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The effect of propranolol (Inderal) on the electrocardiogram of normal subjects
The effect of propranolol (Inderal) on the electrocardiogram of normal subjects Shlomo Stern, M.D. Shlomo Eisenberg, M.D. Jerusalem, Israel
S
ince the introduction of the p adrenergic receptor blocking agent, propranolol, into clinical usei its efficiency as an antiarrhythmic drug has been clearly denlonstrated.2-5 More recently, it has been used in many other common diseases, such as hypertension,6 and coronary artery disease.7-s In spite of the impressive amount of data published on propranolol, the effect of this drug on the electrocardiogram (ECG) of normal individuals has not yet been established. In the following study we investigated changes in the ECG after administration of propranolol in patients with no cardiovascular abnormalities and a normal a priori ECG. The results are described below. Material
and
method
In this study we included 21 patients hospitalized in our medical department because of diseases other than cardiovascular or pulmonary. All patients were in good general condition, were without electrolyte or metabolic disturbances and had normal ECG’s. Fifteen patients were between 18 and 40 years of age, four were above 40 years, and two were between 16 and 18 years. The tests were performed during the morning hours in the following way: a control 12 lead ECG was taken with a From the Cardiovascular University-Hadassah Recived for publication
192
Sanborn 100 direct writing electrocardiograph. Immediately thereafter, propranolol was injected intravenously, in a dose of 10 mg., diluted in 100 ml. of 5 per cent glucose, and was given over a period of 10 to 12 minutes. At the end of the infusion, another 12 lead ECG was performed. No side effects were observed during or after the administration of the drug in any of the patients. The ECG tracings were analyzed for the following data: heart rate, shape, duration, and height of the P wave; P-R interval ; amplitude of the Q, R, and S waves in the different leads; the width of the QRS complex; the electrical axis; the S-T segment; the height and duration of the T wave; the Q-T interval, and this value corrected for the heart rate (Q-T/-\/RR, Bazett formula). Results
When the data from the ECG were analyzed, changes were observed in the following: heart rate, P-R interval, Q-T interval, and the height of the T wave. These changes are summarized in Table I, and illustrative tracings are given in Figs. 1 and 2. It can be seen that all patients exhibited decrease in the heart rate, from an average of 76.2 per minute to an average
Unit and Department of Internal Medical School, Jerusalem, Israel. May 14, 1968.
American Heart Iournal
Medicine
R. Hadassah
F&wary,
1969
University
Hospital
and
Hebrew
Vol. 77, No. 2, pp. 192-19.5
EJect of ~ropranolo/
Table I. Summary propranolol
of changes in heart rate, P-R interval,
Heart rate (min.) Patient NO.
88 53 88 75 55 58 8.5 102 60 77 60 88 48 72 74 80 92 105 75 76 90
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Mean Range
Post ’ propranolo1
76.2 48-105
of 62.2 per came longer
-
I i Control
,
60 48 75 55 52 50 76 6.5 5.5 65 53 70 42 60 56 ;i 72 65 6.5 75 62.2 42-78
minute. in 12
Post propra! nolo1
.12 .14 .14 .12 .I2 .13 .12 .14 .16 .15 -12 .14 .16 .14 .ll .12 .14 .16 .14 .16 .13 0.136 0.11-0.16
The P-R
0.152 0.12-0.18
-~
Control
.16 .18 .18 .12 .12 .16 .14 .18 .16 .1.5 .12 .16 .16 .16 .14 .12 .17 .18 .14 .16 .14
interval
-
(sec.)
-__
.32 .38 .34 .40 .41 .40 .34 .36 .36 .36 .39 .36 .40 .34 .33 .34 .30 .29 .36 .38 .36 0.358 0.29-0.41
be-
and did not change in 9; the average increase was from 0.136 to 0.152 sec. The Q-T interval increased in 11 patients, decreased in four, and did not change in six. When this value was corrected to the heart rate (Q-T/ 1/RR, Bazett formula), a decrease in 20 patients was observed. An increase in the height of the T wave was observed in 12 patients. patients,
Discussion
Clinically, the antiarrhythmic properties of propranolol are very similar to those of quinidine. s Moreover, a synergistic action between the drugs was also demonstrated.‘” In view of these observations we expected that its basic effect cm the KG would be similar to that of yuinidine. Quinidine, as is well known, increases heart rate, increases P-R interval, prolongs
’ Post ’ p~o$:,‘;/ .34 .34 .35 .40 .40 .38 .34 .36 .38 .36 .40 .36 .41 .36 .3.5 .36 .32 .32 .35 .40 .36 0.364 0.32-0.41
193
Q-T, Q-T,, and 7‘ wuve .following
Q-T
P-R (sec.)
---____ Control
on ECG’s of normal subjects
Q-T/dR-R __~
~
Control
Post propranolo1
.39 .36 .41 .44 .39 .39 .41 .47 .36 .41 .39 .44 .36 .37 .37 .40 .38 .39 .40 .43 .44
.34 .31 .39 .38 .36 .34 .38 .38 .36 .38 .38 .39 34 .36 .34 .39 .37 .35 .37 .42 .40
0.400 0.36-0.47
T wave
Post propranolol + + + + + + + + + + + +
increased increased increased no change increased increased no change increased no change no change no change increased no change increased no change no change increased increased increased no change increased
height height height height height height
height height
height height height height
0.368 0.31-0.42
the duration of the QRS complex, prolongs the Q-T interval, induces deviation in the S-T segment, and increases the duration, inversion, and notching of the T wave.” Concerning the heart rate, it has been already established that the action of propranolol differs basically from that of quinidine by inducing bradycardia.2-5 The results of this study demonstrate that other fundamental effects of the two drugs on the ECG are also different. In contrast to the prolongation of electrical systole of the ventricles induced by quinidine, propranolol in 20 out of the 21 patients studied shortened the duration of the Q-T, interval. The other striking effect was an increased height of the T wave oc.curring in 12 of the patients examined. A similar effect was observed OII the T wave by earlier investigators.lz In spite of the decrease in the heart rate, the I’-Ii
194
Am. Heart .I. February, 1969
Stern md Eisenberg
B
A
Fig. 1. interval.
A, Control
ECG.
B, ECG
after
propranolol.
Note
bradycardia,
heightened
T wave,
and shortened
Q-T,
Fig. 2. A, Control interval.
ECG.
B, ECG
after
propranolol.
Note
bradycardia,
heightened
T wave,
and
Q-T,
shortened
Esfeet 0.f $ropranolol
interval did not change in nine instances, which was again an effect not seen after the administration of quinidine; this latter drug invariably prolongs the atria1 conduction time. In view of the above observations, the synergism between propranolol and quinidine in clinical use, and the success with the administration of the two drugs in conlbination’3-15 may lie in the fact that, although they share the important property of reducing the height and slowing the rise time of the membrane action potent&l,‘6 they differ in some other actions. Therefore, each drug may be used in smaller doses, lessening thereby the possible toxic effects but still enhancing the desired antiarrhythmic action. Summary
REFERENCES Black, Smith,
3.
4.
5.
6.
7.
8.
The effect of propranolol (Inderal) on the ECG of normal individuals was studied in 21 subjects. Over a period of 10 minutes, 10 mg. of the drug were administered intravenously. An ECG was performed before and immediately after the infusion. All patients responded with bradycardia. The P-R interval increased in 12 patients and did not change in 9. An increase in the height of the T wave was observed in 12 subjects. The Q-T interval did not change in 6, decreased in 4, and increased in 11. The Q-T, interval (Bazett formula) becatne shorter in all but one subject. This effect is opposite to that of quinidine on the Q-T, interval. The above findings are discussed in the light of the described synergistic action of propranolol with quinidine and the successful combination of them in treating various arrhythmias. I.
2.
J. W., Crowther, A. F., I,. H., and Dornhorst,
9.
10. 11.
12.
13.
14.
15.
16. Shanks, A. C.:
R. G., A new
on ECG’s of normal subjects
195
adrenergic beta-receptor antagonist, Lancet 1:1080, 1964. Rowlands, D. J., Howitt, G., and Markman, P.: Propranolol (Inderal) in disturbances of cardiac rhythm, Brit. M. J. 1:891,1965. Harrison, D. C., Griffin, J. R., and Fiene, T. J.: Effect of beta-adrenergic blockade with propranolol in patients with atria1 arrhythmias, New England J. Med. 273:4X0, 1965. Schanroth, L.: Immediate effects of intravenous propranolol on various cardiac arrhythmias, Am. I. Cardiol. 18:438. 1966. Stern, S., and Braun, ‘K.: Clinical experience with Inderal (propranolol) in supraventricular arrhythmias and sinus tachycardia, Harefuah 71:371, 1966. Prichard, B. N. C., and Gillam, P. M. S.: The use of propranolol in the treatment of hypertension, Brit. M. 1. 2:725. 1964. Wolfson, S., Heinle, R. ‘A., Herman, M. V., Kemp, H. G., Sullivan, j. M., and Gorlin, Ii.: Propranolol and angina pectoris, Am. J. Cardiol. 18:345, 1966. Grant, R. H. E., Keelan, P., Kernohan, R. J., Leonard, J. C., Nancekievill, L., and Sinclair, K.: Multicenter trial of propranolol in angina pectoris, Am. J. Cardiol. 18:361, 1966. Braunwald, E.: An editorial introduction to the Symposium on beta-adrenergic receptor blockade, Am. J. Cardiol. 18:303, 1966. Stern, S.: Synergistic action of propranolol with quinidine, AM. HEART J. X2:569, 1966. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1956. The Macmillan Comoanv. D. 713. Nordenfelt, 0.: Orthosta& GC’G changes and the adrenergic beta-receptor blocking agent, propranolol (Inderal), Acta med. scandinav. 178:393, 1965. Stern, S.: Conversion of chronic atrial fibrillation to sinus rhythm with combined propranolol and quinidine treatment, AM. HEAKT J. 74:170, 1967. Stern, S., and Borman, J. B.: Early conversion of atria1 fibrillation after open-heart surgery by combined propranolol and quinidine treatment. Israel J. M. SC. In press. Reynolds, E. W., Jr., and VanderArk, C. I~.: Treatment of quinidine resistant arrhythmias with the combined use of quinidine and propranolol, Circulation 36:221, 1967 (abstr.). Vaughan Williams, E. M.: Mode of action of beta receptor antagonists on cardiac muscle, Am. J. Cardiol. 18:399, 1966.
S
ince the introduction of the p adrenergic receptor blocking agent, propranolol, into clinical usei its efficiency as an antiarrhythmic drug has been clearly denlonstrated.2-5 More recently, it has been used in many other common diseases, such as hypertension,6 and coronary artery disease.7-s In spite of the impressive amount of data published on propranolol, the effect of this drug on the electrocardiogram (ECG) of normal individuals has not yet been established. In the following study we investigated changes in the ECG after administration of propranolol in patients with no cardiovascular abnormalities and a normal a priori ECG. The results are described below. Material
and
method
In this study we included 21 patients hospitalized in our medical department because of diseases other than cardiovascular or pulmonary. All patients were in good general condition, were without electrolyte or metabolic disturbances and had normal ECG’s. Fifteen patients were between 18 and 40 years of age, four were above 40 years, and two were between 16 and 18 years. The tests were performed during the morning hours in the following way: a control 12 lead ECG was taken with a From the Cardiovascular University-Hadassah Recived for publication
192
Sanborn 100 direct writing electrocardiograph. Immediately thereafter, propranolol was injected intravenously, in a dose of 10 mg., diluted in 100 ml. of 5 per cent glucose, and was given over a period of 10 to 12 minutes. At the end of the infusion, another 12 lead ECG was performed. No side effects were observed during or after the administration of the drug in any of the patients. The ECG tracings were analyzed for the following data: heart rate, shape, duration, and height of the P wave; P-R interval ; amplitude of the Q, R, and S waves in the different leads; the width of the QRS complex; the electrical axis; the S-T segment; the height and duration of the T wave; the Q-T interval, and this value corrected for the heart rate (Q-T/-\/RR, Bazett formula). Results
When the data from the ECG were analyzed, changes were observed in the following: heart rate, P-R interval, Q-T interval, and the height of the T wave. These changes are summarized in Table I, and illustrative tracings are given in Figs. 1 and 2. It can be seen that all patients exhibited decrease in the heart rate, from an average of 76.2 per minute to an average
Unit and Department of Internal Medical School, Jerusalem, Israel. May 14, 1968.
American Heart Iournal
Medicine
R. Hadassah
F&wary,
1969
University
Hospital
and
Hebrew
Vol. 77, No. 2, pp. 192-19.5
EJect of ~ropranolo/
Table I. Summary propranolol
of changes in heart rate, P-R interval,
Heart rate (min.) Patient NO.
88 53 88 75 55 58 8.5 102 60 77 60 88 48 72 74 80 92 105 75 76 90
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Mean Range
Post ’ propranolo1
76.2 48-105
of 62.2 per came longer
-
I i Control
,
60 48 75 55 52 50 76 6.5 5.5 65 53 70 42 60 56 ;i 72 65 6.5 75 62.2 42-78
minute. in 12
Post propra! nolo1
.12 .14 .14 .12 .I2 .13 .12 .14 .16 .15 -12 .14 .16 .14 .ll .12 .14 .16 .14 .16 .13 0.136 0.11-0.16
The P-R
0.152 0.12-0.18
-~
Control
.16 .18 .18 .12 .12 .16 .14 .18 .16 .1.5 .12 .16 .16 .16 .14 .12 .17 .18 .14 .16 .14
interval
-
(sec.)
-__
.32 .38 .34 .40 .41 .40 .34 .36 .36 .36 .39 .36 .40 .34 .33 .34 .30 .29 .36 .38 .36 0.358 0.29-0.41
be-
and did not change in 9; the average increase was from 0.136 to 0.152 sec. The Q-T interval increased in 11 patients, decreased in four, and did not change in six. When this value was corrected to the heart rate (Q-T/ 1/RR, Bazett formula), a decrease in 20 patients was observed. An increase in the height of the T wave was observed in 12 patients. patients,
Discussion
Clinically, the antiarrhythmic properties of propranolol are very similar to those of quinidine. s Moreover, a synergistic action between the drugs was also demonstrated.‘” In view of these observations we expected that its basic effect cm the KG would be similar to that of yuinidine. Quinidine, as is well known, increases heart rate, increases P-R interval, prolongs
’ Post ’ p~o$:,‘;/ .34 .34 .35 .40 .40 .38 .34 .36 .38 .36 .40 .36 .41 .36 .3.5 .36 .32 .32 .35 .40 .36 0.364 0.32-0.41
193
Q-T, Q-T,, and 7‘ wuve .following
Q-T
P-R (sec.)
---____ Control
on ECG’s of normal subjects
Q-T/dR-R __~
~
Control
Post propranolo1
.39 .36 .41 .44 .39 .39 .41 .47 .36 .41 .39 .44 .36 .37 .37 .40 .38 .39 .40 .43 .44
.34 .31 .39 .38 .36 .34 .38 .38 .36 .38 .38 .39 34 .36 .34 .39 .37 .35 .37 .42 .40
0.400 0.36-0.47
T wave
Post propranolol + + + + + + + + + + + +
increased increased increased no change increased increased no change increased no change no change no change increased no change increased no change no change increased increased increased no change increased
height height height height height height
height height
height height height height
0.368 0.31-0.42
the duration of the QRS complex, prolongs the Q-T interval, induces deviation in the S-T segment, and increases the duration, inversion, and notching of the T wave.” Concerning the heart rate, it has been already established that the action of propranolol differs basically from that of quinidine by inducing bradycardia.2-5 The results of this study demonstrate that other fundamental effects of the two drugs on the ECG are also different. In contrast to the prolongation of electrical systole of the ventricles induced by quinidine, propranolol in 20 out of the 21 patients studied shortened the duration of the Q-T, interval. The other striking effect was an increased height of the T wave oc.curring in 12 of the patients examined. A similar effect was observed OII the T wave by earlier investigators.lz In spite of the decrease in the heart rate, the I’-Ii
194
Am. Heart .I. February, 1969
Stern md Eisenberg
B
A
Fig. 1. interval.
A, Control
ECG.
B, ECG
after
propranolol.
Note
bradycardia,
heightened
T wave,
and shortened
Q-T,
Fig. 2. A, Control interval.
ECG.
B, ECG
after
propranolol.
Note
bradycardia,
heightened
T wave,
and
Q-T,
shortened
Esfeet 0.f $ropranolol
interval did not change in nine instances, which was again an effect not seen after the administration of quinidine; this latter drug invariably prolongs the atria1 conduction time. In view of the above observations, the synergism between propranolol and quinidine in clinical use, and the success with the administration of the two drugs in conlbination’3-15 may lie in the fact that, although they share the important property of reducing the height and slowing the rise time of the membrane action potent&l,‘6 they differ in some other actions. Therefore, each drug may be used in smaller doses, lessening thereby the possible toxic effects but still enhancing the desired antiarrhythmic action. Summary
REFERENCES Black, Smith,
3.
4.
5.
6.
7.
8.
The effect of propranolol (Inderal) on the ECG of normal individuals was studied in 21 subjects. Over a period of 10 minutes, 10 mg. of the drug were administered intravenously. An ECG was performed before and immediately after the infusion. All patients responded with bradycardia. The P-R interval increased in 12 patients and did not change in 9. An increase in the height of the T wave was observed in 12 subjects. The Q-T interval did not change in 6, decreased in 4, and increased in 11. The Q-T, interval (Bazett formula) becatne shorter in all but one subject. This effect is opposite to that of quinidine on the Q-T, interval. The above findings are discussed in the light of the described synergistic action of propranolol with quinidine and the successful combination of them in treating various arrhythmias. I.
2.
J. W., Crowther, A. F., I,. H., and Dornhorst,
9.
10. 11.
12.
13.
14.
15.
16. Shanks, A. C.:
R. G., A new
on ECG’s of normal subjects
195
adrenergic beta-receptor antagonist, Lancet 1:1080, 1964. Rowlands, D. J., Howitt, G., and Markman, P.: Propranolol (Inderal) in disturbances of cardiac rhythm, Brit. M. J. 1:891,1965. Harrison, D. C., Griffin, J. R., and Fiene, T. J.: Effect of beta-adrenergic blockade with propranolol in patients with atria1 arrhythmias, New England J. Med. 273:4X0, 1965. Schanroth, L.: Immediate effects of intravenous propranolol on various cardiac arrhythmias, Am. I. Cardiol. 18:438. 1966. Stern, S., and Braun, ‘K.: Clinical experience with Inderal (propranolol) in supraventricular arrhythmias and sinus tachycardia, Harefuah 71:371, 1966. Prichard, B. N. C., and Gillam, P. M. S.: The use of propranolol in the treatment of hypertension, Brit. M. 1. 2:725. 1964. Wolfson, S., Heinle, R. ‘A., Herman, M. V., Kemp, H. G., Sullivan, j. M., and Gorlin, Ii.: Propranolol and angina pectoris, Am. J. Cardiol. 18:345, 1966. Grant, R. H. E., Keelan, P., Kernohan, R. J., Leonard, J. C., Nancekievill, L., and Sinclair, K.: Multicenter trial of propranolol in angina pectoris, Am. J. Cardiol. 18:361, 1966. Braunwald, E.: An editorial introduction to the Symposium on beta-adrenergic receptor blockade, Am. J. Cardiol. 18:303, 1966. Stern, S.: Synergistic action of propranolol with quinidine, AM. HEART J. X2:569, 1966. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, New York, 1956. The Macmillan Comoanv. D. 713. Nordenfelt, 0.: Orthosta& GC’G changes and the adrenergic beta-receptor blocking agent, propranolol (Inderal), Acta med. scandinav. 178:393, 1965. Stern, S.: Conversion of chronic atrial fibrillation to sinus rhythm with combined propranolol and quinidine treatment, AM. HEAKT J. 74:170, 1967. Stern, S., and Borman, J. B.: Early conversion of atria1 fibrillation after open-heart surgery by combined propranolol and quinidine treatment. Israel J. M. SC. In press. Reynolds, E. W., Jr., and VanderArk, C. I~.: Treatment of quinidine resistant arrhythmias with the combined use of quinidine and propranolol, Circulation 36:221, 1967 (abstr.). Vaughan Williams, E. M.: Mode of action of beta receptor antagonists on cardiac muscle, Am. J. Cardiol. 18:399, 1966.