Reports on Therapy Effect of Sotalol on Clinical Arrhythmias RAVI PRAKASH, MD WILLIAM W. PARMLEY, MD, FACC HOWARD N. ALLEN, MD JACK M. MATLOFF, MD, FACC Los Angeles, California From the Departments of Cardiology and Thoracic and Cardiovascular Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif. This study was supported in part by U.S. Public Health Service Grant 5-SOl- RR-05468. Manuscript received April 19, 1971, accepted August 2, 1971. Address for reprints: William W. Parmley, MD, Department of Cardiology, Cedars of Lebanon Hospital, 4833 Fountain Ave., Los Angeles, Calif. 90029. VOLUME 29, MARCH 1972 Sotalol (MJ 1999) was administered to 20 patients for the treatment of 22 episodes of supraventricular and 6 episodes of ventricular arrhythmias. The dose range was 9 to 50 mg intravenously and 20 to 80 mg orally given every 6 hours. In 4 of 6 patients supraventricu- lar tachycardia was converted to normal sinus rhythm. In 4 with episodic supraventricular tachycardia, Sotalol prevented further re- currences in all. In 1 patient atrial flutter was converted to normal sinus rhythm. In 3 others with atrial flutter, and in 3 with atrial fibrillation, Sotalol slowed the ventricular response from an average rate of 125 to 72 beats/min. In 1 patient with episodic atrial fibrilla- tion and another with ‘episodic ventricular tachycardia, Sotalol pre- vented further recurrences. In 1 of 2 patients Sotalol decreased the frequency of premature atrial contractions; in 5 patients with pre- mature ventricular contractions, it abolished them in 2 and reduced their frequency in the other 3. Side effects included transient hypo- tension in 3 patients and bradycardia sufficient to require reducing the dose of Sotalol in 4. It is concluded that Sotalol is a moderately effective antiarrhythmic drug which may be preferable to other beta adrenergic blocking agents because of its lack of substantial myo- cardial depressant effects. Beta adrenergic blocking agents, such as propranolol, are being used with increasing frequency for the treatment of clinical car- diac arrhythmias1s2 One of the potentially serious side effects of such drugs is their direct production of myocardial depression which can precipitate or worsen congestive heart failure?%* So- talol@ (MJ 1999) is a newer beta adrenergic blocking agent which produces less myocardial depression than propranoloF-7; it thus might be a safer drug to use in patients with heart failure if it is as effective in the treatment of arrhythmias. Although Sotalol antagonizes experimental arrhythmias pro- duced by epinephrine* as does propranolol,l it is not a local anes- thetic agent and may be less effective than propranolol in prevent- ing ouabain-induced arrhythmiasP Furthermore, directionally op- posite effects on intracellular action potentials suggest that So- talol and propranolol may have different antiarrhythmic effects, aside from their beta blocking pr0perties.l” The present study was undertaken in a group of patients with a variety of atria1 and ventricular arrhythmias to evaluate the clinical effectiveness of Sotalol as an antiarrhythmic agent. 397
Transcript
Reports on Therapy
Effect of Sotalol on Clinical Arrhythmias
RAVI PRAKASH, MD WILLIAM W. PARMLEY, MD, FACC HOWARD N. ALLEN, MD JACK M. MATLOFF, MD, FACC
Los Angeles, California
From the Departments of Cardiology and Thoracic and Cardiovascular Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif. This study was supported in part by U.S. Public Health Service Grant 5-SOl- RR-05468. Manuscript received April 19, 1971, accepted August 2, 1971.
Address for reprints: William W. Parmley, MD, Department of Cardiology, Cedars of Lebanon Hospital, 4833 Fountain Ave., Los Angeles, Calif. 90029.
VOLUME 29, MARCH 1972
Sotalol (MJ 1999) was administered to 20 patients for the treatment of 22 episodes of supraventricular and 6 episodes of ventricular arrhythmias. The dose range was 9 to 50 mg intravenously and 20 to 80 mg orally given every 6 hours. In 4 of 6 patients supraventricu- lar tachycardia was converted to normal sinus rhythm. In 4 with episodic supraventricular tachycardia, Sotalol prevented further re- currences in all. In 1 patient atrial flutter was converted to normal sinus rhythm. In 3 others with atrial flutter, and in 3 with atrial fibrillation, Sotalol slowed the ventricular response from an average rate of 125 to 72 beats/min. In 1 patient with episodic atrial fibrilla- tion and another with ‘episodic ventricular tachycardia, Sotalol pre- vented further recurrences. In 1 of 2 patients Sotalol decreased the frequency of premature atrial contractions; in 5 patients with pre- mature ventricular contractions, it abolished them in 2 and reduced their frequency in the other 3. Side effects included transient hypo- tension in 3 patients and bradycardia sufficient to require reducing the dose of Sotalol in 4. It is concluded that Sotalol is a moderately effective antiarrhythmic drug which may be preferable to other beta adrenergic blocking agents because of its lack of substantial myo- cardial depressant effects.
Beta adrenergic blocking agents, such as propranolol, are being used with increasing frequency for the treatment of clinical car- diac arrhythmias1s2 One of the potentially serious side effects of such drugs is their direct production of myocardial depression which can precipitate or worsen congestive heart failure?%* So- talol@ (MJ 1999) is a newer beta adrenergic blocking agent which produces less myocardial depression than propranoloF-7; it thus might be a safer drug to use in patients with heart failure if it is as effective in the treatment of arrhythmias.
Although Sotalol antagonizes experimental arrhythmias pro- duced by epinephrine* as does propranolol,l it is not a local anes- thetic agent and may be less effective than propranolol in prevent- ing ouabain-induced arrhythmiasP Furthermore, directionally op- posite effects on intracellular action potentials suggest that So- talol and propranolol may have different antiarrhythmic effects, aside from their beta blocking pr0perties.l”
The present study was undertaken in a group of patients with a variety of atria1 and ventricular arrhythmias to evaluate the clinical effectiveness of Sotalol as an antiarrhythmic agent.
397
PRAKASH ET AL.
TABLE I
Intravenously Administered Sotalol
Case Ane tyr)
tl0.
_ . . & Sex Origin Type
1 56M ASHD SVT
2 70M RHD PVC
3 28M PHD SVT
4 75M ASHD SVT
5 57F ASHD A FI
6 58F ASHD SVT
7 66F Acute MI SVT
8 72M Acute MI SVT
9 82F ASHD A FI
10 61M Acute MI PVC, PAC
11 58M PHD A FI
12 82M ASHD A FI
13 46M ASHD PAC
14 87F ASHD A Fib
Dose of
Sotalol
(mg) Effect
20 No effect
20 PVC abolished
20 No effect
12 NSR
9 NSR
20 NSR
10 NSR
20 NSR
35 Slowing of HR
40 Decreased
50 Slowing of HR 16 Slowing of HR
10 No effect
20 Slowing of HR
A Fib = atrial fibrillation; A FI = atrial flutter; ASHD = arterio-
All patients were hospitalized at the time of the initial administration of Sotalol, and were evaluated by history, physical examination, electrocardiogram and chest roentgenogram. Tables I and II contain a descrip- tion of each patient, the type of arrhythmia, the dose of Sotalol given and the effect obtained. Of a total of 20 patients, 14 were given Sotalol intravenously for an acute arrhythmia (Table I). Four of these patients and 6 additional patients received Sotalol orally as prophy- lactic therapy for recurrent arrhythmias (Table II). Four patients thus appear in both tables. Fifteen pa- tients had coronary artery disease (3 with acute myo- cardial infarction), 2 rheumatic heart disease, 1 pri- mary myocardial disease and 1 hypertension with the “sick sinus” syndrome. Sotalol was given intravenously in a bolus of 2 to 10 mg every 5 minutes as required, with an average total dose of 21 mg (range 9 to 40 mgi. During intravenous administration, the electrocardio- gram was continuously monitored and rhythm strips were obtained at frequent intervals. The average oral dose of Sotalol was 160 mg (range 80 to 320 mg/day) administered in 4 divided doses. If patients were re- ceiving other antiarrhythmic drugs, these were discon- tinued before administration of Sotalol. Patients receiv- ing maintenance doses of digitalis continued to receive the same doses. Sotalol was not administered to preg- nant women, patients with bronchial asthma, or those with a high degree of atrioventricular (A-V) block.
Results
Sotalol, Acute Therapy
A summary of the results is listed in Table Effects were noted within 1 to 5 minutes of last dose of Sotalol.
III. the
Age Dose of
(yr) Arrhythmia Sotalol
Case & ~~ @g/6 no. Sex Origin Type hours) Effect
1 56M ASHD SVT 40 No recurrence,
6 mo
6 58F ASHD SVT 80 No recurrence,
6mo
10 61M ASHD; acute PVC 20-60 Frequency of
Ml PVC’s reduced
14 87F ASHD A Fib 40 Reduced ven-
tricular rate
15 55F RHD SVT, PAC 40 No recurrence,
7 mo 16 64F ASHD A Fib 40 Reduced ven-
tricular rate
17 62M ASHD VT 40 No recurrence,
6 mo 18 71F ASHD PVC 40 Frequency of
PVC’s reduced 19 75M ASHD SVT, PVC 40 No effect 20 72F Hypertension; A Fib 20 No recurrence,
“sick sinus” 6 mo syndrome
VT = ventriculartachycardia; other abbreviations as in Table I.
398 The American Journal of CARDIOLOGY
Supraventricular tachycardia: In 4 of 6 pa- tients, conversion to sinus rhythm occurred, and there was no effect on the rhythm of 2 patients. The dose of Sotalol ranged from 10 to 20 mg.
Atria1 flutter: Sotalol produced conversion to normal sinus rhythm in 1 of 4 patients ; a decrease in ventricular rate was achieved in the other 3 by increasing the A-V block. The dose of Sotalol ranged from 9 to 50 mg. Figure 1 illustrates the results of a dose of 6 mg of Sotalol given intra- venously to a 57 year old woman with atria1 flutter associated with an acute myocardial infarction. After slowing of the ventricular response there was conversion to normal sinus rhythm.
Atria1 fibrillation: In 3 patients, Sotalol pro- duced an increase in A-V block which slowed the ventricular rate from an average value of 125 to 72 beats’min and resulted in clinical improvement in each patient.
Premature ventricular contractions: These were abolished in 2 patients and decreased from an average of 8,‘min to 2/‘min in the 3 remaining patients. The effects lasted for periods ranging from 10 minutes to 5 hours.
Premature atria1 contractions: In 1 of the 2 patients Sotalol decreased the frequency of the premature beats; in the other it had no effect.
Sotalol, Chronic Therapy
The effects of orally administered Sotalol on the frequency of recurrent episodic arrhythmias are
TABLE II
Orally Administered Sotalol
SOTALOL IN CLINICAL ARRHYTHMIAS
listed in Table II. Three of 4 patients with par- oxysmal supraventricular tachycardia have not had a recurrence during an average follow-up period of 6 months. One patient each with recur- rent atria1 fibrillation and ventricular tachycardia, had their recurrent arrhythmias abolished over an average follow-up period of 6 months. Two pa- tients with chronic atria1 fibrillation who were re- ceiving digitalis were given supplemental doses of Sotalol to control their ventricular rate since they were prone to digitalis toxicity. The oral dose of Sotalol ranged from 20 to 80 mg 4 times a day.
Total Conversion Increased No Cases to NSR A-V Block Abolished Decreased Effect
SVT 6 A FI 4
A Fib 3
PVC 5
PAC 2
4
1
. . .
. . .
. . .
. . . 3
3
. . .
. . .
. . .
. . . . . 2
. . .
. . . 2
. . . . . . . . . . . 3 . . . 1 1
Abbreviations as in Table I.
Side Effects
Side effects were relatively minor. Although all patients showed a slowing of heart rate, there was no detectable evidence of a worsening of conges- tive heart failure. Bradycardia occurred in 4 pa- tients and was controlled by reducing the dose of Sotalol. Three patients receiving Sotalol intrave- nously experienced a transient decrease of 16 mm Hg in systemic blood pressure, which was clini- cally insignificant. One patient receiving Sotalol orally complained of breast discomfort which cleared spontaneously although administration of Sotalol was continued.
BEFORE SOTALOL
SOTALOL
0845
Discussion
The results of our study indicate that Sotalol is
Figure 1. Effects of Sotalol on atrial flutter in a 57 year old woman after an acute myocardial infarction. Administration of 6 mg of Sotalol intravenously successfully converted the flutter to normal sinus rhythm.
a moderately effective antiarrhythmic agent for certain arrhythmias. When given orally, it was ef- fective in preventing further episodes of recurrent tachyarrhythmias. When given intravenously, it was moderately effective in controlling supraven- tricular arrhythmias, by either conversion to nor- mal sinus rhythm or reduction of the ventricular response by increasing the degree of A-V block. Although the number of patients treated were few, our results suggest that the antiarrhythmic spec- trum of Sotalol is similar to that of propranolol.lB2
artery ligation or infusion of ouabain have been conflicting and may relate to the lack of effect of Sotalol on automaticity.5~RJ*~‘4
Mechanism of antiarrhyt hmic effects : One mechanism responsible for the antiarrhythmic ef- fects of Sotalol is its beta adrenergic blocking ef- fect. This is best exemplified by the increase in A-V block which results in a decrease in the ven- tricular response to atria1 tachyarrhythmias. It is not known whether Sotalol has other antiarrhyth- mic effects unrelated to beta blockade. Although Sotalol is devoid of the nonspecific antiarrhythmic effects seen with other beta blocking agents,s,9J1 studies of its effects on the action potential have shown that it prolongs the action potential dura- tion and the effective refractory period.lO This latter effect might be responsible for antiarrhyth- mic actions similar to those of quinidine.5
Experimental studies of the antiarrhythmic ef- fects of Sotalol have shown it to be uniformly effec- tive in ventricular arrhythmias induced by hydro- carbon and epinephrine in the dog.12,13 However, results with arrhythmias produced by coronary
Myocardial effects : Several studies have dem- onstrated the lack of substantial myocardial de- pressant effects of Sotalol, in both the intact dog”J5 and man.16--l* Doses as high as 60 mg/kg of Sotalol have been given to volunteers without incident.” Similar results have been obtained in vitro with the rabbit left atria1 preparation, in which neither the d- nor Z-optical isomers had any significant ef- fect on the force of contraction despite their markedly different beta blocking pr0perties.l” Re- cent studies in ihe isolated cat papillary muscle not only demonstrated a lack of substantial myo- cardial depressant effects but also showed that Sotalol produced an increase in force at dose levels of 10m4 to ~O-“M.~ This effect was unrelated to in- trinsic catecholamine sympathomimetic stores since the same results were obtained in cats de- pleted of catecholamines by reserpine. In our study, side effects attributable to myocardial de- pression were minimal, consisting of transient hypotension or bradycardia. However, it must be remembered that even if the direct myocardial de- pressant effects of Sotalol are minimal, the beta blocking effects may theoretically worsen conges- tive heart failure in a patient who is greatly de- pendent on sympathetic stimulation to maintain compensation.20
VOLUME 29. MARCH 1972 399
TABLE III
Summary of Results: Acute Therapy with Sotalol
PRAKASH ET AL.
In summary, Sotalol (MJ 1999) appears to be a moderately effective antiarrhythmic agent for ar- rhythmias of the same general type as those for which propranolol is effective. It has the additional advantage of producing less direct myocardial de- pression and thus may be preferable in situations
associated with borderline or overt congestive heart failure.
Acknowledgment
Supplies of Sotalol were generously supplied by Dr. Fernando Marroquin of Mead-Johnson,
2. Gianelly R, Griffin JR, Harrison DC: Propranolol in the treatment and prevention of cardiac arrhythmias. Ann Intern Med 66:667-676, 1967
3. Epstein SE, Braunwald E: The effect of beta adrenergic blockade on patterns of urinary sodium excretion. Stud- ies in normal subjects and in patients with heart disease. Ann Intern Med 65:20-27, 1966
4. Bay G, Lund-Larsen P, Lorentsen E, et al: Haemody- namic effects of propranolol (Inderal) in acute myo- cardial infarction. Brit Med J 1:141-143, 1967
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7. Parmiey WW, Chuck L: Lack of intrinsic myocardial de- pressant effects of the beta-blocker sotalol (MJ 1999) as compared to propranolol (abstr). Circulation 42: suppl 3:188, 1970
8. Somani P, Fleming JG, Chan GK, et al: Antagonism of epinephrine-induced cardiac arrhythmias by 4-@iso- propylamino-1-hydroxyethyl)-methane sulfonanilide (MJ 1999). J Pharmacol Exp Ther 151:32-37, 1966
9. Lucchesi BR, Whitsitt LS: The pharmacology of beta- adrenergic blocking agents. Progr Cardiovasc Dis 11: 410-430, 1969
10. Strauss HC, Bigger JT Jr, Hoffman BF: Electrophysio- logical and beta-receptor blocking effests of MJ-1999 on dog and rabbit cardiac tissue. Circ Res 26:661-678, 1970
11. Somani P, Watson DL: Antiarrhythmic activity of the dextro-and-levorotatory isomers of 4-(2.isopropylamino- l-hydroxyethyl) methanesulfonanilide (MJ 1999). J
amino-l-hydroxyethyl) methanesulfonanilide (MJ 1999) on ventricular fibrillation induced by coronary occlusion. Acta Physiol Lat Amer 16:206-207, 1966
13. Kaumann AJ, Aramendia P: Prevention of ventricular fibrillation by coronary ligation. J Pharmacol Exp Ther 164:326-332, 1968
14. Sharma PL: Mechanism of action of a new adrenergic beta-receptor antagonist, MJ 1999, in the prevention of halothane-adrenaline-induced and ouabain-induced ven- tricular tachycardia in the dog. Indian J Med Res 55: 1357-1365, 1967
15. Puri PS, Bing RJ: Effects on myocardial contractility, hemodynamics and cardiac metabolism of a new beta adrenergic blocking drug, sotalol. Dis Chest 55:235-239, 1969
16. Thumala A, Hammermeister KE, Campbell WB, et al: Hemodynamic studies with Sotalol in man, performed at rest, on exercise and during right ventricular pacing (abstr). Amer J Cardiol 26:662, 1970
17. Rao SB, Kelly JJ, Cohn KE, et al: Hemodynamic re- sponse to exercise and isoproterenol in normal individ- uals and in congestive failure during beta-adrenergic blockade with MJ 1999 (abstr). Circulation 37: suppl 6: 161, 1968
18. Brooks H, Banas J Jr, Meister S, et al: Sotalol-induced beta blockade in cardiac patients. Circulation 17:99-109, 1970
19. Levy JV, Richards Y: lnotropic and chronotropic effects of a series of beta-adrenergic blocking drugs: some structure-activity relationships. Proc Sot Exp Biol Med 122:373-379, 1966
20. Gaffney TE, Braunwald E: Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure. Amer J Med 34: 320-324, 1963
