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Treatment of cardiac arrhythmias with beta-adrenergic blocking agents
Treatment with Clinical
of cardiac
beta-adrenergic and experimental
arrhythmias blocking
agents
studies
Steven Wolfson, M.D. Sanford I. Robbins, B.A. Norman Krasnow, M.D.* Brooklyn, N. Y.
R
apid progress has been made in the past decade in the treatment of cardiac arrhythmias. The introduction of electrical techniques for the conversion or control of many serious arrhythmias has gained rapid acceptance and widespread use. Nevertheless, arrhythmias which have not thus far proved to be amenable to electrical methods of control continue to pose difficult problems for the clinician. During this period, few new pharmacologic approaches have proved to be useful. Knowledge of the influence of catecholamines on the mechanical and electrical properties of the heart has been extended. However, the relationship of catecholamines to clinical arrhythmias, and in particular to arrhythmias provoked by digitalis therapy, remains unclear. The introduction of effective means for blockade of beta-adrenergic receptors provides an additional potent tool for study. Pronethalol was introduced by Black and Stephenson’ in 1962, as an effective betaadrenergic blocking agent, and Vaughan From
Williams and Sekiya2 noted that this drug had an antiarrhythmic effect in guinea pigs. A subsequent analogue with similar properties, propranolol, was introduced in 1964.3 The purpose of the present study was to evaluate the effects of these two agents in the treatment of clinical and experimentally induced arrhythmias. These agents were shown to be useful drugs in specific circumstances. Like most therapeutic agents, however, they have toxic effects. This study describes several hazards of, and contraindications to, the administration of pronethalol or propranolol. Animal studies suggest a different mode of action than adrenergic blockade. Materials
and
methods
Clinical studies. Twenty-two patients with clinical arrhythmias were included in this series. There were 13 men and 9 women, 30 to 88 years of age. In addition, 5 subjects with normal sinus rhythm were studied. Arrhythmias were studied only if the mechanism was well defined and stable, and its relationship to the adminis-
the Department of Medicine, State University of New York Downstate Medical Center, and the Medical Service, Kings County Hosoital Center. Brooklyn. N. Y. This work was &ported by Gran; I-361 from the Health Research Council of the City of New York, and Grant HE 07982 from the National Heart Institute. Bethesda, Md. Received for publication Nov. 2. 1965. *Career Scientist of the Health Research Council of the City of New York. Address: Department of Medicine, State University of New York Downstate Medical Center, 4.50 Clarkson Ave., Brooklyn, N. Y., 11203.
177
178
Am. Heavt 3. August, 1966
WoJfson, Robbins, und Krasnow
E.I..
M
59
Chrnnic
bronchiti’s
G.K.
k‘
8(J
Ai\.
F
80
1.X..
M
72
A.S.
F
88
Hypertensive heart disease, CHF, digitalis toxicit> ASHI), CHF, digitalis toxicit)Emphyselna, CHF, pneumothorax ASHD, CHIT
F.A.
F
61
RHD
J.S.
M
80
ASHD. talis
I.N.
M
85
ASH11
F.M.
M
30
J.G.
F
60
J.W.
F
57
E.F.
F
77
Atria1 septal defect, pulmonic stenosis, CHF RHD, mild mitral stenosis RHD, mitral insufficiency, CHF, digitalis toxicity ASHD, CHF
J.D.
M
4.5
W.D
M
60
RHD, mitral ficienrj ASHD, CHF
D.G.
M
60
ASHD.
A.V.
M
46
A.C.
M
57
CR.
M
41
J.S.
M
46
RHD, mitral valve prosthesis, CHF RHD, severe mitral stenosis, pulmonary hypertension, CHF Hyperthyroidism (controlled), myocarditis (?) RHD, MS, AI, endocarditis (?), digitalis toxicity
J.M.
M
45
CHF, toxicit?
digi-
Atria1 tibrillation, VPC (bigeminy), \‘R 100 Atrial flutter, 2:1 conduclion, 1’1~ 130 A-V dissociation with ventricular captures, atria1 rate 93, VR SO Atria1 Butter, 2-.3:1 conduction, VIZ 110 Sinus tachycardia, wandering atria1 pacemaker, 1” A-V block IVandering atria1 pacem,iker c VIK VR SO-120 atria1 flL:tter, ;:l concluc[inn, VK 70
unless
SO
NW,
\,‘K 60
50
VPC
abolished,
25
3-4:l
conduction,
50
Captures atrial
50 SO
100
VR 80 VR 80
disappeared, rate 80, \IR
Atrial flutter, conduction, KSR
42
4-5:1 \:R 70
No change
50
Atria1 fibrillation, 100 Atria1 librillation, abolished, VR
VPC
50
WC,
SO SO
VR VPC 80
VPC increased in number, VR 120 Atria1 fibrillation, VR 80
5t Atria1 flutter, 4:l conduction, VR 80 100 Carotid sipus massage increased block, VR 110 901 Ko effect 50
Atrial tachycardia with 1:l conduction (2:l with carotid sinus pressure), VR 125 NSR, inromplete A-V dissociation (nodal rate 271, WC (multiform, bidirectional), VR 60
otherwise
75
Carotid sinus massage increased block, VR 75
fibrillation,
140
VR
50
Atria1
Atria1 librillation, VPC, 1-K 90 Atria1 tachycardia, (137/ min.), nodal tachycardia, A-V dissociation, VR 107 NSR, VPC, VR 70
HCVD; chronic renal disease with uremia, digitalis toxicity
rhythm,
VR
Atria1 flutter, 2-3:l rondllrtion VR 100 Atria1 Blotter, 2:l conduction, VR 130
CHF
Nodal
fibrillation,
VR
160
.iO
Atria1
\‘R 100 Atrial fibrillation, \:1i 110 ;\lrinl librillation,
insuf-
*Dose refers to dose of pronethalol in milligrams tPropranolo1 intravenously (mg.). ~Propranolol orally per day (mg.) RZZD: Rheumatic disease. ASHD: Arteriosclerotic failure. AZ: Amtic insufficiency. MS: Mitral VR: Ventricular rate per minute.
:\trial premature c-ontractions, \-Ii 150-180 SSR, VPC ihigeminy 1, \.R 80
Complete cardiac
5t VPC
heart arrest
abolished,
block,
\TR 60
5t
Atria1 forus slowed to 104; 1:l conduction, \‘R 104
5t
Complete A-V dissociation (nodal rate 33, with increased aberrant conduction), VPC unchanged, VR 60
stated.
heart disease. HCVD: Hypertensive cardiovascular stenosis. VPC: Ventticular premature contractions.
disease. NSR:
CNF: Congestive heart Normal sinus rhythm.
Volume 72 Number 2
179
Cardiac arrhythmias treated with beta-adrenergic blocking agents
Table I. Clinical arrhythmias treated with pronethalol-Cont’d I
)
Patient
Sex I
I
Age (yr.1
R.R.
F
41
N.F.
F
48
Clinical
diagnosis
( I
~
I RHD (mild mitral insufficiency; 2 yr. after open mitral valvuloplasty), digitalis toxicity ASHD, acute myocardial infarction; shock, digitalis toxicity
Atria1 fibrillation, VR 155
NSR; VPC VR 120
tration of digitalis clear. No patient with bronchospasm on auscultation was accepted. Congestive heart failure was not a contraindication for the purposes of this acute study. The subjects were given either pronethalol,* 50 mg., or propranolol,* 5 mg., intravenously, over a S-minute period. In 2 cases, an additional 50 mg. of pronethalol was given intravenously 20 minutes after the initial dose. Blood pressure was monitored by cuff frequently. Two patients (A.V., R.R.) were given the drug only orally. Three patients were subsequently treated with oral pronethalol (300 mg. three times daily) or propranolol (30 mg. three times daily). Animal studies. Twenty-four studies were performed on 1.5 mongrel dogs, approximately 15 kilograms in weight, anesthetized with intravenous pentobarbital (20 mg. per kilogram). A polyethylene catheter was introduced percutaneously into a peripheral vein. Electrocardiograms were monitored continuously. Ouabain (1 .O mg.) was given intravenously and additional doses (0.25 mg.) were repeated every 10 to 15 minutes until either ventricular tachycardia or multiple ventricular premature contractions were produced. The total dose of ouabain required for each animal averaged 65 mg. per kilogram. When the toxic rhythm had been stabilized for at least 10 minutes, pronethalol (mean dose *We
Rhythm
are indebted to Dr. Alex Sahagian-Edwards Laboratories, New York, for generous supplies drugs. The name Nethalide is used in the United pronethalol.
of Ayerst of these States for
Dose* (wir.)
Result I
801 Atria1 fibrillation, VPC, VR 65
VPC,
(bigeminy),
50
no
Nodal rhythm, A-V sociation, VR 75
dis-
5 mg. per kilogram) was given intravenously over several minutes. Electrocardiographic effects occurred within 20 minutes. The animals were allowed to recover for several days from the procedure and then were given reserpine intraperitoneally, 0.1 mg. per kilogram daily for at least 2 or 3 days. This regimen has been shown to lower myocardial (atrial) catecholamines to 2 per cent of control levels.*s5 Ouabain was again given, according to the same schedule, until toxicity developed. Pronethalol (mean dose 3.3 mg. per kilogram) was then administered. Ouabain alone was given to 7 animals until ventricular tachycardia developed, and they were monitored without further treatment until death. Clinical
results
(Table I)
All patients who responded to pronetha101 or propranolol did so within 15 minutes after completion of the infusion. One patient complained of nausea several minutes after treatment; this was relieved by an intramuscular injection of 200 mg. of trimethobenzamide (Tigan, Roche). No other side effects were noted. The duration of effective blockade averaged 4 hours after intravenous administration, and somewhat longer after oral administration. The electrocardiographic changes that followed the administration of pronethalol can be divided into the effects produced upon the sinus node, the atria, the atrioventricular node, and the ventricles. Since pronethalol was used in the majority of cases (see Table I), the results will be
180
Wo!fson, Robbins, md Krnsnow
Table II. Summary
of the e$ects qf pronethalol
Rhythm
in clinical arrhythmias
Number patients
/
of
Result
of patients)
(number
Sinus NSR With
6 A-V
dissociation
3
Slowed (5) Developed A-V Slowed (3)
2 5 5 1
Abolished (2) No atria1 effect (5) So atrial effect (5) Atria1 rate slowed (1)
5 6 3 1
Ventricular rate slowed Ventricular rate slowed Increased block (3) Cardiac arrest (1)
6 4
Abolished Abolished
dissociation
( 1)
Atria1 Extrasystoles Flutter Fibrillation Tachycardia A-V node Atriral flutter Atria1 fibrillation Dissociation Tachycardia Ventricular Extrasystoles Due to digitalis Kot due to digitalis
described in terms of this agent, although the effects of propranolol were similar. A. Sinus rhythm. Of 8 patients with a sinus mechanism (Table II), the resting sinus rates slowed in 6 by 6 beats per minute. Five patients were exercised and had lesser increments in heart rate (10 beats per minute) after pronethalol. There was no change in the configuration of the P wave. B. Atria1 arrhythmias. Two subjects had multiple atria1 premature contractions, with ventricular rates of 120 to 150 per minute. The premature beats were abolished by pronethalol in each case, resulting in a stable nodal rhythm in one case, and normal sinus rhythm in the other. The resultant ventricular rates averaged 80 per minute. In neither case was the arrhythmia thought to be related to digitalis toxicity. Pronethalol had no effect upon the atria1 mechanism in 10 patients with atria1 flutter or atria1 fibrillation (Fig. 1). One patient (J.S.) with atria1 tachycardia and 2:l block, due to digitalis, had slowing of the ectopic atria1 focus and ventricular rate, but the 2:l relationship persisted. C. Atrioventricular node. Pronethalol con-*-~-.-L.. ---A .._^ -1 ^ -:--:c-?.-e ,.l,.... :,, ,c
(5) (6)
in 5 in 1
the ventricular response in atria1 fibrillation. Initial ventricular rates of 90 to 170 per minute were slowed to 65 to 90 per minute. In 4 patients of this group, digitalis had failed to slow the ventricular rate, despite clinical evidence of toxicity. Pronethalol was also given to 5 patients with atria1 flutter. Three patients responded with increased A-V block and decreased ventricular rates. In 2 patients the ventricular rate slowed transiently during carotid sinus massage only after pronethalol. The above-mentioned effects occurred despite the presence of congestive heart failure, severe anoxia (one case), and a spontaneous pneumothorax (one case). Three patients with complete A-V dissociation were treated. In 2 patients, pronethalol slowed both the atria1 and ventricular foci, and ventricular captures disappeared (Fig. 2). The third subject, with rheumatic mitral stenosis, very severe pulmonary hypertension, and heart failure, had a nodal tachycardia, a slower atria1 tachycardia, and A-V dissociation (Fig. 3). In the attempt to abolish the ectopic tachycardia, which was severely compromising cardiac output, 50 mg. of pronethal-1
.(/r-c
A.ron
A.IO~
< m;n,,tm
The
natimt
Cardiac arrhythmias
..,
i-y
;:.
:
treated with beta-adrenergic
blocking agents
181
:c
:”
I
I
Fig. 1. A, Atria1 fibrillation with rapid ventricular response despite digoxin, 1.0 mg daily. B, Atria1 flutter with 2:l response. In each case, pronethalol slows the ventricular rate without effect on the atria1 mechanism.
CONTROL ,~l6A&LlSlOiKITY
SOMIN. AFTER PRONElHAiOlf50
AS.
ng I.V.)
Fig. 2. A-V dissociation secondary to digitalis intoxication. Pronethalol slowed the atria1 rate from 93 to 80 per minute, the ventricular rate from 50 to 42 per minute, and abolished ventricular captures (C).
developed complete heart block with an idioventricufar rhythm as the infusion was completed, and within 2 minutes cardiac arrest supervened. Rapid intravenous administration of isoproterenol and intracardiac epinephrine, as well as the usual resuscitative measures, were unable to reverse the arrest. D. Ventricular eflects. No changes in QRS configuration or duration were noted. Pronethalol was successful in 5 of 6 patients in abolishing ventricular extrasystoles which were considered to be due
to digitalis toxicity (Fig. 4), but one of these subjects developed A-V dissociation. Of 4 patients with frequent ventricular premature beats unrelated to digitalis, one responded to pronethalol. One of the refractory patients (E.F.) presented with atria1 fibrillation, a rapid ventricular response, and frequent ventricular ectopic beats. She had received 1.6 mg. of lanatoside C. Pronethalol slowed the ventricular rate, but the extrasystoles increased in frequency. She was then treated with additional lanatoside C, with further slowing
182
Wolfson, Robbins, and Krasnow
Fig. 3. A-V dissociation with sinus and nodal tachycardia in a patient with mitral stenosis and severe pulmonary hype :rtension. Cardiac arrest followed progressive slowing of the nodal, sinus, and ventricular pacemakers.
of the ventricular
rate and abolition of the
extra beats. Animal
studies
(Table
111)
Eight dogs had 11 episodes of ouabaininduced ventricular arrhythmia, treated with pronethalol. In 7 of these episodes, pronethalol caused reversion to a supraventricular tachycardia. When 6 of these animals had been pretreated with reserpine, they also developed ventricular tachycardia after ouabain. All 6 episodes of ventricular tachycardia were successfully converted to a supraventricular mechanism (although in 2 cases the result was only transient) (Fig. 5). In this small group of animals there was no increase in the toxic dose of ouabain after reserpine. None of the animals succumbed to ouabain toxicity when pronethalol was
given, even when the ventricular arrhythmia did not revert to a sinus mechanism during the 3-hour period of observation. By contrast, 7 animals were given ouabain until toxicity developed, but pronethalol was withheld. All died of arrhythmia. either ventricular standstill or fibrillation. Discussion
Sympathomimetic agents have found wide clinical application both for their potentiation of cardiac contractility and their stimulatory effect on pacemaker sites.6 Adrenergic stimulation of the heart produces7,s increased rhythmicity of the sinus node, a shortened refractory period in atria1 muscle, more rapid atrioventricular conduction, and enhanced activity of idioventricular pacemakers. These effects are thought to be subserved by betaadrenergic receptors within the hearLgJO
Volume Number
72 2
Cardiac arrhythmias
Fig. 4. Reversal digitalis toxicity.
treated with beta-adrenergic
of ventricular bigeminy due to Note- also slowing of sinus rate.
Hoffman’ suggests that the increased rate of diastolic depolarization of pacemaker cell membranes is the cellular basis for increased rhythmicity and automaticity. He considers that all pacemaker sites, defined as “automatic cells,” are located within the conduction system. Wallace and Sarnoff” have shown that conduction in Purkinje tissue and ventricular myocardium is not significantly affected by sympathetic nerve stimulation. Given this broad spectrum of activity, it might prove to be valuable, in certain circumstances, to minimize sympathetic influences upon the heart. Until recent years, however, selective beta-adrenergic blockade has not been possible. The dichloro derivative of isoproterenol offered
blocking agents
183
promise in this direction, but further experience showed that it has a significant intrinsic sympathomimetic effect.r2 In 1962, pronethalol, the naphthyl derivative of isoproterenol, was introduced’ and proved to be an effective antagonist of the beta-adrenergic catecholamines. It prevented the chronotropic and inotropic effects of intravenous isoproterenol and stellate ganglion stimulation in both animals and man.‘J3 In addition, it produced a bradycardia in acutely sympathectomized animals and thus is thought to be effective against myocardial stores of catecholamines. However, 11 per cent of rats given pronethalol in high doses for prolonged periods of time developed lymphosarcomas. Propranolol, a noncarcinogenic analogue with pharmacologic properties similar to pronethalol, has now replaced pronethalol.3 Arrhythmias
Evidence has been presented which suggests that pronethalol may be a potent antiarrhythmic agent. The data demonstrate effects of beta-adrenergic blockade at several levels of the pacemaker and conduction system of the heart. The 5 patients with normal sinus rhythm showed slowing of cardiac rate both at rest and exercise rates. This result is consistent with reported studies utilizing both pronethalol and catecholamine-depleting agents in animal and human subjects.‘J3-‘* One patient with complete A-V
Table III. Reversal of ouabain-induced ventricular tachycardia in the dog by pronethalol before and after reserpine pretreatment Quabain, Number trials Without
of
meandose
Arrhythmia
(w.1
reserpine 11
1.3
Ventricular tachycardia
Pronethalol, dose* (range)
110 (Z-180)
mean
Result
(mg.)
Supraventricular Ventricular
With reserpine pretreatment 6
1.2
Ventricular tachycardia
6.5 (25160)
Supraventricular Ventricular
*Includes tTransient
4 trials in 2.
with
equivalent
dose
(l/10)
of propranolol.
tachycardia tachycardia
tachycardia tachycardia
7t 4
6 0
Fig. 5. Ouabain-induced sinus merhanism.
ventricular
tachycardia
in the
dissociation had slowing of both the sinus and ventricular rates, as did dogs with surgical heart block treated with reserpine by Roberts and Nfodell.1g There was no change in the atria1 rate of atria1 flutter, consistent with reports of others.14J5 Atria1 premature contractions, however, have been decreased in number. Reversal of paroxysmal atria1 tachycardia with block caused by digitalis toxicity has been reported,14 although in the present case only slowing of the ectopic focus was achieved. Pronethalol consistently slowed conduction across the A-V node, as evidenced by slowing of the ventricular rate in atria1 flutter and fibrillation, and development of A-V dissociation. This effect is consistent jvith the results of experimental studies. Conduction through the A-V node is increased by sympathetic nerve stimulation11,20-22 and decreased by acute or chronic sympathectomy or treatment with reserpine.23 Reserpine has also been shown to increase A-V block in patients with atria1 fibrillation.24 The results thus far suggest that pronethalol may inhibit ventricular extrasystoles,
reserpinized
dog.
F’roncthalol
r~a11~et1
r(:vcrsiou
to ;I
particularly when caused by digitalis toxicity. This has been shown by others.2J3J4J5-27 Adrenergic blockade by other means can also prevent or reverse ventricular irritability related to digitalis toxicity,24,26J8 but the fundamental relationship between digitalis and catecholamines is unclear. Tanz2g~RnJ1 reported abolition of the positive inotropic effect of ouabain upon cat papillary muscles when the strips \vere pretreated Lvith dichloroisoproterenol, reserpine, or guanethidine. other workers, using diverse means of inhibiting catecholamine activity, have found that pronethalol,L reserpine,23s32 acute or chronic sympathectomy, total cardiac denervation,“” or flTM-lo”* do not inhibit the positive inotropic action of digitalis preparations. The present studies in animals indicate that the ventricular irritability caused by digitalis is not solely related to adrenergic stimuli, since the dogs pretreated with reserpine also developed ventricular ectopic rhythms in response to ouabain. Similarly, digitalis toxicity may be observed in the totally denervated heart? or the reserpinized cat papillary muscle.28
Volume Number
72 2
Cardiac arrhythmias
treated with beta-adrenergic
Moreover, the present data show that pronethalol reverses ouabain-induced ventricular tachycardia even in reserpinepretreated dogs, suggesting a mechanism of action other than beta-blockade.* Lucchesi27 and Somani and Lum” also concluded from time-dose relationships and the effects on action potentials that pronethalol has a nonspecific action which may be responsible for its antiarrhythmic effect. Clinical indications contraindications
and
The indications for the use of pronethalol in cardiac arrhythmias appear thus far to be limited but specific. The most useful effect has been the slowing of the ventricular rate in atria1 fibrillation or flutter when this was not otherwise possible by large or toxic doses of digitalis. It also produces a rapid and relatively prolonged reversal of increased ventricular irritability, especially when caused by digitalis. This may be particularly useful when the administration of potassium is not effective or is contraindicated. Unlike calcium versenate, pronethalol need not be infused repeatedly. On the other hand, the underlying congestive failure for which digitalis was prescribed may be aggravated by the prolonged use of the adrenergic blockade. The only death reported due to pronethal01occurred in the present series, although we are aware of several others, two instances in subjects with congenital heart disease.43 Pronethalol is contraindicated in the presence of bradycardia, since the rates of all pacemaker sites are lowered by the drug. Complete A-V dissociation or a high degree of A-V block would also appear to preclude the use of pronethalol, since the higher pacemakers may be suppressed along with the lower ones. The hazard is analogous to the use of quinidine in this situation. No signs of increased pulmonary con*It
is possible that the small residual stores of catecholamines not removed by reserpine (approximately 2 per cent)cJ might constitute an effective trigger for digitalis-induced arrhythmias. In this sense. it is difficult to exclude the possibility that pronethalol may produce its effects by betablockade alone.
blocking agents
18.5
gestion were encountered in this study in 14 patients with congestive heart failure treated with a single intravenous dose of pronethalol. Although the cardiac output of normal subjects is not decreased after guanethidine,36 reserpine,37 sympathectomy, or pronethalo1,15*38s3g subjects with congestive heart failure may be dependent upon a cathecholamine stimulus for adequate myocardial function, and thus may react to long-term administration of pronethalol with a worsening of their conUntil additional gestive heart failure. 14,40,41 data are available, therefore, the presence of moderate to severe congestive heart failure should be considered to be a relative contraindication to the chronic administration of pronethalol. Perhaps an exception would be the case in which a rapid ventricular rate is contributing to the failure. Beta-adrenergic blockade may cause a fall in venous return, since it has been shown that beta-receptors in the peripheral venous bed subserve venoconstriction.42 This suggests that pronethalol should be used with caution in conditions such as pulmonary hypertension and congestive heart failure, in which an adequate venous return is essential for maintaining cardiac output. In addition, the drug blocks the bronchodilator effects of the catecholamines, and its use should be avoided when bronchospasm is present. Finally, a potential hazard exists in stenosis of the semilunar valves, since, experimentally, catecholamines may be required to maintain adequate velocity or force of ventricular contraction.44 Summary
Twenty-seven subjects with various cardiac rhythms were treated with intravenous pronethalol or propranolol. Slowed sinus rhythmicity, decreased A-V node conduction, and decreased ventricular premature contractions (particularly if caused by digitalis) were observed. One death occurred in a patient with A-V dissociation, severe pulmonary hypertension, and congestive heart failure. No other significant side effects were seen. These two drugs are considered to be quite useful in controlling ventricular responses to atria1 flutter or fibrillation,
186
Wolfson,
Robbins, and Kramow
and in certain cases of ventricular irritability. They are rapid acting and potent. Their use may be hazardous when brad\-cardia or A-V dissociation is present, or *if the arrhythmia is complicated by severe congestive heart failure or bronchospastic pulmonary disease. Data in animals confirm the reversal of digitalis toxicity and suggest a mechanism of action in addition to beta-adrenergic blockade. REFERENCES 1.
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Black, J. M:., and Stephenson, J. S.: Pharmacology of a new adrenergic beta-receptorblocking compound (Nethalide), Lancet 2:311, 1962. Vaughan Williams, E. M., and Sekiya, A.: Prevention of arrhythmias due to cardiac glycosides by block of sympathetic o-receptors, Lancet 1:420, 1963. Black, J. j&T., Crowther, A. F., Shanks, R. G. Smith, I,. H., and Dornhorst, A. C.: A new adrenergic beta-receptor antagonist, Lancet 1:1080, 1964. Morrow, D. H., Gaffney, T. E., and Chidsey, C. A.: The effect of norepinephrine infusion on reserpine-induced myocardial catecholamine depletion: Implications in anesthesiology, Anesth. & Analg. 42:2 1, 1963. Gaffney, T. E., Chidsey, C. A., and Braunwald, E.: Study of the relationship between the neurotransmitter store and adrenergic nerve block induced by reserpine and guanethidine, Circlllation Res. 12:264, 1963. Friedberg, C. K.: Disease of the heart, ed. 2, Philadelphia, 19.56, W. B. Saunders Co. Hoffman. B. F.. and Cranefield. P. F.: The physiolo&al b&s of cardiac arrhythmias, Am. J. Med. 37:670, 1964. Goodman, L. S., and Gilman, A.: The pharmacological basis of therapeutics, ed. 2, New York, 1958, The Macmillan Co., p. 483. Furrhgott, 12. A.: The receptors for epinephrine and norepinephrine (adrenergic receptors), Pharmacol. Rev. 11:429, 1959. Ahlquist, Ii. P.: A study of the adrenotropic receptor, Am. J. Physiol. 153:586, 1948. \X’allnce. A. G.. and Sarnoff. S. I.: Effects of cardiac sympathetic nerve s&u&ion on conduction in the heart, Circtilation Res. 14:86, 1964. L)resel, P. E.: Blockade of some cardiac actions of adrenaline by dichlorisoproterenol, Canad. J. Biochem. 38:375, 1960. T)ornhorst. A. C.. and Robinson. B. F.: Clinical pharmacoloyv of n beta-adreneraic-blocking agent (Netdalide), Lancet 2:314, 1962. ’ Stock. I. P. P.. and Dale. N.: Beta-adrenerzic receptor blockade in cardiac arrhythmias, Brit. M. J. 2:1230, 1963. SchrGder, G., and WerkG, L.: Nethalide, a beta-adrenergic blocking agent, Clin. Pharmacol. & Therap. 5:159, 1964. _1
16.
(Xick, G., and Braunwald. tl.: Relative inlportance of sympathetic and p;lr;rsJ’nlp;lthetic nervous systems in rontrol of heart rate, Fed. Proc. 23:412, 1964. 17 James, T. N‘., and Nadeau, Ii. :I.: The chronotropic and vagal-blocking actions of naphthylisoproterenol studied by direct perfusion of the sinus node, J. Pharmacol. & I’xper. Themp. Id3:350, 196-c. 18 Green, E. \\‘., ,md James, T. N.: Chronotropic action of re>erpine and guanethidine studied by direct perfusion of the sinus node, Clin. Res. 12:183, 1964. 19. Roberts, J., ;lnd Model], \V. : Pharmacologic evidence for the importance of catecholamines in cardiac rhlthmicity, Circulation Res. 9:171, 1961. LO. K,rayer, O., Mandoki, J. J., and Mendez, C.: Studies on veratrum alkaloids. N\‘l. The action of epinephrine and of veratramine on the functional refractor!. period of the auriculoventricular transmission in the heart lung preparation of the dog, J. Pharmacol. & Exper. Therap. 103:412, 1951. 21. Siebelys, A. r\., Hoffman, B. I;., Enson, Y., Farrell. I. E.. and Brooks. C. McC.: Effects of I-epinephrine and I-norep’inephrine in cardiac excitability, Am. J. Physiol. 175:1, 1953. J., Mandoki, J. J., and Pilnr, G.: The 22. Alanis, functional discontinuities of the auriculoventricular node, Acta Phl.siol. Lat. Am. 10:96, 1960. D. H., Gaffney, ‘I’. E., and Braunwald, 23. Morrow, IX.: Studies on digitalis. 1’111. Effect of autonomic innervation and of myocardial catecholamine stores upon the cardiac action of ouabain. 1. I’harmacol. & Exner. Theran. 140:236; 1$63. 24. Lawn, Ii., Ehrlich, I.., Lipschultz, B., and Blake, J.: Effect of digitalis ilr patients receiving reserpine, Circ&tion 2411185, 1961. 25. Tavlor. K. I’.. lohnston. C. I.. and Tose. A. D.: Reversal of digitalis intoxication” by betaadrenergic blockade with pronethnlol, New England J. illed. 271:877, 1964. 26. Erlij, D., and Mendez, Ii.: The modification of digitalis intoxication by excluding adrenergir influences on the heart, J. Pharmacol. & Exper. Therap. 144:07, 1964. 27. Lurchesi, B. I~.: The action of Nethalide upon experimentally induced cardiac arrhythmias, I. Pharnracol. & Exuer. Theran. 145:286. 1964. 28. ‘Roberts, J., [to, Ii., Reilly, ‘J., and Cairoli, 1,‘. J.: Influence of reserpine and OTM-10 OII digitalis-induced ventricular arrhythmia, Circulation Res. 13:149. 196.1. Ii. I).: The .release of catecholamine> 29. Tanz, following ouabain, Pharmacologist 2:95, 1960. 30. Tanz, R. D. : The action of ouabain on cardiac muscle treated with reserpine and dichloroisoproterenol, J. Pharmacol. & Exper. Therap. 144:205, 1964. Ii. I).: In vitro inotropic response to 31. Tanz. ouabain and Ca++ following DCI, reserpine and euanethidine. Fed. Proc. 23:123. 1964. J ., and Ervin, R.: The effect of 32. Yeln&ky, ouabain on cardiac nutomaticity in reserpine.
,
. .
I
Volume Number
72 2
Cardiac arrhythmias
treated with beta-adrenergic
pretreated dogs, AM. HEART J. 62:687, 1961. William, V. L., Cooper, T., and Hanlon, C. R.: Digitalis tolerance of the denervated heart, Fed. Proc. 24:486, 1965. 34. Somani, P., and Lum, B. K. : The anti-arrhythmic action of beta-adrenergic blocking agents, J. Pharmacol. & Exper. Therap. 147:194, 1965. 3.5. Harrison, I>. C., Griffin, J. R., and Fiene, T. J.: Effects of Beta-adrenergic blockade with propranolol in patients with atrial arrhythmias, New England J. Med. 273:410, 1965. 36. Chamberlain, D. A., and Howard, J.: Guanethidine and methyldopa: A hemodynamic study, Brit. Heart 1. 26528. 1964. 37. Kahler, R. i., Gaffney, T. E., and Braunwald, E.: The effects of autonomic nervous system inhibition on the circulatory response to muscular exercise, J. Clin. Invest. 41:1981, 1962. 38. Chamberlain, D. A., and Howard, J.: The hemodynamic effects of beta-sympathetic blockade, Brit. Heart J. 26:213, 1964. 39. Harrison, D. C., Braunwaid, E., Glick, G., Mason, D. T., Chidsey, C. A., and Ross, J., Jr.: 33.
‘IO.
41.
42.
43. 44.
blocking agents
187
Effects of beta-adrenergic blockade on the circulation, with particular reference to observations in patients with hypertrophic subaortic stenosis, Circulation 29:84, 1964. Chidsey, C. A., Harrison, D. C., and Braunwald, E.: Augmentation of the plasma norepinephrine response to exercise in patients with conrestive heart failure. New Eneland 1. Med. 26f:650, 1962. ” Gaffney, T. E., and Braunwald, E.: Importance of the adrenergic nervous system in the support of circulatory-function in patients with conrestive heart failure. Am. 1. Med. 34:320. 1963. kaiser, G. A., Ross,‘J., Jr.: and Braunwaid, E.: Alpha and beta adrenergic receptor mechanisms in the systemic venous bed, J. Pharmacol. 8: Exper. Therap. 144:156, 1964. Dressier, W., and Jonas, S.: Personal communication. Black, W. L., and Rolett, E. L.: Cardiovascular alpha-adrenergic properties of dopamine, Circulation 32:II-51, 1965.
of cardiac
beta-adrenergic and experimental
arrhythmias blocking
agents
studies
Steven Wolfson, M.D. Sanford I. Robbins, B.A. Norman Krasnow, M.D.* Brooklyn, N. Y.
R
apid progress has been made in the past decade in the treatment of cardiac arrhythmias. The introduction of electrical techniques for the conversion or control of many serious arrhythmias has gained rapid acceptance and widespread use. Nevertheless, arrhythmias which have not thus far proved to be amenable to electrical methods of control continue to pose difficult problems for the clinician. During this period, few new pharmacologic approaches have proved to be useful. Knowledge of the influence of catecholamines on the mechanical and electrical properties of the heart has been extended. However, the relationship of catecholamines to clinical arrhythmias, and in particular to arrhythmias provoked by digitalis therapy, remains unclear. The introduction of effective means for blockade of beta-adrenergic receptors provides an additional potent tool for study. Pronethalol was introduced by Black and Stephenson’ in 1962, as an effective betaadrenergic blocking agent, and Vaughan From
Williams and Sekiya2 noted that this drug had an antiarrhythmic effect in guinea pigs. A subsequent analogue with similar properties, propranolol, was introduced in 1964.3 The purpose of the present study was to evaluate the effects of these two agents in the treatment of clinical and experimentally induced arrhythmias. These agents were shown to be useful drugs in specific circumstances. Like most therapeutic agents, however, they have toxic effects. This study describes several hazards of, and contraindications to, the administration of pronethalol or propranolol. Animal studies suggest a different mode of action than adrenergic blockade. Materials
and
methods
Clinical studies. Twenty-two patients with clinical arrhythmias were included in this series. There were 13 men and 9 women, 30 to 88 years of age. In addition, 5 subjects with normal sinus rhythm were studied. Arrhythmias were studied only if the mechanism was well defined and stable, and its relationship to the adminis-
the Department of Medicine, State University of New York Downstate Medical Center, and the Medical Service, Kings County Hosoital Center. Brooklyn. N. Y. This work was &ported by Gran; I-361 from the Health Research Council of the City of New York, and Grant HE 07982 from the National Heart Institute. Bethesda, Md. Received for publication Nov. 2. 1965. *Career Scientist of the Health Research Council of the City of New York. Address: Department of Medicine, State University of New York Downstate Medical Center, 4.50 Clarkson Ave., Brooklyn, N. Y., 11203.
177
178
Am. Heavt 3. August, 1966
WoJfson, Robbins, und Krasnow
E.I..
M
59
Chrnnic
bronchiti’s
G.K.
k‘
8(J
Ai\.
F
80
1.X..
M
72
A.S.
F
88
Hypertensive heart disease, CHF, digitalis toxicit> ASHI), CHF, digitalis toxicit)Emphyselna, CHF, pneumothorax ASHD, CHIT
F.A.
F
61
RHD
J.S.
M
80
ASHD. talis
I.N.
M
85
ASH11
F.M.
M
30
J.G.
F
60
J.W.
F
57
E.F.
F
77
Atria1 septal defect, pulmonic stenosis, CHF RHD, mild mitral stenosis RHD, mitral insufficiency, CHF, digitalis toxicity ASHD, CHF
J.D.
M
4.5
W.D
M
60
RHD, mitral ficienrj ASHD, CHF
D.G.
M
60
ASHD.
A.V.
M
46
A.C.
M
57
CR.
M
41
J.S.
M
46
RHD, mitral valve prosthesis, CHF RHD, severe mitral stenosis, pulmonary hypertension, CHF Hyperthyroidism (controlled), myocarditis (?) RHD, MS, AI, endocarditis (?), digitalis toxicity
J.M.
M
45
CHF, toxicit?
digi-
Atria1 tibrillation, VPC (bigeminy), \‘R 100 Atrial flutter, 2:1 conduclion, 1’1~ 130 A-V dissociation with ventricular captures, atria1 rate 93, VR SO Atria1 Butter, 2-.3:1 conduction, VIZ 110 Sinus tachycardia, wandering atria1 pacemaker, 1” A-V block IVandering atria1 pacem,iker c VIK VR SO-120 atria1 flL:tter, ;:l concluc[inn, VK 70
unless
SO
NW,
\,‘K 60
50
VPC
abolished,
25
3-4:l
conduction,
50
Captures atrial
50 SO
100
VR 80 VR 80
disappeared, rate 80, \IR
Atrial flutter, conduction, KSR
42
4-5:1 \:R 70
No change
50
Atria1 fibrillation, 100 Atria1 librillation, abolished, VR
VPC
50
WC,
SO SO
VR VPC 80
VPC increased in number, VR 120 Atria1 fibrillation, VR 80
5t Atria1 flutter, 4:l conduction, VR 80 100 Carotid sipus massage increased block, VR 110 901 Ko effect 50
Atrial tachycardia with 1:l conduction (2:l with carotid sinus pressure), VR 125 NSR, inromplete A-V dissociation (nodal rate 271, WC (multiform, bidirectional), VR 60
otherwise
75
Carotid sinus massage increased block, VR 75
fibrillation,
140
VR
50
Atria1
Atria1 librillation, VPC, 1-K 90 Atria1 tachycardia, (137/ min.), nodal tachycardia, A-V dissociation, VR 107 NSR, VPC, VR 70
HCVD; chronic renal disease with uremia, digitalis toxicity
rhythm,
VR
Atria1 flutter, 2-3:l rondllrtion VR 100 Atria1 Blotter, 2:l conduction, VR 130
CHF
Nodal
fibrillation,
VR
160
.iO
Atria1
\‘R 100 Atrial fibrillation, \:1i 110 ;\lrinl librillation,
insuf-
*Dose refers to dose of pronethalol in milligrams tPropranolo1 intravenously (mg.). ~Propranolol orally per day (mg.) RZZD: Rheumatic disease. ASHD: Arteriosclerotic failure. AZ: Amtic insufficiency. MS: Mitral VR: Ventricular rate per minute.
:\trial premature c-ontractions, \-Ii 150-180 SSR, VPC ihigeminy 1, \.R 80
Complete cardiac
5t VPC
heart arrest
abolished,
block,
\TR 60
5t
Atria1 forus slowed to 104; 1:l conduction, \‘R 104
5t
Complete A-V dissociation (nodal rate 33, with increased aberrant conduction), VPC unchanged, VR 60
stated.
heart disease. HCVD: Hypertensive cardiovascular stenosis. VPC: Ventticular premature contractions.
disease. NSR:
CNF: Congestive heart Normal sinus rhythm.
Volume 72 Number 2
179
Cardiac arrhythmias treated with beta-adrenergic blocking agents
Table I. Clinical arrhythmias treated with pronethalol-Cont’d I
)
Patient
Sex I
I
Age (yr.1
R.R.
F
41
N.F.
F
48
Clinical
diagnosis
( I
~
I RHD (mild mitral insufficiency; 2 yr. after open mitral valvuloplasty), digitalis toxicity ASHD, acute myocardial infarction; shock, digitalis toxicity
Atria1 fibrillation, VR 155
NSR; VPC VR 120
tration of digitalis clear. No patient with bronchospasm on auscultation was accepted. Congestive heart failure was not a contraindication for the purposes of this acute study. The subjects were given either pronethalol,* 50 mg., or propranolol,* 5 mg., intravenously, over a S-minute period. In 2 cases, an additional 50 mg. of pronethalol was given intravenously 20 minutes after the initial dose. Blood pressure was monitored by cuff frequently. Two patients (A.V., R.R.) were given the drug only orally. Three patients were subsequently treated with oral pronethalol (300 mg. three times daily) or propranolol (30 mg. three times daily). Animal studies. Twenty-four studies were performed on 1.5 mongrel dogs, approximately 15 kilograms in weight, anesthetized with intravenous pentobarbital (20 mg. per kilogram). A polyethylene catheter was introduced percutaneously into a peripheral vein. Electrocardiograms were monitored continuously. Ouabain (1 .O mg.) was given intravenously and additional doses (0.25 mg.) were repeated every 10 to 15 minutes until either ventricular tachycardia or multiple ventricular premature contractions were produced. The total dose of ouabain required for each animal averaged 65 mg. per kilogram. When the toxic rhythm had been stabilized for at least 10 minutes, pronethalol (mean dose *We
Rhythm
are indebted to Dr. Alex Sahagian-Edwards Laboratories, New York, for generous supplies drugs. The name Nethalide is used in the United pronethalol.
of Ayerst of these States for
Dose* (wir.)
Result I
801 Atria1 fibrillation, VPC, VR 65
VPC,
(bigeminy),
50
no
Nodal rhythm, A-V sociation, VR 75
dis-
5 mg. per kilogram) was given intravenously over several minutes. Electrocardiographic effects occurred within 20 minutes. The animals were allowed to recover for several days from the procedure and then were given reserpine intraperitoneally, 0.1 mg. per kilogram daily for at least 2 or 3 days. This regimen has been shown to lower myocardial (atrial) catecholamines to 2 per cent of control levels.*s5 Ouabain was again given, according to the same schedule, until toxicity developed. Pronethalol (mean dose 3.3 mg. per kilogram) was then administered. Ouabain alone was given to 7 animals until ventricular tachycardia developed, and they were monitored without further treatment until death. Clinical
results
(Table I)
All patients who responded to pronetha101 or propranolol did so within 15 minutes after completion of the infusion. One patient complained of nausea several minutes after treatment; this was relieved by an intramuscular injection of 200 mg. of trimethobenzamide (Tigan, Roche). No other side effects were noted. The duration of effective blockade averaged 4 hours after intravenous administration, and somewhat longer after oral administration. The electrocardiographic changes that followed the administration of pronethalol can be divided into the effects produced upon the sinus node, the atria, the atrioventricular node, and the ventricles. Since pronethalol was used in the majority of cases (see Table I), the results will be
180
Wo!fson, Robbins, md Krnsnow
Table II. Summary
of the e$ects qf pronethalol
Rhythm
in clinical arrhythmias
Number patients
/
of
Result
of patients)
(number
Sinus NSR With
6 A-V
dissociation
3
Slowed (5) Developed A-V Slowed (3)
2 5 5 1
Abolished (2) No atria1 effect (5) So atrial effect (5) Atria1 rate slowed (1)
5 6 3 1
Ventricular rate slowed Ventricular rate slowed Increased block (3) Cardiac arrest (1)
6 4
Abolished Abolished
dissociation
( 1)
Atria1 Extrasystoles Flutter Fibrillation Tachycardia A-V node Atriral flutter Atria1 fibrillation Dissociation Tachycardia Ventricular Extrasystoles Due to digitalis Kot due to digitalis
described in terms of this agent, although the effects of propranolol were similar. A. Sinus rhythm. Of 8 patients with a sinus mechanism (Table II), the resting sinus rates slowed in 6 by 6 beats per minute. Five patients were exercised and had lesser increments in heart rate (10 beats per minute) after pronethalol. There was no change in the configuration of the P wave. B. Atria1 arrhythmias. Two subjects had multiple atria1 premature contractions, with ventricular rates of 120 to 150 per minute. The premature beats were abolished by pronethalol in each case, resulting in a stable nodal rhythm in one case, and normal sinus rhythm in the other. The resultant ventricular rates averaged 80 per minute. In neither case was the arrhythmia thought to be related to digitalis toxicity. Pronethalol had no effect upon the atria1 mechanism in 10 patients with atria1 flutter or atria1 fibrillation (Fig. 1). One patient (J.S.) with atria1 tachycardia and 2:l block, due to digitalis, had slowing of the ectopic atria1 focus and ventricular rate, but the 2:l relationship persisted. C. Atrioventricular node. Pronethalol con-*-~-.-L.. ---A .._^ -1 ^ -:--:c-?.-e ,.l,.... :,, ,c
(5) (6)
in 5 in 1
the ventricular response in atria1 fibrillation. Initial ventricular rates of 90 to 170 per minute were slowed to 65 to 90 per minute. In 4 patients of this group, digitalis had failed to slow the ventricular rate, despite clinical evidence of toxicity. Pronethalol was also given to 5 patients with atria1 flutter. Three patients responded with increased A-V block and decreased ventricular rates. In 2 patients the ventricular rate slowed transiently during carotid sinus massage only after pronethalol. The above-mentioned effects occurred despite the presence of congestive heart failure, severe anoxia (one case), and a spontaneous pneumothorax (one case). Three patients with complete A-V dissociation were treated. In 2 patients, pronethalol slowed both the atria1 and ventricular foci, and ventricular captures disappeared (Fig. 2). The third subject, with rheumatic mitral stenosis, very severe pulmonary hypertension, and heart failure, had a nodal tachycardia, a slower atria1 tachycardia, and A-V dissociation (Fig. 3). In the attempt to abolish the ectopic tachycardia, which was severely compromising cardiac output, 50 mg. of pronethal-1
.(/r-c
A.ron
A.IO~
< m;n,,tm
The
natimt
Cardiac arrhythmias
..,
i-y
;:.
:
treated with beta-adrenergic
blocking agents
181
:c
:”
I
I
Fig. 1. A, Atria1 fibrillation with rapid ventricular response despite digoxin, 1.0 mg daily. B, Atria1 flutter with 2:l response. In each case, pronethalol slows the ventricular rate without effect on the atria1 mechanism.
CONTROL ,~l6A&LlSlOiKITY
SOMIN. AFTER PRONElHAiOlf50
AS.
ng I.V.)
Fig. 2. A-V dissociation secondary to digitalis intoxication. Pronethalol slowed the atria1 rate from 93 to 80 per minute, the ventricular rate from 50 to 42 per minute, and abolished ventricular captures (C).
developed complete heart block with an idioventricufar rhythm as the infusion was completed, and within 2 minutes cardiac arrest supervened. Rapid intravenous administration of isoproterenol and intracardiac epinephrine, as well as the usual resuscitative measures, were unable to reverse the arrest. D. Ventricular eflects. No changes in QRS configuration or duration were noted. Pronethalol was successful in 5 of 6 patients in abolishing ventricular extrasystoles which were considered to be due
to digitalis toxicity (Fig. 4), but one of these subjects developed A-V dissociation. Of 4 patients with frequent ventricular premature beats unrelated to digitalis, one responded to pronethalol. One of the refractory patients (E.F.) presented with atria1 fibrillation, a rapid ventricular response, and frequent ventricular ectopic beats. She had received 1.6 mg. of lanatoside C. Pronethalol slowed the ventricular rate, but the extrasystoles increased in frequency. She was then treated with additional lanatoside C, with further slowing
182
Wolfson, Robbins, and Krasnow
Fig. 3. A-V dissociation with sinus and nodal tachycardia in a patient with mitral stenosis and severe pulmonary hype :rtension. Cardiac arrest followed progressive slowing of the nodal, sinus, and ventricular pacemakers.
of the ventricular
rate and abolition of the
extra beats. Animal
studies
(Table
111)
Eight dogs had 11 episodes of ouabaininduced ventricular arrhythmia, treated with pronethalol. In 7 of these episodes, pronethalol caused reversion to a supraventricular tachycardia. When 6 of these animals had been pretreated with reserpine, they also developed ventricular tachycardia after ouabain. All 6 episodes of ventricular tachycardia were successfully converted to a supraventricular mechanism (although in 2 cases the result was only transient) (Fig. 5). In this small group of animals there was no increase in the toxic dose of ouabain after reserpine. None of the animals succumbed to ouabain toxicity when pronethalol was
given, even when the ventricular arrhythmia did not revert to a sinus mechanism during the 3-hour period of observation. By contrast, 7 animals were given ouabain until toxicity developed, but pronethalol was withheld. All died of arrhythmia. either ventricular standstill or fibrillation. Discussion
Sympathomimetic agents have found wide clinical application both for their potentiation of cardiac contractility and their stimulatory effect on pacemaker sites.6 Adrenergic stimulation of the heart produces7,s increased rhythmicity of the sinus node, a shortened refractory period in atria1 muscle, more rapid atrioventricular conduction, and enhanced activity of idioventricular pacemakers. These effects are thought to be subserved by betaadrenergic receptors within the hearLgJO
Volume Number
72 2
Cardiac arrhythmias
Fig. 4. Reversal digitalis toxicity.
treated with beta-adrenergic
of ventricular bigeminy due to Note- also slowing of sinus rate.
Hoffman’ suggests that the increased rate of diastolic depolarization of pacemaker cell membranes is the cellular basis for increased rhythmicity and automaticity. He considers that all pacemaker sites, defined as “automatic cells,” are located within the conduction system. Wallace and Sarnoff” have shown that conduction in Purkinje tissue and ventricular myocardium is not significantly affected by sympathetic nerve stimulation. Given this broad spectrum of activity, it might prove to be valuable, in certain circumstances, to minimize sympathetic influences upon the heart. Until recent years, however, selective beta-adrenergic blockade has not been possible. The dichloro derivative of isoproterenol offered
blocking agents
183
promise in this direction, but further experience showed that it has a significant intrinsic sympathomimetic effect.r2 In 1962, pronethalol, the naphthyl derivative of isoproterenol, was introduced’ and proved to be an effective antagonist of the beta-adrenergic catecholamines. It prevented the chronotropic and inotropic effects of intravenous isoproterenol and stellate ganglion stimulation in both animals and man.‘J3 In addition, it produced a bradycardia in acutely sympathectomized animals and thus is thought to be effective against myocardial stores of catecholamines. However, 11 per cent of rats given pronethalol in high doses for prolonged periods of time developed lymphosarcomas. Propranolol, a noncarcinogenic analogue with pharmacologic properties similar to pronethalol, has now replaced pronethalol.3 Arrhythmias
Evidence has been presented which suggests that pronethalol may be a potent antiarrhythmic agent. The data demonstrate effects of beta-adrenergic blockade at several levels of the pacemaker and conduction system of the heart. The 5 patients with normal sinus rhythm showed slowing of cardiac rate both at rest and exercise rates. This result is consistent with reported studies utilizing both pronethalol and catecholamine-depleting agents in animal and human subjects.‘J3-‘* One patient with complete A-V
Table III. Reversal of ouabain-induced ventricular tachycardia in the dog by pronethalol before and after reserpine pretreatment Quabain, Number trials Without
of
meandose
Arrhythmia
(w.1
reserpine 11
1.3
Ventricular tachycardia
Pronethalol, dose* (range)
110 (Z-180)
mean
Result
(mg.)
Supraventricular Ventricular
With reserpine pretreatment 6
1.2
Ventricular tachycardia
6.5 (25160)
Supraventricular Ventricular
*Includes tTransient
4 trials in 2.
with
equivalent
dose
(l/10)
of propranolol.
tachycardia tachycardia
tachycardia tachycardia
7t 4
6 0
Fig. 5. Ouabain-induced sinus merhanism.
ventricular
tachycardia
in the
dissociation had slowing of both the sinus and ventricular rates, as did dogs with surgical heart block treated with reserpine by Roberts and Nfodell.1g There was no change in the atria1 rate of atria1 flutter, consistent with reports of others.14J5 Atria1 premature contractions, however, have been decreased in number. Reversal of paroxysmal atria1 tachycardia with block caused by digitalis toxicity has been reported,14 although in the present case only slowing of the ectopic focus was achieved. Pronethalol consistently slowed conduction across the A-V node, as evidenced by slowing of the ventricular rate in atria1 flutter and fibrillation, and development of A-V dissociation. This effect is consistent jvith the results of experimental studies. Conduction through the A-V node is increased by sympathetic nerve stimulation11,20-22 and decreased by acute or chronic sympathectomy or treatment with reserpine.23 Reserpine has also been shown to increase A-V block in patients with atria1 fibrillation.24 The results thus far suggest that pronethalol may inhibit ventricular extrasystoles,
reserpinized
dog.
F’roncthalol
r~a11~et1
r(:vcrsiou
to ;I
particularly when caused by digitalis toxicity. This has been shown by others.2J3J4J5-27 Adrenergic blockade by other means can also prevent or reverse ventricular irritability related to digitalis toxicity,24,26J8 but the fundamental relationship between digitalis and catecholamines is unclear. Tanz2g~RnJ1 reported abolition of the positive inotropic effect of ouabain upon cat papillary muscles when the strips \vere pretreated Lvith dichloroisoproterenol, reserpine, or guanethidine. other workers, using diverse means of inhibiting catecholamine activity, have found that pronethalol,L reserpine,23s32 acute or chronic sympathectomy, total cardiac denervation,“” or flTM-lo”* do not inhibit the positive inotropic action of digitalis preparations. The present studies in animals indicate that the ventricular irritability caused by digitalis is not solely related to adrenergic stimuli, since the dogs pretreated with reserpine also developed ventricular ectopic rhythms in response to ouabain. Similarly, digitalis toxicity may be observed in the totally denervated heart? or the reserpinized cat papillary muscle.28
Volume Number
72 2
Cardiac arrhythmias
treated with beta-adrenergic
Moreover, the present data show that pronethalol reverses ouabain-induced ventricular tachycardia even in reserpinepretreated dogs, suggesting a mechanism of action other than beta-blockade.* Lucchesi27 and Somani and Lum” also concluded from time-dose relationships and the effects on action potentials that pronethalol has a nonspecific action which may be responsible for its antiarrhythmic effect. Clinical indications contraindications
and
The indications for the use of pronethalol in cardiac arrhythmias appear thus far to be limited but specific. The most useful effect has been the slowing of the ventricular rate in atria1 fibrillation or flutter when this was not otherwise possible by large or toxic doses of digitalis. It also produces a rapid and relatively prolonged reversal of increased ventricular irritability, especially when caused by digitalis. This may be particularly useful when the administration of potassium is not effective or is contraindicated. Unlike calcium versenate, pronethalol need not be infused repeatedly. On the other hand, the underlying congestive failure for which digitalis was prescribed may be aggravated by the prolonged use of the adrenergic blockade. The only death reported due to pronethal01occurred in the present series, although we are aware of several others, two instances in subjects with congenital heart disease.43 Pronethalol is contraindicated in the presence of bradycardia, since the rates of all pacemaker sites are lowered by the drug. Complete A-V dissociation or a high degree of A-V block would also appear to preclude the use of pronethalol, since the higher pacemakers may be suppressed along with the lower ones. The hazard is analogous to the use of quinidine in this situation. No signs of increased pulmonary con*It
is possible that the small residual stores of catecholamines not removed by reserpine (approximately 2 per cent)cJ might constitute an effective trigger for digitalis-induced arrhythmias. In this sense. it is difficult to exclude the possibility that pronethalol may produce its effects by betablockade alone.
blocking agents
18.5
gestion were encountered in this study in 14 patients with congestive heart failure treated with a single intravenous dose of pronethalol. Although the cardiac output of normal subjects is not decreased after guanethidine,36 reserpine,37 sympathectomy, or pronethalo1,15*38s3g subjects with congestive heart failure may be dependent upon a cathecholamine stimulus for adequate myocardial function, and thus may react to long-term administration of pronethalol with a worsening of their conUntil additional gestive heart failure. 14,40,41 data are available, therefore, the presence of moderate to severe congestive heart failure should be considered to be a relative contraindication to the chronic administration of pronethalol. Perhaps an exception would be the case in which a rapid ventricular rate is contributing to the failure. Beta-adrenergic blockade may cause a fall in venous return, since it has been shown that beta-receptors in the peripheral venous bed subserve venoconstriction.42 This suggests that pronethalol should be used with caution in conditions such as pulmonary hypertension and congestive heart failure, in which an adequate venous return is essential for maintaining cardiac output. In addition, the drug blocks the bronchodilator effects of the catecholamines, and its use should be avoided when bronchospasm is present. Finally, a potential hazard exists in stenosis of the semilunar valves, since, experimentally, catecholamines may be required to maintain adequate velocity or force of ventricular contraction.44 Summary
Twenty-seven subjects with various cardiac rhythms were treated with intravenous pronethalol or propranolol. Slowed sinus rhythmicity, decreased A-V node conduction, and decreased ventricular premature contractions (particularly if caused by digitalis) were observed. One death occurred in a patient with A-V dissociation, severe pulmonary hypertension, and congestive heart failure. No other significant side effects were seen. These two drugs are considered to be quite useful in controlling ventricular responses to atria1 flutter or fibrillation,
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and in certain cases of ventricular irritability. They are rapid acting and potent. Their use may be hazardous when brad\-cardia or A-V dissociation is present, or *if the arrhythmia is complicated by severe congestive heart failure or bronchospastic pulmonary disease. Data in animals confirm the reversal of digitalis toxicity and suggest a mechanism of action in addition to beta-adrenergic blockade. REFERENCES 1.
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