free from symptoms. He has been able to go back to work without In the treatment H e advocates

of paresis with malarial fever, the drug can maintain the blood pres-

further attacks by the daily use of the drug. disease. 7. In shock

These authors believe

that ephedrine may exercise a specific alleviative effect on the

I n acute circulatory collapse it is still a question how much good ephedrine can do. 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, concluded 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 Miller In one of surgical shock in a single patient, with encouraging results. reported real improvement in two cases in profound shock. The drug is not indicated in late stages 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 numusually 75 without beneficial ber of cases of shock and hemorrhage, EPHEDEJNE AKD BELATED SUBSTANCES

result, even though the drug was given intravenously (unpublished). 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. ephedrine intravenously. mm. Hg. the patient gradually sank and died some five hours later. which ephedrine was given. One of them rapidly recovered and the other Althausen and Schumacher reported two cases in a state of surgical shock in Similarly, in a patient dying of postan operative peritonitis Rudolf and Graham, administered 100 mgm. of The systolic blood pressure rose from unrecordable level to 86 mm. Hg. within 2 minutes and later to 130 The good effects lasted for some 45 minutes and then

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. operation. 8. In Adams-Stokes' syndrome In a single case of complete heart block T. G. Miller gave a subcutaneous 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. ventricular complexes was The shape of to the P-wave and time to the time. observed alter from The action usually lasts longer than the

Hollingsworth was the first to report a case of Adams-Stokes' syndrome in 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. was therefore resumed. complete heart block with syncope and convulsions in which ephedrine gave complete relief. The patient was given 30 mgm. doses three times The drug was then discontinued and the patient a day during the first week and 20 mgm. doses three times a day during the next two weeks. 76 K. K. CHEN AND CARL P. SCHMIDT had no further attacks for 10 weeks afterwards, during which time he was ambulatory. P. As a nasal astringent She found that a D r . Alice H . Cook (cited by Fetterolf and Sponsler) was the first to use ephedrine locally in the nose and throat. 10 per cent solution of ephedrine causes almost instant shrinkage of After three It weeks the drug was withheld but the attacks recurred in 48 hours. Stecher reported a similar case of

an engorged nasal mucous membrane and that the action is more rapid and complete than t h a t of a 4 per cent solution of cocaine. This subject was investigated more thoroughly by Fetterolf and Sponsler who used a 5 per cent solution in 17 patients and found it so effective t h a t they described ephedrine as a drug which, for use in the nose, has all the advantages of epinephrine with perhaps none of its disadvantages. Following the application to the anterior part of the lower The maximum is established in. from l to turbinate b y means of a cotton brush, contraction begins in from a few seconds to one minute. In spite of a small area of application the turbinate in every case contracts throughout its entire length. The general outline of the medial surContraction is so complete face changes from convex to concave. fits a gray tint at the maximum of the action. is often seen with epinephrine. 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. secondary congestion, as with epinephrine. others. surgery is contraindicated 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 a n d the drug can be applied by (1) spraying, which is best for children, (2) topical application with cotton on a probe, and (3) introduction and as an adjunct to surgery, and (3) chronic* accessory sinus disease in children where surgery should be used Similar favorable results have been obtained with weaker solutions (1 to 3 per cent) by Fiske, Proetz, and Kennon advocates the use of ephedrine in (1) acute nasal accessory sinus disease, (2) chronic nasal sinus disease where There is no No white ischemia occurs, as Relaxation begins in 2 hours and the finger. 5 minutes or in an average time, for their series, of 2$ minutes.

and the mucosa becomes so thin and flat that it fits the bone as a glove The color is altered to a paler hue and assumes

EPHEDSINE AND RELATED SUBSTANCES into the nose on cotton packs.

77

Fifteen infants having definite evi-

dence of ethmoiditis were treated by this author in the following manner: 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. least were benefited by such a regime. to be in contact with the nasal mucosa for more than a few seconds. pack left in situ for 3 minutes causes no more contraction than after a shorter time. change in the rapidity or duration of the action. free ventilation and drainage for a period of 3 to 6 hours. 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. page of excessive nasal secretions in cases of hay fever. sneezing in some patients. Leopold and Miller Gaarde and Maytum reported that ephedrine given orally produces a stopThey noticed actual observed Merkel also tried ephedrine in 3 cases of epistaxis and claimed to obtain good The drug brings about Daily use over a period of 10 days shows no A Twelve patients at Ephedrine does not need

shrinkage of the nasal mucous membranes in similar cases b y the same method of administration. In experimental animals (dogs), a contracintration of the nasal mucosa and accessory sinuses following the

venous injection or local application of ephedrine has been demonstrated 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 in 1887. ephedrine produces mydriasis in most people in from 40 to 60 minutes. The use mydriatic He observed that a 6 to 7 per cent solution of The first ophthalmological work with ephedrine was done by Miura

of a 10 per cent solution in 18 patients did not cause a maximal dilatation 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. effects result from prolonged use. treatments daily for IS days showed no pathological changes. 78 K. K. CHEN AND CARL P. SCHMIDT tion of mydriasis varies from 5 to 20 hours. are more susceptible than ydung adults. seem to respond well. results in 1889. Children and aged people The diseased iris does not identical The duraThere is no increase in intra-ocular One patient receiving three

pressure,no irritation or inflammation follows its instillation and no ill

De Vriesse published practically

Inouje encountered a case in which the instillation of Groenouw re0.01 The

ephedrine precipitated an acute attack of glaucoma.

ported 100 cases he studied in which the following mixture was used: ephedrine hydrochloride, 1 gram; homatropine hydrochloride, gram; and water, 10 cc. Merck named this mixture Mydrin.

mydriasis with this combination begins in 8^ minutes, reaches its maximum in 34 minutes and lasts for from 4 to 6 hours. dation is not interfered with by this solution. pupil contracts to 5.6 mm. in diameter. The accommoresults MarIn strong light the

Similar favorable

have been reported by Suker, Snell, Cattaneo and Stephenson. moiton not long ago (1911) gave a re'sume* of this work on ephedrine. All these authors advocated the use of ephedrine in the of the fundus on account of the rapid action, absence of cycloplegia, short duration of mydriasis and harmlessness of the drug. the

exploration

Since

recent extensive study of ephedrine interest in its use in ophthalmology has been revived. 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. mydriatic for Chen and Poth found that ephedrine is an efficient Middleton and Chen observed that a 10 per cent solution of ephedrine, or the same concentration with the addition

Caucasians but is of little value in dilating the pupil of the Chinese

and of negroes. and under

The investigation was made both in diffuse illumination with accurate

daylight

controlled

measurements.

The same difference used indiscriminately

in mydriatic action in these three races was in clinics. The question seems not to be

observed with cocaine and euphiJialmine, which have hitherto been 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, t h a t a 1 to 3 per cent solution of ephedrine is a valuable drug to produce EPHEDBINE AND BELATED SUBSTANCES 79 The same author ob2\ mydriasis for ophthalmoscopic examination. by pilocarpine within 5 to 10 minutes.

served that the effect of ephedrine on the human pupil is counteracted Similarly, Muller, after 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. cently, Chen and Poth found that the dilated pupil in amount of homatropine or euphthalmine is added. upon the accommodation. ReCaucasians mixtures

under the influence of ephedrine is made more stable to light if a small The have a short duration of action and some (but only little) influence As a result a better view of the eye ground Some subjects experience a In uveitis is obtained without inconveniencing the patient by blurring of vision. The solutions are but little irritating. burning sensation which lasts for about 30 to 60 seconds. fails to dilate the pupil. 11. As an antidote for narcotic drugs C. F. Schmidt observed in experimental animals that by its pressor action but also to stimulate the respiratory center directly. He advocates the use of ephedrine and epinephrine in serious depression or failure of the respiration, such as following morphine, in preferephedrine possesses the power not only to increase the O 3 supply of the brain

and iritis, however, ephedrine, or its mixtures with other mydriatics,

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 Subsequent reports seem to bear out ampules with scopolamine and morphine, or scopolamine and eucodal (dihydroxycodeine hydrochloride). his point. In psychiatry Guttmann used hypodermically

containing 1 mgm. of scopolamine and 25 mgm. of ephedrine in all cases of senile dementia, arteriosclerosis and 2 excited cardiac psychoses. Duping sleep these individuals had a quiet smooth breathing instead of snoring. The addition of ephedrine apparently does not affect the In surgery, Streissler reported 26 ampules narcotic action of scopolamine.

cases in which he injected subcutaneously morphine and 80 K. K. CHEN AND GAEL P. SCHMIDT

containing 1 part of scopolamine and 25 parts of ephedrine to produce analgesia and anesthesia. According to Streissler, 2\ 25 mgm. of ephedrine. These drugs are given in divided dosage. hours before the operation the patient

should be given 10 mgm. of morphine and 1 mgm. of scopolamine with After 15 minutes 10 mgm. of morphine are If sleep is not deep l hours before operagiven and 15 minutes later 1 mgm. of scopolamine with 25 mgm. of ephedrine is again injected. given. tion, 0.5 to 1 mgm. with ephedrine, which is an extra dose, should be Finally, \ hour before operation, 10 mgm. of morphine, toWith gether with 1 mgm. of scopolamine plus ephedrine are injected. these medications the pain sensation disappears before tactile sensation. There is no anxiety, fear or resistance on the part of the patient Many operations can be done under In during induction of anesthesia.

this form of analgesia and anesthesia, such as amputations of the breast, surgical treatment of the stomach or gall bladder, etc. only as little as possible. not made stertorous. young vigorous persons ether may be given during the operation, but The pulse rate is often unchanged but is Respiration is slowed but remains elevated for two Vomitusually accelerated after the operation. hours after the operation. ing does not occur.

The blood pressure

The patient wakes up in 4 to 6 hours with

complete amnesia and euphoria and without any struggling.

T h e pain in the wound is not so severe.

There were no postoperative complications that could be definitely attributed to the drugs. Lubitz, working at the same clinic, reported 14 Moro used this combination of more cases, using the same medication. for painless delivery.

scopolamine, ephedrine and morphine in 32 urological cases, and OstrCil 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. 12. In Merck has patented the scopolamine-ephedrine combination in England and Austria. dermatology In view of the fact that ephedrine resembles epiT. G. Miller treated two cases of acute by mouth and 81 recorded beneficial a. In urticaria.

nephrine it has been tried out clinically in allergic conditions other than asthma and hay fever. urticaria with ephedrine given results.

EPHEDRINE AND RELATED SUBSTANCES

Kesten made a careful study with ephedrine in a large series. Several patients

She found that in 11 cases of chronic urticaria with angioneurotic oedema, 7 were cured, 2 improved and 2 unaffected. in this group had had urticaria almost continuously for years but became free from symptoms after taking the drug and remained so for some months after the medication had been discontinued. are less favorable in cases without oedema. Results Of 6 patients with chronic I n 3 cases of Similarly,

urticaria 2 had complete relief, 2 showed improvement and the remaining 2 no change, following the oral use of ephedrine. there was practically no relief except for lessened itching. papular urticaria, 2 of erythema multiforme and 2 of chronic eczema in a case of mild urticaria following the administration of serum but with no other symptoms of serum sickness, ephedrine produced no relief. 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. Encouraging 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 turpentine. Stokes and ephedrine in anaphylactic reactions from mine injections.

Mclntyre studied 68 cases which showed reactions towards arsphenaThey found that in 57.5 per cent of them ephedrine relieved such symptoms as nausea, headache, vertigo, dizziness, urticaria, pruritus, pain, choking, coughing and repeated nitritoid crises. Besides, ephedrine reduced the fall of blood pressure from 28 to 6 mm. Hg. c. In leprosy. 13 cases. hours. The fact that epinephrine relieves the nerve pains the of lepers led Muir and Chatterji to use ephedrine for this purpose in They found that ephedrine does not interfere with simultaneous use of potassium iodide, and its action lasts for 12 to 24 In their opinion, the beneficial effect is probably due to contraction of the arterioles of the nerve trunks, thereby relieving their 82 K. Z. CHEN AND CARL P. SCHMIDT vascular engorgement. does not give relief. They admit that in certain cases ephedrine Cochrane and Mittra reported 10 cases of leprosy They consider it Ephedrine has no

in which the lepra reactions, such as nerve pain, joint pain, swelling and other manifestations, were controlled by ephedrine. an extremely useful lepra reactions. The relief is usually complete. drug in relieving the distressing symptoms of

action on the temperature, nor does it reduce the eruptions which appear during reactions in skin cases. According to these authors, the and ephedrine like epilepra reactions are allergic manifestations 13. In dysmenorrhea activity, Lang used ephedrine in 30 cases of

nephrine, is able to alleviate allergic conditions. Assuming that dysmenorrhea is due to local or general increase of parasympathetic essential dysmenorrhea. half to one-third. There was not only complete freedom from

or diminution of pain, but also diminution of menstrual flow by oneEphedrine was given as soon as pain appeared, One patient experienced pain and a feeling Palpitation and tremor were observed in other usually 2 to 3 times a day. of cold in the legs. 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. between the Kreitmair showed that qualitatively there is no difference action of natural and synthetic ephedrines. Thus, detoxifying

it has a prolonged pressor action, antispasmodic action, tiveness by mouth.

action against scopolamine or morphine, oxytocic action and effecHis results are in general confirmed by Chen and Coelho by Pak and Read, although the last two authors believe that the synthetic product is less sympathomimetic than the natural. EPEEDEINE AND RELATED SUBSTANCES 83 extrasystoles, changes in Q.R.S. and alteration in T waves, block, and finally ventricular drine. fibrillation, with various doses of synthetic epheAs with the natural drug, Chen found relaxation of the isolated in chloralosed dogs observed with electrocardiograms the appearance of

rabbit's intestine, hyperglycemia in rabbits, mydriatic action in animals and in men, contraction of the nasal m u c o u s membrane and accessory sinuses and a decrease followed b y volume, with synthetic ephedrine. an increase of the kidney H e 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 n o t e d a primary leucopenia and secondary leucocytosis following t h e subcutaneous injection of synthetic ephedrine. when given by mouth, like the natural, produces hyperglycemia and inhibits the conversion of carbohydrates into fat. results. Cannavd obtained similar Euler and Liljestrand showed t h a t synthetic ephedrine in and Lublin showed t h a t t h e synthetic product,

men increases the O2 consumption and t h e minute cardiac output. Synthetic ephedrine delays the emptying time of the stomach decreases the gastric acidity, as reported b y Takacs. Fonseca and

Trincao state that oral administration diminishes but subcutaneous

injection increases the gastric acidity. Quantitatively, Kreitmair in his preliminary communication concluded that there was no difference between t h e natural and synthetic ephedrines. rectal administration. a weaker pressor action in men. are much less uniform than by that of natural ephedrine. Compared indirectly in pithed cats against epinephrine, t h e 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 t o be about 1:2. Schaumann, and Launoy and Nicolle arrived a t t h e same conclusion. k 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 illuminaPa Chen in 9 subjects found that the changes in blood pressure by the oral use of synthetic ephedrine Petow and Wittkower, Saxl, and Berger, Ebster and Heuer, on the other hand, seem to agree t h a t synthetic ephedrine has Hess shared the same opinion for men by oral or

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. by oral administration. Chen recorded that synthetic and natural ephePak and King drines, in the form of the hydrochlorides, given intravenously, both have a M.L.D. of 60 mgm. per kilogram in white rabbits. Read state that synthetic ephedrine is less toxic than natural ephedrine in frogs, rats, rabbits and dogs; the reverse is true for hamsters. and Pak studied in anesthetized dogs the ratio of the shrinkage of the nasal mucous membrane produced by natural and synthetic ephedrines, respectively, and determined it to be 1:0.8. Regarding the toadcity, Kreitmair found it to be the same in mice either by intravenous injection or

Clinically, synthetic ephedrine has been tried wherever ephedrine is indicated. bronchial asthma by oral use of synthetic ephedrine.

natural Their results

Petow and Wittkower treated 20 cases of

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 11 asthmatBerics with synthetic ephedrine and recorded improvement in 10.

ger and Ebster in an elaborate investigation recorded unquestionable benefit from synthetic ephedrine in 10 cases of asthma and less significant results in 2 severe cases of the same ailment. good results in 16. same drug and reported relief in 60 per cent, temporary or irregular improvement 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 compound have also been reported by Jankowski, Beck, Guttmann, and H>mTning. The majority of these investigators appear to agree that synthetic ephedrine is useful, like the natural product, in the prevention and arrest of mild and moderate attacks of asthma but less promisEPHEDRINE AND BELATED SUBSTANCES 85 ing in severe cases, and that it has a weaker action but produces less untoward symptoms than natural ephedrine. dose lies between 25 and 150 mgm. per os. Saxl treated 11 cases of emphysema w i t h 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 pulmonary tuberculosis. ephedrine. In hay fever Berger a n d Ebster, !ELreitmair and application of synthetic Nardelli advocated the oral use and local T h e dosage of synthetic ephedrine varies according to individual tolerance, but the average Neustadt studied 22 cases of bronchial asthma with synthetic ephedrine, and obtained S6gard treated 70 cases of asthma with the

Berger and Ebster observed relief of headaches in one

case of hemicrania with angioneurotic oedema, b u t no effect in a case

of chronic urticaria. by Nardelli in three cases of of arsphenamine intolerance. the untoward symptoms of withdrawal of m o r p h i n e in two addicts, and Parade and Voit in arresting the attacks i n a single case of AdamsStokes' syndrome. was given by mouth. In practically every instance, synthetic ephedrine For acute infectious rhinitis, Berger and Ebster Slack Michalowsky w a s successful in relieving Poppe in controlling malaise from roentgenological treatment, alimentary urticaria and two cases Improvement of symptoms was reported by Frankel in a severe case of urticaria, by Sack in 20 cases of eczema, and

used a 5 per cent solution of synthetic ephedrine as a spray. 3 cases of acute rhinitis, a topical application of t h e 5 per cent solution produces a marked contraction of the t u r b i n a t e s . other cases of swollen turbinates, where natural ephedrine and synthetic

(cited by Chen) found that in 4 cases of hypertrophied turbinates and

In a few

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 a n opera singer, with symptoms of sneezing, running of the eyes a n d dyspnea which were controlled by the oral administration of s y n t h e t i c ephedrine. Sattle advocated the use of synthetic ephedrine 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 o n e s yielding natural or I86 K. Z. CHEN AND CAK1 F. SCFMTDT in ophthalmology. According to him, a solution containing 5 per c e n t of synthetic

ephedrine. solution

The mydriatic action of pseudoephedrine was first studied He observed that a 10 to 12 per cent

by De Vriesse (1889).

when applied locally to the eye of men produces, in from 30 to 35 minutes, mydriasis which lasts from 6 to 9 hours. no changes in intra-ocular pressure. Giinsburg (1891) in an extensive study on animals and 120 patients presented evidence that the mydriasis 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 Fujii depression, block, arrhythmia and stoppage of the frog's heart at diastole, following the administration of pseudoephedrine. (1925) made a comparaHe reported It dilates the tive investigation of pseudoephedrine with ephedrine. weaker mydriatic action on the enucleated frog's eye. There are no secondary effects after a single instillation, nor after its prolonged use, and

that pseudoephedrine has a weaker pressor action in rabbits and a blood vessels in small doses but constricts them in large concentrations, 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. the isolated rabbit's uterus in all concentrations. It contracts 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 Chen made a similar comRead and by Chopra, Dikshit and Pillai.

parative study, and reported that pseudoephedrine has a weaker pressor 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 concentration 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. drine. Liljestrand Pak and Read found that ergotoxine does that pseudoephedrine the contracts the not invert, but cocaine abolishes, the pressor action of pseudoepheobserved isolated guinea pig's uterus and human uterus and that it has a stimulating action on the fundus of but no effect on the trigone. rabbit's urinary bladder

Quantitatively, Chen, Wu and Henriksen recently compared indiEPHEDRINE AND BELATED SUBSTANCES 87 rectly in pithed cats the pressor action of pseudoephedrine and ephedrine, and found the average ratio of the intensity to be 1:5.17; that is, ephedrine is about 5 times as strong as pseudoephedrine. Read, by direct comparison in anesthetized dogs, concluded ephedrine is twice as strong as pseudoephedrine. subject to criticism, as shown by Pittenger. Pak and that

Their method is

King and Pak compared The the

the shrinkage of the nasal mucous membrane in anesthetized dogs with ephedrine and pseudoephedrine and found the ratio to be 1:0.38. toxicity was compared by Fujii who found less toxic in frogs but more toxic in mice. In white rabbits that pseudoephedrine is

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 rabbits pseudoephedrine is less toxic than ephedrine in frogs, rats, and dogs; the reverse is true in hamsters. Clinically, Howard and Lee tried out a 10 per cent solution of pseudoephedrine in their eye clinic and concluded that it is an uncertain mydriatic and has no place in the treatment and examination of ophthalmic 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 Z-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. I t 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 epinephrine, /-ephedrine is found to be about 3 times as strong as dephedrine, and (/-pseudoephedrine 7 times as strong as /-pseudoephedrine. /-Ephedrine, the strongest isomer, is 35 times as powerful as When given by /-pseudoephedrine, the weakest isomer of the six.

88 K. K. CHEN AKD CARL P. SCHMIDT mouth to men in the same quantity, ^-ephedrine and /-pseudoephedrine do not appear to raise the systolic blood pressure while the other four isomers do. TABLE 4 Pharmacological activity of the optical isomers of ephedrine rf-PseudotfWPseudo J-Pseudo XATIO OT FEZSSOX ACTION IN ANIUALS 35.15 26 40 11 90 6 80 400 1.00 PXBSSOX ACTION IN ILLS) DTWHUB XABBITB mtm. ptr 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 /3phenylethylamine in white rabbits, given subcutaneously, is 300 mgm. per kilogram of body weight. Phenylethanolamine, CBHS-CHOH-CHJ-NHS, was first synthesized by Kolshorn (Ber. deut. chem. Gesell., 1904, xxxvii, 2474), later by Rosenmund (Ber. deut. chem. Gesell., 1913, xlvi, 1034), and Mannich and Thiele (Arch. Phann., 1915, cdiii, 181), and is covOf the two sets of isomers ^-ephedrine and J-pseudoephedrine have the least toxicity.

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 phenylMiller and Piness ethanolamine is on the smooth muscles directly. EPHEDRINE AND BELATED SUBSTANCES but its activity on the congested nasal mucous membrane is in every respect comparable to that of ephedrine. general confirmed by Chen, Wu and Henriksen. Nor-ephedrine, CeHs-CHOH-CHCHs-NHz, was obtained in a Gesell., MydriaPat. racemic form by Rabe and Hallensleben (Ber. deut. chem. cdv, 140). 27,056). Nagai patented his product under the name of Their results are in 89

showed that this compound does not raise the blood pressure in men when taken by mouth and is useless in the treatment of asthma,

1910, xliii, 2622), Calliess, Nagai, and Eberhard (Arch. Phann., 1917, tine in the United States (U. S. Pat. 1,356,877) and in Japan (Jap Miura found that this compound {mydriatine) mydriatic action in men. is not impaired.

has a strong

The pupil begins to dilate in 20 to 30 minThe accommodation

utes and the mydriasis lasts for 24 to 36 hours.

Hirose first observed its pressor action in animals. Their data show that the M.L.D of

Amatsu and Kubota concluded that its action is quantitatively the same as that of ephedrine. gram in frogs, and 400 to 500 mgm. per kilogram in rabbits. Henriksen conclude from their study of Chen, Wu and ephedrine homologs and mydriatine sulphate, given subcutaneously, is 0.4r-0.5 mgm. per

isomers that primary amines are more powerful than their corresponding methylated derivatives, and predicted that nor-ephedrine would be stronger than JZ-ephedrine. given This has been found to be true. The compound also raises the systolic blood pressure in men when

by mouth in 50 mgm. dosage. rabbits is approximately into six optical isomers.

Its M.L.D. intravenously in albino per kilogram of body weight.

70 mgm.

Kanao succeeded in resolving the racemic mixtures of nor-ephedrine According to Hirose (cited by Kanao), the order of activity of these optical isomers is as follows: NorwZ-pseudoephedrine > nor-rfZ-ephedrine = nor-J-ephedrine Nor-tZ-ephedrine < nor-/-epLedrine Nor-i-pseudoephedrine > nor-Z-pseudoephedrine < nor-/-ephedrine Nor-i-pseudoephedrine also occurs in Ma Huang, as shown by Smith, and confirmed by Nagai and Kanao. Chen, Wu and Henriksen It raises reported that nor-d-pseudoephedrine has a weaker action than /- or dlephedrine, but a stronger action than ^-pseudoephedrine. the systolic blood pressure in men when given by mouth. Tiffeneau, and TifFeneau, L6vy and Boyer synthesized three com90 K. K. CHEN AND CARL F. SCHMIDT pounds of the general formula where R is ethyl, propyl or phenyl. The ethyl compound, C 6 H B -CHOH-pressor CHCaH B -NH 2 , called nor-homoephedrine, has a prolonged COHB-CHOH-CHR-NHS,

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 The propyl and than that of ephedrine (Chen, Wu and Henriksen). Levy and Boyer. Hyde, Browning and Adams synthesized a series of compounds of the general formula G J H B - C H O H - C H R ' - N H R " , where R' is hydrogen, methyl, or -propyl, and R " propylj w-butyl or -amyl. is methyl, ethyl, -propyl, isoMost of these substances, including two

phenyl derivatives have a depressor action, as reported by Tiffeneau,

prepared by Manskein which R ' is methyl and R " is oxyethyl or benzylwere studied pharmacologically and compared with ephedrine by Chen, Wu and Henriksen. 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' or R " is equal to a propyl or higher alkyl group. They are weaker than ephedrine. The general conclusion drawn by these workers was that with increase

ELanao prepared a similar series of compounds of the general formula C fl H B -CHOH-CHCH 3 -NHR, benzyl, 0-hydroxybenzyl, where R is ethyl, iso-amyl, heptyl, 0-vanillyl, vanillyl, piperonyl, m,p-dih.y-

droxybenzyl, furfuryl or citryl.

He states that the hydrochloride of

the citryl derivative has a strong local anesthetic action. Z-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 where R' is was reached by Curtis with a series of tertiary amines related to ephedrine of the general formula propyl or butyl. the formula CeHe-CHOH-CHCHa-NR'R", methyl or ethyl, and R " is methyl, ethyl, oxyethyl, -propyl, isoSome of these compounds, however, produce dilataThe tertiary amine of prepared by Hyde, Chen, tion of the bronchi equal to that of ephedrine. C 6 H 6 -CHOH-CHC2H B -N(C4H 8 ) 2 ,

Browning and Adams, has a depressor action, as shown by Wu and Henriksen.

Nagai synthesized the following two substances with the idea that EPHEDRINE AND RELATED SUBSTANCES action of epinephrine: CH-CHCHa-N(CjHn)i I 0 CO-CeH 5 Allocain A CaHj CH CHCH NHC 2 H 1 1 0-CO-CBHB 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 CQHB-CHOH-CH clinical use does not seem justifiable. Beaufour prepared w-methoxymethylephedrine, (CH 2 - OCH3) -N(CH3)2, and found it to have a local anesthetic action. 91 they might possess the anesthetic property of cocaine and the styptic

Brauchli

and

Cloetta

reported

that

diallylephedrine,

C e H s -CH-

(OC 3 H 6 ) CHCH 8 NCH 3 (C 8 H 6 ), has a depressor action. Emde and Runne synthesized a-isoephedrine, CHOH-CHs. C 6 H 6 -CHNHCH 8 -This compound is of interest because ephedrine for

some time was considered to have the same structural formula. Duli&re made synthetically several ethers of phenylpropanolamine, and studied their pharmacological action. Tyramine, HO<^ stronger pressor action than ephedrme but to be useless when given by mouth in men, as shown by Chen and Meek. Sympatol, HO<^ ^>CH0H- CHNHCH3, 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. the introduction of a methyl group on the of the compound HO<( a-C-atom from the N-atom prolongs the action, Chen, Wu and Henriksen suggested the synthesis )>CHOH CHCH3 NH 2 , which was soon I t has in achieved by Hartung of Sharp and Dohme, Baltimore. toxic, than either dl- or /-ephedrine in animals, but it has not been demon92 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 drine, CHsO^ a greater pressor action than nor-homoephedrine. methoxyephedrine, CH 8 O found them to have no pressor action in rabbits. I t is universally agreed that epinephrine HO<^ ^>CHOH CHj CHaO^ methoxy-^-oxyephedrine, HO<^ Kohler prepared pand mand )>CHOH CHCHs NHCHs, ^-methoxy-norhomoephe^>CHOH - CHCsH s NH a , and found it to possess In view of the fact that the presence of an OH group at the ^-position usually intensifies the action, and y>CH a CH 2 NH 2 , was proven to have a

fact a prolonged and stronger pressor action, and is much less

^>CHOH CHCHa NHCH 8 ,

HO NHCH3, has a strong but fleeting weaker but more prolonged effects HO<^ than HO ephedrine, as shown by Hirose. The compound HO the German patent literature (D.R.P. 254,438, 256,750, 269,327) (1920). The and has been studied pharmacologically by Tiffeneau HO<( ^>CHOH CHCHa NH 2 , is mentioned in when given by mouth. action, while ephedrine has a action. The latter produces systemic 0-Dihydroxyphenylethanolamine,

^>CHOH CH a NH 8 , also has a stronger pressor action

latter found that an Z-isomer resolved from its racemic mixture has 60 to 75 per cent of the activity of Z-epinephrine, but he did not study the duration of its action nor its absorption from the gastrointestinal tract. I t 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 l^O-COCH, O-COCHj O-COCHi where R 1 is methyl, ethyl or propyl, R J is methyl, heptyl, benzyl, piperonyl, diacetoxybenzyl, acetovanillyl or furfuryl and R 8 is methyl, EPHEDRINE AND RELATED SUBSTANCES heptyl, benzyl or diacetoxybenzyl. substances has not been reported. From the above account it appears that there is no difficulty synthesizing compounds related to ephedrine that are in stronger 93 The physiological activity of these

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 and this has made ephedrine particularly useful clinically because the drug can be given by mouth. Among the synthetic compounds, ^/-epheresemble natural ephedrine most closely Some other compounds have a strong drine and <f/-norephedrine and deserve a clinical trial. from the N-atom. The absorbability from the gastrointestinal tract seems to be a peculiar feature of ephedrine,

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 the Ephedra. species The are other constituents that are present in Chinese pseudoephedrine, nor-i-pseudoephedrine,

Z-methylephedrine, and ^-methylpseudoephedrine. 2. Ephedrine is a stable compound. Its solutions are not decomposed 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 stimufibers. In cerIt lation of the myoneural junctions of the sympathetic

tain instances, there is an additional stimulation of the ganglia. muscles. 5. In animals, ephedrine does not have a marked effect on any of the body secretions. 94 K. K. CHEN AND CARL F. SCHMIDT 6. There is an increase in the formed elements of the blood and

has been claimed by some investigators that it acts on the smooth

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 Individuals who do not have a vago-

by mouth or by injection.

sympathetic equilibrium may experience untoward symptoms. 11. Ephedrine has been used with success in the treatment of bronchial asthma, hay fever, whooping cough, bronchitis, postural hypotension 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. ogy, shock and dysmenorrhea is promising. 12. 13. Compared with epinephrine, ephedrine has a less intense but Of the many synthetic compounds, dZ-ephedrine and dl-noimore prolonged action. ephedrine deserve more extensive clinical trials. This review is intended to be as concise as possible. desired. Naturally the authors could not discuss many valuable papers as fully as they The literature consists of all those articles available on or before November 1, 1929. REFERENCES ABEL, J. J.: Chemistry in Relation to Biology and Medicine with Especial Reference to Insulin and other Hormones. Grosshinrbde auf den chloralhydratschlaf. joriii, 453 AIXES, G. A.. The Comparative Physiological Action of Phenylethanolamine. Jour. Pharm. Exp. Ther., 1927, sxrii, 121. ALTHATJSEN, T. L, AND SCHUMACHEB, J. C.: Clinical Results with Ephedrin Therapy. Arch. Int. Med, 1927, ri, 851. AMATSTJ, H. AND KUBOTA, S.: tJber die pharmakologischen Wirkung des Ephedrins und Mydriatins sdv, 77 (original in Japanese), 5 (abstract in German). EPHEDRINE AND RELATED SUBSTANCES 95 Kyoto Igaku Zassi, 1913, x, 301 (original in Japanese); 1917, Arch, intern, de Pharmacodyn. et de Ther., 1913, Science, 1927, kvi, 307 and 377. AIBXLA, Y.: (Jber die Einwirkung verschiedener Erregungsmittel der Its value in dermatol-

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To", T.: Uber die Wirkung von Exzitantien auf Atemmechamk und Geswechsel des normalen Menschen. Arch. Exp. Path. Pharm, 1927, exxv, 1. Fortsch. d. Therap., 1927, iii, 791. DE VEER, A.: Therapeutische Umschau. de rasthme. Bull. gfin. Ther., 1928, clxxix, 367. VAIXERY-RADOT, P. AND BLAMOUTEER, P.: L'epheclrine dans le traitement de rasthme. Bull, et men. Soc. meU d'HAp de Paris, 1928, Iii, 1324. VESTENRTC, N. N.: Ephedra vulgaris (s. monostachyd). 1897, Lsii, 110. VILLARET, M , JusTiN-BESANgoN, L., AND VEXENAT Recherches sur le muscle bronchique isol6. Comp. rend. soc. biol., 1929, c, 806. WAGNER, W.: Ueber Eukodal-Skopolamin-Ephedrin (Merck). Wchnschr., 1928, lxxv, 737. WALLACE, H. K.: Use of Ephedrine in Spinal Anesthesia. Med. Assoc, 1928, xc, 144. EPHEDRINE AND RELATED SUBSTANCES 117 WEHKBEQI, H. L.: Ephedrine in Spinal Anesthesia. 1928, v, 178. WEHEBUM, H. L.: Ephedrin in Spinal Anesthesia. Analgesia, 1928, vii, 218. WILKINSON, G. R.: Ephedrine in Asthma and Allied Conditions; Clinical Report. Jour. jour. Amer. Med. Assoc., South. Carolina Med. Assoc, 1927, rriii, 272. WILMER, H. B.: Treatment of Bronchial Asthma. 1927, lrnrix, 956. WILSON, C. P., PPLCTTRR, C. AND HABBISON, T. R.: The Effect of Ephedrine on the Minute Anesthesia and Brit. Jour. Anesth, Jour. Amer. Munch, med. Actions des poisons sympathique et du parasympathique. Jahresb. Pharm.,

VAIXERY-RADOT, P. AND BLAMOUTEER, P.: Ephldrin dans le traitement

Cardiac Output of Normal Dogs. Arch. Int. Med., 1928, xli, 622. WILSON, J. A.: Ephedrine Hyperglycemia in Dogs and Rabbits. Pharm. Ezp. Ther., 1927, xxz, 209. WHIIAMB, J. B.: The Assay of Ephedra wlgaris. Jour. Amer. Pharm. Assoa, 1928, xvii, 430. Wu, S. T. AND READ, B. E.': Ephedrine, N. N. R.; a Review with Case Reports. China Allgemein. med. Zeit. chines. Reich., 1923, i, 13 Med. Jour., 1927, xli, 1010. YUAN, S. F.: Ma Huang. (in Chinese). 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 Allocain A, 91 AUocain 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 Jour.

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-Dihydrojcyphenylethanolamine, 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. ephedrme, 18, 55, 59, 66, 76, 94 Ergotamine, see ergotozine

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 Hodgkin's disease, 43, 44 Hypotension, use in, 72,94 lin, 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 Lupinus 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-norhomoephedrine, 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 Myxedema, 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 djerve, 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 {LoKgo pealii), 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 ephedrin^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 Venous pressure, effect on, 23 Turpentine reactions, use in, 81 Voluntary muscle, action on, 46 Turtle's heart, action on, 24 I * ramine

' S0 ' 91 Whooping cough, use in, 70, 94 Ureter, action on, 39 Urine, effect on, 42, 64 Yield of ephedrine, 9 Urticaria, use in, 80 seasonal variation, 10 Uterus, action on, 39, 93 YoMmbine, effect on pressor action, 50 S S a a n n s the s T T a a c c h h of e e art" each artist or independent of manufacture craftsman He befrom creation.

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