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Ethyl-nor-epinephrine by inhalation for bronchial asthma; A comparison with epinephrine
ETHYL-NOR-EPINEPHRINE BY INHALATION FOR BRONCHIAL ASTHMA; A COMPARISON WITH EPINEPHRINE MILTON
M. HARTMAN,
M.D., SAN E’RANCISCO,CALIF.
INCE the use of 1 per cent epinephrine by direct inhalation was described by Graeser,3 it has been extensively used but has proved to be a mixed blessing. In the hands of well-informed physicians with a knowledge of the pathologic physiology involved in asthma and the pharmacology of epinephrine, this drug, by inhalation, has been a useful aid. Under the supervision of relatively uninformed physicians and pharmacists or under the self-supervision of totally uninformed laymen it has been productive of little good and some harm. The adverse effects stem from two sources: (A) The local vasoconstrictor effect on mucous membranes, resulting in dryness, increased susceptibility to infection, ulceration, and gangrene. In this category belong cases of acute and chronic ulceration of the lymphoid nodules of the oral pharynx, ulceration of the tonsils, acute and chronic laryngitis, and ulceration of the vocal cords and other structures of the larynx. Changes in the trachea and main bronchi are rarer. (B) The effects due to overdosage. It, is commonly forgotten that epinephrine for inhalation is ten times stronger than that for injection. Whether the inhaled material gets to the bronchioles or not, most of it is eventually al)sorbed. Assuming complete absorption, 0.05 cc. or one drop by inhalation is equivalent to 0.5 cc. of a l:l,OOO solution (the usual dose) by injection. One frequently sees patients (and hears stories of others) who have used 10 to 12 drops at one inhalation and 3 cc. (equivalent to 30 cc. of epincphrine, 1 :l,OOO, by injection) during one night. They did not realize that, if a therapeutic dose did not afford relief, they may have been refractory to the drug. Instead of relief from wheezing they had tachycardia, tremor, headache, nausea, and other toxic effects. The margin between therapeutic and toxic doses of epinephrine is relatively small. The author and his associates previously reported on the pharmacolo,T and parenteral use in asthma of a new sympathomimetic drug, ethyl-nor-epinephrine.‘” Chemically, it is l- (3,4-dihydroxyphenyl) -2-amino-l-butanol. To recapitulate briefly, when injected in$amuscularly or subcutaneously in approximately twice the dosage employed with epinephrine, it gave equivalent relief in uncomplicated extrinsic asthma.2 In asthma with bronchial infection it was less efficacious than ENE lacked the pressor effect of epinephrine; actually the epinephrine.* diastolic pressure was moderately lowered, with a widening of the pulse pressure and slight acceleration of the heart rate. ENE did not provoke nausea and vomiting; this made it preferable for use in children. No angina was pro*For convenience the abbreviation “ENE” for ethyl-nor-epinephrine will be used hereafter. 106
S
TABLE I.
COMPARATIVE RESULTS OF ENE AND EPINEPHRINE BY INHALATION IN TWENTY-EIGHT CASES OF UNCOMPLICATED EXTRINSIC ASTHMA
a $ g mE B E
4 4 3 ‘
12
:
4
16
ii B
3
24 23 27 27 29 .31
31 33 34 35 35 38 40
: E B E
43 is :?(I 51
: R n E n E
4 3 %
4 I CI 4
0 2
4 3 3 4
2 i
4 2
2
4
Sone None Recurrent ulceration tonsils No ulceration from
0 z
1 ,
:
1 ?
*
*
3 1
44
4 1
, :,
4 2
2,
4 i4
2
4 2
: 4
1 4 2 2
:
-
Kane
*
2 4
3
4 3
f
Epinephrine
ESE
n’one None SOIN? None None Chronic laryngitis- 3 months Cleared up in 2 days None None Sane Xone None Xonr Sane None Xone Sane Pione
4
(1
of
None
3
4
E -B c -
4
SOIK!
3
I
63
* * -
*
i
4
4
*
1
3
B E
-
-
3 2
60
*
4
2
2
-
4
3
E
-
1
4
56
-
3
1
2
Manic reaction; no local None None None Recurrent ulceration of tonsils No local effects I;one None Xone Tone None None Sone Nune None Kane Chronic ulcerative pharyngitis Cleared up under ENE None Kane -l’one
3 4
B E 4 B E 3 13 E 4 Ii 3 E F 4 Ii E 4 n
-
4 i4
3
B E B
-
i *
4
4
E E B E B E
*
None None None None
‘4
3
21
-
LOCAL EFFECTS ON UPPER RESPIRATORY TRACT (AND PSYCHOTIC REACTIOKS)
4
2 i
4 2
1
E”
-
j 4
I2 8 ;L
4 4
4
Ei B E
2
L 4
8 2 g z E
4
B = ENE
Ulcerative laryngitis5 weeks Cleared up in 4 days None None None None Sl = slight
108
THE
JOURNAL
OF
ALLERGY
duced in patients with associated cardiac or hypertensive disease; this made ii preferable in this group. Finally, tremor and ner\-ousness in general were Clinical trial of EXE hy encountered less with ENI than with epinephrine. the inhalation met,hod in these two general t,ypes of asthma was the next. logical step. METHOD
Since it was found thal: a solution of I3XE, 1 500, was equivalent to 1 :l,OOO epinephrine ?I>- injertion, in this study a 2 per cent, solution of ENE was used in the inhalat,ion studies for comparison with the effect of 1 per cent epinephrinr. The same makes of nehulizers were used, or the x-cry same nrhnlizers, thoroughly cleaned between drug changes. The cases selected were ones in which the effects, both good and had, of epinephrine 1)~ inhalation were already known. The patient was told to use the same number of deep inhalations, two to four.
--
ZZZ
--
B E D0 -E E B E B
,
/
& z Ls cz h
T *
E B E B E
-
B E B E B E B E
Y + -
B E R
v -
Ei
-
E E
-
B
-
i
-
-
-
E n E
-
22 -4 iz iz 02 __.B2 - * ii - - -f *-- - - - -.r- -
=
Epinephrine
I3
=
EISE
--
XI
e g b _, 2 g E: -
-
i -
-*
-
1,OCAL EFFECTS RESPIRATORY
ON TPPEI: TRACT
Kane None Chronic laryngotracheitis Cleared on changing to ENE None None None None Recurrent pharyngeal glceration Freedom from ulcers None None Kane Kane None Sane Recurrent acute laryngotracheitis So recurrence under EXE Sane Kane None None None Xone 1LJleerated vocal cords-
Clearance ENE None - None -
on
change
to
HARTMAN
:
ETHYL-NOR-EPINEPHRINE
COMPARED
WITH
109
EPINEPHRINE
RESULTS
Table I shows the results obtained in uncomplicated extrinsic asthma, Table II shows those obtained in asthma complicated by bronchial infection, and Table III gives a summary of the observations in both groups. Speed of relief is noted on a scale from “0” (absent) to “4” (maximum). Otherwise they are noted “-” for absent or “*” for present, TABLE NUMBER TYPE
III.
SUMMARY
OF CASES
28
CASES
14 CASES
UNCOMPLICATED EXTRINSIC ASTHMA
OF ASTHafA
EPINEPHRINE TREATED
DRUG USED SPEED
OF OBSERVATIOSS
ASTHMA
ENE TREATED
WITH BRONCHIAL INFECTION
EPINEPHRINE TREATED
OF RELIEF
Rapid Slow None
23 5 0
(4* and 3”) (2* and 1”)
DEC;REE OF RELIEF
High Partial Xone
(4* (2* ’
I
and 3*) and 1”)
NUMBER RELIEVED NUMBER OF FAILURES UNDESIRABLE LOCAL EFFECTS UPPER RESPIRATORY TRACT SYSTEMIC
SIDE
Tremor Nervousness Nausea Tachycardia Angina Rise in Blood Mania TABLE
IV.
(
28 0
ON
17 9 2
23 5 0 (1000/o)
10 4 0
17 9 z 26 (93%) 2 (7%) 0
11 3
0 2 0’ 2 0 0 0
3
‘>
'(0%) 5
-I
ENE TREATED
.-
..-
5 4 5 9 (64%) 5 (36%) 0
EFFECTS
5 6 4 3 3 3 1
Pressure RELATIVE
-
OF ENE
IMPORTANCE
AND
4 2 3 2 2 0
EPINEPHRINE
ON MECHANISMS
ISVOLFED
ZZ
LUMEN-INCREASING EFFECT
1. Relaxation of bronchiolar ( smooth muscle spasm 2. Lessening of mucosal edema due to improved lymphatic drainage allotved by relaxation of bronehospasm 3. Lessening of vascular bed mucosa through vasoconstriction 4. Lessening of mucosal edema b.y diminution the arteriolar-venule pressure differential 5. Lessening of secretion indirectly through constriction of vessels supplying m u e0 u s glands and eaithelium
* = pr’esent - =
absent
EFFECT POSSESSED BY EPINEPHRINE
*
-
EFFECT POSSESSED BY ENE
* *
RELATIVE IMPORTANCE OF EFFECT IN 1JNCOMPLICATED EXTRINSIC AND FLEFLEX ASTHMA *ii**
RELATIVE IMPORTANCE OF EFFECT IN ASTHMA WITH BRONCIII$L INFECTION its*
x*x
xx
**
*xx
** *
-
**
xi*
110
THE
JOURNAL
OF
ALLERGY
COMMENT
An analysis of results requires a consideration of the mechanisms of action of these two drugs in the t,wo types of asthma. These arc summarized in Table IV. In “pure” or uncomplicated asthma the relasat,ion of bronchospasm and the lessening of edema through the improved lymphatic drainage are accomplished equally well by both medications. Epinephrine has the advantage of vasoconst,riction on surface application which calls forth the other lumenincreasing factors shown. These initial effects due t,o vasoconstriction giyc more speedy relief also. IIowever, t,hat same vasoconstriction of epinephrine sIows its absorption through the mucous membrane and delays the bronchodilator effect. ENE, because of its lack OF yasoconstrictor l)ower, does not hare this initial antiedema and antisecretor~- cf&ct ot’ epinephrine, but it, apparently arrives more rapidly at the myoneural junctions of the bronchiolar smooth muscle cells. The effects art, therefore, approximately equal in uncomplicated extrinsic asthma. In ast,hma complicated by bronchitis or secondary t,o it, ho\wver, the congestion, edema, and mucous production arc significant factors ul)on which ENE has little or no effect. Hence in this type it is not surprising that it) should fail entirely in some instances and, in genwal, be less cffcctiw than cpinephrine. In anotlicr series of eighteen cases, all of which resl)onded to ENE, all were found to respond to epinephrinc. This series was not studied as carefully as the previous one, the only objcet bein g to see if tlicrc wew any cases relieved t)J ENE which epincphrine failed to relieve. The results of both series sho~\etl that ENE is not apt to be eRect,ive by inhalation if epinel)hrine is not,. Theoretically, when used by the inhalation method for the relief of asthma, neit,her of these drugs should cause any undesirable systemic actions. We would like to conceive of a minimum amount of the ihug applied at t,he point Of maximum effectiveness. Actually, however, the rate of absorption by t,his method is unpredictable, and t.hc impatient asthmatic patient, laboring for his breath, is prone to disregard instructions. The more des1)erat.c or more unintelligwlt he is, the more he will use his own judgment. Strictly speaking, significant nausea, nervousness, tremor, tachycardia, pressor effect, or angina by this method should properly be regarded as signs of ovrdosugc Or toxic cffccts. To he realistic, however, we have to regard any actions accompanying the tlosc OF inhaled drug that the patient, deems nccc~~ary to rcliew his asthma as side rffccts;, undesirable bui mow or less incvitablc. In the analysis of tlicw cflccts, systemic and local, the first notable Ccaturc is the lack of angina, nausea, and pressor effect in the ENE series. The sw~nd feature is t,he greatly lessened incidence and severity of tachycardia, tremor, and nervousnew in the ENPI series. Third, and of great importance, is t,he lack of unwanted local effect on the upper respiratory tract mucous membrane when using ENE. Whether to prescribe ENE or epinephrine 1)~ inhalation, then, depends upon the t~ype of asthma, the expected frequency of use, the intelligence of the patient, the frequency of supervisory medical consultation, and the incident and type
HARTMAN
:
E’Inru-iuc)It-EPINEPHRINE
COMPARED
of side reactions. Both drugs have their advantages there is a limited field for the supervised use of each.
WITH
111
EPINEPHRINE
and disadvantages,
and
‘SUMMARY
1. In uncomplicated asthma of extrinsic origin 2 per cent ENE is almost as effective as 1 per cent epinephrine by inhalation, their bronchodilator powers being equal. 2. In asthma complicated by bronchial infection epinephrine is definitely more effective than ENE, presumably because of its additional vasoconstrictor action. 3. Undesirable local effects on the upper respiratory tract encountered so frequently with epinephrine do not occur with ENE. 4. Toxic effects from inhalation of ENE are rare and minimal; those effects from epinephrine inhalation are frequent and often serious. 5. Choice of medication depends on several enumerated factors. The ENE used Chemical Company.
in these
investigations
was supplied
through
the courtesy
of the Winthrop
REFERENCES
1. Tainter,
N. L., Cameron, 1%‘. M., Whitsell, L, J., and Hartma& of Ethylnorsuprarenin, J. Pharmacol. & Exper. Therap. 2. Hartman, M. M.: Parenteral Use of Rutanefrine in Asthma; nephrine, Ann. Allergy 3: No. 5, 1945. 3. Graeser, J. B.: Inhalation of Epinephrjne Hydrochloride for toms, J. ALLERGY 6: 415, 1935. 450 S.ks
SUTTER STREET FHBNCISCO, CALIF.
M. M.: Clinical Actions 81: 269, 1944. A Comparison J$rith EpiRelief
of
Asthmatic
syrnp-
M. HARTMAN,
M.D., SAN E’RANCISCO,CALIF.
INCE the use of 1 per cent epinephrine by direct inhalation was described by Graeser,3 it has been extensively used but has proved to be a mixed blessing. In the hands of well-informed physicians with a knowledge of the pathologic physiology involved in asthma and the pharmacology of epinephrine, this drug, by inhalation, has been a useful aid. Under the supervision of relatively uninformed physicians and pharmacists or under the self-supervision of totally uninformed laymen it has been productive of little good and some harm. The adverse effects stem from two sources: (A) The local vasoconstrictor effect on mucous membranes, resulting in dryness, increased susceptibility to infection, ulceration, and gangrene. In this category belong cases of acute and chronic ulceration of the lymphoid nodules of the oral pharynx, ulceration of the tonsils, acute and chronic laryngitis, and ulceration of the vocal cords and other structures of the larynx. Changes in the trachea and main bronchi are rarer. (B) The effects due to overdosage. It, is commonly forgotten that epinephrine for inhalation is ten times stronger than that for injection. Whether the inhaled material gets to the bronchioles or not, most of it is eventually al)sorbed. Assuming complete absorption, 0.05 cc. or one drop by inhalation is equivalent to 0.5 cc. of a l:l,OOO solution (the usual dose) by injection. One frequently sees patients (and hears stories of others) who have used 10 to 12 drops at one inhalation and 3 cc. (equivalent to 30 cc. of epincphrine, 1 :l,OOO, by injection) during one night. They did not realize that, if a therapeutic dose did not afford relief, they may have been refractory to the drug. Instead of relief from wheezing they had tachycardia, tremor, headache, nausea, and other toxic effects. The margin between therapeutic and toxic doses of epinephrine is relatively small. The author and his associates previously reported on the pharmacolo,T and parenteral use in asthma of a new sympathomimetic drug, ethyl-nor-epinephrine.‘” Chemically, it is l- (3,4-dihydroxyphenyl) -2-amino-l-butanol. To recapitulate briefly, when injected in$amuscularly or subcutaneously in approximately twice the dosage employed with epinephrine, it gave equivalent relief in uncomplicated extrinsic asthma.2 In asthma with bronchial infection it was less efficacious than ENE lacked the pressor effect of epinephrine; actually the epinephrine.* diastolic pressure was moderately lowered, with a widening of the pulse pressure and slight acceleration of the heart rate. ENE did not provoke nausea and vomiting; this made it preferable for use in children. No angina was pro*For convenience the abbreviation “ENE” for ethyl-nor-epinephrine will be used hereafter. 106
S
TABLE I.
COMPARATIVE RESULTS OF ENE AND EPINEPHRINE BY INHALATION IN TWENTY-EIGHT CASES OF UNCOMPLICATED EXTRINSIC ASTHMA
a $ g mE B E
4 4 3 ‘
12
:
4
16
ii B
3
24 23 27 27 29 .31
31 33 34 35 35 38 40
: E B E
43 is :?(I 51
: R n E n E
4 3 %
4 I CI 4
0 2
4 3 3 4
2 i
4 2
2
4
Sone None Recurrent ulceration tonsils No ulceration from
0 z
1 ,
:
1 ?
*
*
3 1
44
4 1
, :,
4 2
2,
4 i4
2
4 2
: 4
1 4 2 2
:
-
Kane
*
2 4
3
4 3
f
Epinephrine
ESE
n’one None SOIN? None None Chronic laryngitis- 3 months Cleared up in 2 days None None Sane Xone None Xonr Sane None Xone Sane Pione
4
(1
of
None
3
4
E -B c -
4
SOIK!
3
I
63
* * -
*
i
4
4
*
1
3
B E
-
-
3 2
60
*
4
2
2
-
4
3
E
-
1
4
56
-
3
1
2
Manic reaction; no local None None None Recurrent ulceration of tonsils No local effects I;one None Xone Tone None None Sone Nune None Kane Chronic ulcerative pharyngitis Cleared up under ENE None Kane -l’one
3 4
B E 4 B E 3 13 E 4 Ii 3 E F 4 Ii E 4 n
-
4 i4
3
B E B
-
i *
4
4
E E B E B E
*
None None None None
‘4
3
21
-
LOCAL EFFECTS ON UPPER RESPIRATORY TRACT (AND PSYCHOTIC REACTIOKS)
4
2 i
4 2
1
E”
-
j 4
I2 8 ;L
4 4
4
Ei B E
2
L 4
8 2 g z E
4
B = ENE
Ulcerative laryngitis5 weeks Cleared up in 4 days None None None None Sl = slight
108
THE
JOURNAL
OF
ALLERGY
duced in patients with associated cardiac or hypertensive disease; this made ii preferable in this group. Finally, tremor and ner\-ousness in general were Clinical trial of EXE hy encountered less with ENI than with epinephrine. the inhalation met,hod in these two general t,ypes of asthma was the next. logical step. METHOD
Since it was found thal: a solution of I3XE, 1 500, was equivalent to 1 :l,OOO epinephrine ?I>- injertion, in this study a 2 per cent, solution of ENE was used in the inhalat,ion studies for comparison with the effect of 1 per cent epinephrinr. The same makes of nehulizers were used, or the x-cry same nrhnlizers, thoroughly cleaned between drug changes. The cases selected were ones in which the effects, both good and had, of epinephrine 1)~ inhalation were already known. The patient was told to use the same number of deep inhalations, two to four.
--
ZZZ
--
B E D0 -E E B E B
,
/
& z Ls cz h
T *
E B E B E
-
B E B E B E B E
Y + -
B E R
v -
Ei
-
E E
-
B
-
i
-
-
-
E n E
-
22 -4 iz iz 02 __.B2 - * ii - - -f *-- - - - -.r- -
=
Epinephrine
I3
=
EISE
--
XI
e g b _, 2 g E: -
-
i -
-*
-
1,OCAL EFFECTS RESPIRATORY
ON TPPEI: TRACT
Kane None Chronic laryngotracheitis Cleared on changing to ENE None None None None Recurrent pharyngeal glceration Freedom from ulcers None None Kane Kane None Sane Recurrent acute laryngotracheitis So recurrence under EXE Sane Kane None None None Xone 1LJleerated vocal cords-
Clearance ENE None - None -
on
change
to
HARTMAN
:
ETHYL-NOR-EPINEPHRINE
COMPARED
WITH
109
EPINEPHRINE
RESULTS
Table I shows the results obtained in uncomplicated extrinsic asthma, Table II shows those obtained in asthma complicated by bronchial infection, and Table III gives a summary of the observations in both groups. Speed of relief is noted on a scale from “0” (absent) to “4” (maximum). Otherwise they are noted “-” for absent or “*” for present, TABLE NUMBER TYPE
III.
SUMMARY
OF CASES
28
CASES
14 CASES
UNCOMPLICATED EXTRINSIC ASTHMA
OF ASTHafA
EPINEPHRINE TREATED
DRUG USED SPEED
OF OBSERVATIOSS
ASTHMA
ENE TREATED
WITH BRONCHIAL INFECTION
EPINEPHRINE TREATED
OF RELIEF
Rapid Slow None
23 5 0
(4* and 3”) (2* and 1”)
DEC;REE OF RELIEF
High Partial Xone
(4* (2* ’
I
and 3*) and 1”)
NUMBER RELIEVED NUMBER OF FAILURES UNDESIRABLE LOCAL EFFECTS UPPER RESPIRATORY TRACT SYSTEMIC
SIDE
Tremor Nervousness Nausea Tachycardia Angina Rise in Blood Mania TABLE
IV.
(
28 0
ON
17 9 2
23 5 0 (1000/o)
10 4 0
17 9 z 26 (93%) 2 (7%) 0
11 3
0 2 0’ 2 0 0 0
3
‘>
'(0%) 5
-I
ENE TREATED
.-
..-
5 4 5 9 (64%) 5 (36%) 0
EFFECTS
5 6 4 3 3 3 1
Pressure RELATIVE
-
OF ENE
IMPORTANCE
AND
4 2 3 2 2 0
EPINEPHRINE
ON MECHANISMS
ISVOLFED
ZZ
LUMEN-INCREASING EFFECT
1. Relaxation of bronchiolar ( smooth muscle spasm 2. Lessening of mucosal edema due to improved lymphatic drainage allotved by relaxation of bronehospasm 3. Lessening of vascular bed mucosa through vasoconstriction 4. Lessening of mucosal edema b.y diminution the arteriolar-venule pressure differential 5. Lessening of secretion indirectly through constriction of vessels supplying m u e0 u s glands and eaithelium
* = pr’esent - =
absent
EFFECT POSSESSED BY EPINEPHRINE
*
-
EFFECT POSSESSED BY ENE
* *
RELATIVE IMPORTANCE OF EFFECT IN 1JNCOMPLICATED EXTRINSIC AND FLEFLEX ASTHMA *ii**
RELATIVE IMPORTANCE OF EFFECT IN ASTHMA WITH BRONCIII$L INFECTION its*
x*x
xx
**
*xx
** *
-
**
xi*
110
THE
JOURNAL
OF
ALLERGY
COMMENT
An analysis of results requires a consideration of the mechanisms of action of these two drugs in the t,wo types of asthma. These arc summarized in Table IV. In “pure” or uncomplicated asthma the relasat,ion of bronchospasm and the lessening of edema through the improved lymphatic drainage are accomplished equally well by both medications. Epinephrine has the advantage of vasoconst,riction on surface application which calls forth the other lumenincreasing factors shown. These initial effects due t,o vasoconstriction giyc more speedy relief also. IIowever, t,hat same vasoconstriction of epinephrine sIows its absorption through the mucous membrane and delays the bronchodilator effect. ENE, because of its lack OF yasoconstrictor l)ower, does not hare this initial antiedema and antisecretor~- cf&ct ot’ epinephrine, but it, apparently arrives more rapidly at the myoneural junctions of the bronchiolar smooth muscle cells. The effects art, therefore, approximately equal in uncomplicated extrinsic asthma. In ast,hma complicated by bronchitis or secondary t,o it, ho\wver, the congestion, edema, and mucous production arc significant factors ul)on which ENE has little or no effect. Hence in this type it is not surprising that it) should fail entirely in some instances and, in genwal, be less cffcctiw than cpinephrine. In anotlicr series of eighteen cases, all of which resl)onded to ENE, all were found to respond to epinephrinc. This series was not studied as carefully as the previous one, the only objcet bein g to see if tlicrc wew any cases relieved t)J ENE which epincphrine failed to relieve. The results of both series sho~\etl that ENE is not apt to be eRect,ive by inhalation if epinel)hrine is not,. Theoretically, when used by the inhalation method for the relief of asthma, neit,her of these drugs should cause any undesirable systemic actions. We would like to conceive of a minimum amount of the ihug applied at t,he point Of maximum effectiveness. Actually, however, the rate of absorption by t,his method is unpredictable, and t.hc impatient asthmatic patient, laboring for his breath, is prone to disregard instructions. The more des1)erat.c or more unintelligwlt he is, the more he will use his own judgment. Strictly speaking, significant nausea, nervousness, tremor, tachycardia, pressor effect, or angina by this method should properly be regarded as signs of ovrdosugc Or toxic cffccts. To he realistic, however, we have to regard any actions accompanying the tlosc OF inhaled drug that the patient, deems nccc~~ary to rcliew his asthma as side rffccts;, undesirable bui mow or less incvitablc. In the analysis of tlicw cflccts, systemic and local, the first notable Ccaturc is the lack of angina, nausea, and pressor effect in the ENE series. The sw~nd feature is t,he greatly lessened incidence and severity of tachycardia, tremor, and nervousnew in the ENPI series. Third, and of great importance, is t,he lack of unwanted local effect on the upper respiratory tract mucous membrane when using ENE. Whether to prescribe ENE or epinephrine 1)~ inhalation, then, depends upon the t~ype of asthma, the expected frequency of use, the intelligence of the patient, the frequency of supervisory medical consultation, and the incident and type
HARTMAN
:
E’Inru-iuc)It-EPINEPHRINE
COMPARED
of side reactions. Both drugs have their advantages there is a limited field for the supervised use of each.
WITH
111
EPINEPHRINE
and disadvantages,
and
‘SUMMARY
1. In uncomplicated asthma of extrinsic origin 2 per cent ENE is almost as effective as 1 per cent epinephrine by inhalation, their bronchodilator powers being equal. 2. In asthma complicated by bronchial infection epinephrine is definitely more effective than ENE, presumably because of its additional vasoconstrictor action. 3. Undesirable local effects on the upper respiratory tract encountered so frequently with epinephrine do not occur with ENE. 4. Toxic effects from inhalation of ENE are rare and minimal; those effects from epinephrine inhalation are frequent and often serious. 5. Choice of medication depends on several enumerated factors. The ENE used Chemical Company.
in these
investigations
was supplied
through
the courtesy
of the Winthrop
REFERENCES
1. Tainter,
N. L., Cameron, 1%‘. M., Whitsell, L, J., and Hartma& of Ethylnorsuprarenin, J. Pharmacol. & Exper. Therap. 2. Hartman, M. M.: Parenteral Use of Rutanefrine in Asthma; nephrine, Ann. Allergy 3: No. 5, 1945. 3. Graeser, J. B.: Inhalation of Epinephrjne Hydrochloride for toms, J. ALLERGY 6: 415, 1935. 450 S.ks
SUTTER STREET FHBNCISCO, CALIF.
M. M.: Clinical Actions 81: 269, 1944. A Comparison J$rith EpiRelief
of
Asthmatic
syrnp-