Efficacy of Disopyramide Phosphate in the Treatment of Refractory Ventricular Tachycardia

Efficacy of Disopyramide Phosphate in the Treatment of Refractory Ventricular Tachycardia

LOUIS A. VISMARA, MD, FACC ZAKAUDDIN VERA, MD RICHARD R. MILLER, MD, FACC DEAN T. MASON, MD, FACC

Davis and Sacramento, California

From The Section of Cardiovascular Medicine, Departments of Medicine and Physiology, University of California, School of Medicine, Davis and Sacramento, California. This study was supported In part by Research Program Project Grant HL-14780 from The National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received January 3, 1977; revised manuscript received February 11, 1977, accepted February 15, 1977. Address for reprints: Dean T. Mason, MD, Section of Cardiovascular Medicine, Universityof California, School of Medicine, Davis, California 95616.

The effects of Intravenously administered dlsopyramide phosphate were evaluated in seven patients with refractory ventricular tachycardia. All patients had organic heart disease, Including acute infarction (three patients), chronic coronary artery disease (two patients) and cardiomyopathy (two patients). The severity of the heart disease was reflected In the advanced patient age (average 64 years) and the occurrence before disopyramide therapy of cardiac arrest in five patients and congestive heart failure in all seven patients, In five patients, dlsopyramide was given as a bolus injection, 2 mg/kg body weight, followed by an infusion of 20 to 40 mg/hour. The final two patients received 4 mg/kg divided as a bolus Injection and an infusion over 1 hour followed by a 0.4 mg/kg infusion during the next hour. Intravenous administration of disopyramide resulted in more effective electrical stability in all patients and completely eliminated ventricular tachycardia in six. Recurrence of ventrlcular tachycardla was prevented In six patients with subsequent long-term oral administration of disopyramlde. Possible dose-related cardiac pump depression occurred in two patients, but disopyramide was otherwise well tolerated, Therefore, these data document the therapeutic efficacy of disopyramide in the treatment of refractOry life-threatening ventricular tachyarrhythmias.

Recent advances in cardiac monitoring have emphasized the widespread occurrence of ventricular arrhythmias. 1,2 Although they may occur in the absence of orga~lic heart disease, it is established that potentially lethal arrhythmias are ~ommon after acute myocardial infarction or with stable coronary artery disease. 3-6 Further, an increased prevalence of these ectopic rhythms is also reported with mitral valve prolapse 7 and idiopathic hypertrophic subaortic stenosis, s Although development of the coronary care unit concept in the past decade has significantly re: duced in-hospital mortality from primary cardiac arrhythmias, the limitations of currently available antiarrhythmic therapy are well recognized. 9 Not only is the use of these agents limited by relatively frequent adverse effects, but also hazardous ventricular ectopic beats may prove refractory to all forms of available therapy. 1° The present study reports the efficacy of a new antiarrhythmic agent, disopyramide phosphate, for the treatment of refractory life-threatening ventricular tachyarrhythmias. Methods and Materials Patients : The seven patients constituting this study, all men, were initially considered for entry into an ongoing antiarrhythmic efficacy trial comparing disopyramide phosphate (G. D. Searle and Company, Chicago, Illinois) and placebo administered intravenouslyin a double-blindmanner. However, all seven were purposely excluded from this designed efficacy protocol because of the clinical urgency and critical nature of their potentially lethal cardiac arrhythmias. Thus each patient presented with persistent refractory ventricular tachycardia or ventricular fibrillation, or both, unresponsive to currently available medical

June 1977 The AmericanJournalof CARDIOLOGY Volume39

1027

DISOPYRAMIDE PHOSPHATE FOR VENTRICULAR ARRHYTHMIA--VISMARA ET AL.

TABLE I Administration and Responsesto Disopyramide (DP) and Other Antiarrhythmic Agents in Seven Cases Arrhythmia Before DP Therapy

Therapy

IV Bolus Dose

Dose

IV Infusion

Oral

Adverse Drug Effect

Response

Case 1

PVCs 5/rain 15 cardiac arrests (VT/VF)

I

.

+

L L

450 mg divided in 40 min 4 mg/min for 6 hr

O PR PR PR

350 mg/6 hr for 2 days 750 mg divided in 1 hr 6 mg/min for 9 hr 500 rag/4 hr for 3 days

-+.

•

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15 mg/6 hr for 2 days 130 me/1 rain 35 mg/hr for 2 hr 150 rag/6 hr for 3 days

'+'

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D,b DP

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.

PVCs 5/min VT VF

-P

Dizziness Nausea

I

,

,

I

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4

+

4

, PVCs 20/hr

None , ,-,

I PrOs 5/min VT VF

None

Case 2

+

PVCs 5/rain VT

L L

500 mg divided in 1 hr 5 mg/min for 2 hr

VF

Q P D

%

DP DP DP

400 mg/6 hr for 7.5 ~lays 6 mg divided in 2 hr 600 mg divided in 8 hr 154 me/5 min 40 mg/hr for 2 hr 250 mg/6 hr for 2 days

DP

100 mg/6 hr chronically

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None Congestive heert failure None

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+

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Case 5

PVCs 15/rain 10 cardiac arrests (VT/VF)

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+

I PVCs

None 10/min

VT VF + '~.' +

.

,

,

. , ,

I PVCs 2/rain

Possi'b'l; cardiac pump depression

1028

June 1977

The American Journal of CARDIOLOGY

Volume 39

DISOPYRAMIDE PHOSPHATE FOR VENTRICULAR

TABLE

ARRHYTHMIA--VISMAFtAET AL.

I (cont'd)

Arrhythmia Before DP Therapy

Therapy

IV Bol us Dose

Dose

IV Infusion

Oral

Adverse Drug Effect

Response

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..

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•

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f PVCs 5 / m i n I

VT

o 9

I

syndrome Severe diarrhea Nausea Dizziness None

PVCs 1/min

I

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,

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[.

=

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D = d i p h e n y l h y d a n t o i n ; I V = intravenous; KCI = i~otassium chloride; L = lidocaine; P = p r o p r a n c l o l ; PR ~ procainam[de; PVCs = premature ventricular contractions; Q = quinidine; VF = ventricular fibrillation; V T = ventricular tachycardia.

and electrical management; therefore, immediate administration of intravenous disopyramide phosphate therapy was instituted on an emergency basis. Organic heart disease, present in all patients, included chronic coronary arte/,y disease (two patients), acute myocardial infarction (three patients) and congestive cardiomyopathy (two patients). All seven patients were hospitalized during a consecutive period within the 6 months preceding this report• They represent our total experience with the intravenous administration of disopyramide phosphate in the critical clinical setting of persistent refractory ventricular tachycardia or ventricular fibrillation, or both, unresponsive otherwise to the vigorous application of conventional medical treatment. Therapeutic failure of the standard antiarrhythmic medications was defined as follows: persistence of ventricular tachycardia or ventricular fibrillation despite (1) maximal doses of each of these antiarrhythmic agents, or (2) highest therapeutic serum concentrations of these agents; or (3) the development of idiosyncratic or dose-related adverse effects. Further, in all patients these standard agents were unsuccessfully used in multip!e appropriate combinations before administration of disopyramide. Metabolic and electrolyte abnormalities and drug toxicity, including digitalis toxicity, were excluded as causes of ventricular arrhythmias in all patients. Protocol: All patients were evaluated in the coronary care unit, and the ventricular origin of these refractory tachyarrhythmias was documented with standard electrocardiographic criteria utilizing continuously recording electrocardiographic systems (Hewlett-Packard 7800 series or American Optical trendscriber model 7030). Further, the response to intravenous administration of disopyramide phosphate Was also quantified by the real-time analysis of continuous electrocardiographic recordings (Avionics Electrocardiocorder model 445 or the American Optical Trendscriber) which were obtained for at least 4 hours after infusion of disopyramide phosphate.

Informed consent for intravenous administration of disopyramide phosphate was obtained voluntarily from all patients. In five patients a rapid intravenous bolus injection of 2 mg/kg body weight was given, on the average, over approximately 5 minutes, followed by a constant intravenous infusion of 20 to 40 rag/hour. In one of the five (Case 1), who had sustained ventrieular tachyarrhythmia at the onset of the study, the initial loading dose was given as a rapid bolus injection within 1 minute. Because the most recent pharmacokinetic data available concerning disopyramide u indicated that even larger loading doses are usually required to achieve sustained serum therapeutic concentrations (2 to 4 ug/ml), the final two patients (Cases 3 and 4) received a modified intravenous regimen sequentially: 2 mg/kg bolus injection over 8 minutes, 2 mg/kg over 52 minutes and 0.4 mg/kg over the second hour. Results Chronic Coronary Artery Disease

Case h A 69 year old man was hospitalized for increasing angina and congestive heart failure that developed 7 weeks after an uncomplicated acute anterior infarction. Despite symptomatic improvement and absence of further myocardial necrosis after hospitalization, he had 15 primary cardiac arrests (ventricular tachycardia or ventricular fibrillation) requiring resuscitation concurrent with maximal standard antiarrhythmic therapy (Table I). Emergency cardiac catheterization indicated a left ventricular end-diastolic pressure of 18 mm Hg, a cardiac index of 1.7 liters/min per/m 2, a dilated left ventricle with a large anteroapical aneurysm and severe proximal three vessel coronary arterial obstruction. Subsequently, during ventricular tachycardia, a 130 mg intravenous bolus injection of disopyramide resulted in conversion to sinus rhythm (Fig. 1), which was maintained with intravenous infusion of disopyramide, 35 mg/hour for 2 hour% and oral

June 1977

The American Journal of CARDIOLOGY

Volume 39

1029

DISOPYRAMIDE

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administration of disopyramide, 150 mg every 6 hours. Despite severe left ventricular dysfunctiqn the patient tolerated disopyramide well. After 3 days of oral administration of disopyramide without recurrent venticular tachycardia (continuous electrocardiographic monitoring revealed only unifocal premature ventricular contractions, average 20/hour), th.e patient underwent left ventricular aneurysmectomy with saphenous vein bypass graft to the left circumflex artery. Postoperatively there were no serious vent~icular arrhythraias and he was discharged without antiarrhythmic therapy. Case 2= A 54 year old man was hospitalized for recurrent intractable ventricular tachycardia. His complex medical history included (1) saphenous vein bypass to the right coronary artery because of two vessel coronary disease 3 years previously with postoperative inferior vena caval ligation for recurrent pulmonary emboli; (2) mitral t~nd tricuspid valve replacements for biventricular failure 2 years previously; (3) recurrent ventricular tachycardia for 2 years requiring multiple hospitalizations and electrical conversion. In addition t o medical therapy, prior m~successful efforts to control ventricular tachycardia included permanent endocardial pacemaker for overdrive suppression and bilateral cervical sympathectomy. During the current hospital!zation cardiac • catheterization reveialed normal ftmctioning prosthetic valves, marked left ventricular dysfunction (left ventricular enddiastolic pressure 25 mm Hg, cardiac index 2.1 liters/min per

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m2), a large anteroapical aneurysm (left ventricular ejection fraction 20 percent). The bypass graft was thrombosed with 100 percent obstruction of the native right coronary artery and diffuse disease of the left anterior descending coronary artery. Because of intractable ventricular tachycardia (Table I), disopyramide was administered: 154 mg bolus injection over 5 minutes (Fig. 2) followed by a constant infusion (40 rag/hour) over 2 hours. This regimen was well tolerated and abolished the ventricular tachycardia with only 30 unifocal premature ventricular contractions detected during the 2 hours. Subsequently, although oral administration of disopyramide, 250 mg every 6 hours, effectively suppressed ventricular tachyarrhythmias, this medication was reduced to 100 mg because of progressive congestive symptoms. The patient was discharged receiving this dosage with satisfactory control of serious ventricular tachyarrhythmias. Acute

Myocardial

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Case 3: A 75 year old man was hospitalized with an acute inferior myocardial infarction complicated on the 5th hospital day by primary ventricular fibrillation. After resuscitation there was no neurologic or further cardiac damage b u t he continued to have frequent premature ventricular contractions with another four episodes of ventricular tachycardia or ventricular fibrillation, or both, requiring electrical defibrillation despite use of standard antiarrhythmic agents (Table I). Intravenous infusion of disopyramide was then administered as follows: 170 mg in 8 minutes, 170 mg in 52 minutes and 30 mgPnour for 1 hotir. During the 2 hour evaluation of disopyramide therapy, only one'premat~re ventricular contraction occurred. This therapeutic efficacy was continued with 0ral administration of disopyramide (200 mg every 6 hours) with only 75 unff0cal premature ventricular contractions detected with serial 24 hour Holter monitoring. Oral and intravenous administration of disopyramide was well tolerated. Case 4: A 64 year old man was hospitalized with an acute anterior myocardial infarction that was complic.ated on the 10th day by recurrent intractable ventricular tachycardia and ventricular fibrillation despite standard antiarrhythmic

39

DISOPYRAMIDE PHOSPHATE FOR VENTRICULAR ARRHYTHMIA--VlSMARA El" AL_

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therapy (Table I) and pacemaker overdrive suppression. Cardiac catheterization revealed 90 percent diffuse stenosis of all major coronary arteries, a large left ventricular anteroapical aneurysm and depressed left ventricular hemodynamics (left ventricular end-diastolic pressure 22 mm Hg, cardiac index 2.2 liters/rain per m2). Emergency aneurysmectomy was also ineffective in contr.olling ventricular tachycardia and ventricular fibrillation, and 25 electrical shocks were required within a 10 hour postoperative period. Thus intravenous disopyramide was administered: 170 mg bolus injection over 8 minutes and 170 mg infusion over the next 52 minutes with dramatic termination of potentially lethal arrhythmias (Fig. 3). In the next hour 40 mg of disopyramide was infused intravenously and paroxysmal short runs (four to six beats) of ventricular tachycardia recurred. However, oral administration of disopyramide, 200 mg every 6 hours, satisfactorily prevented ventricular tachycardia or ventricular fibrillation for 9 hours. Subsequently, the patient died from staphylococcal septicemia and bilateral pseudomonas pneumonia. Case 5: A 61 year old man with diabetes requiring insulin and a remote inferior myocardial infarction was hospitalized for acute anterior infarction. In the first hour intractable ventricular tachyarrhythmias developed despite administration of standard antiarrhythmic agents (Table I) and he required resuscitation from 10 cardiac arrests in the ensuing 24 hours. During this period the following maximal serum drug levels were noted: quinidine 6.8/~g/ml, procainamide 8.5 pg/ml and lidocaine 5.9/~g/ml. Subsequently an intravenous bolus injection of 150 mg of disopyramide was given after electrical countershook for an episode of sustained ventricular tachycardia that was subsequently abolished (Fig. 4). The satisfactory therapeutic response to disopyramide persisted for the next 45 minutes with only occasional (average 2/min) unifocal premature ventricular contractions. However, progressive hypotension developed that became refractory to therapy and resuscitative measures. Death occurred 3 hours later from intractable cardiogenic shock. Postmortem examination revealed a healed inferior infarction with acute necrosis Ofmore than 50 percent of the left ventricular anterior wall. There was complete obstruction of both the left anterior descending vessel and a dominant right coronary artery,

Congestive Cardiomyopathy Case 6: A 49 year old man was hospitalized for treatment of asymptomatic paroxysmal ventricular tachycardia detected during examination in the cardiac outpatient clinic. Three years previoasly he had congestive heart failure from an idiopathic cardiomyopathy that responded to medical therapy.

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FIGURE 4. Case • 5. Continuous electrocardiographic monitoring record (A and B) demonstrating persistent ventrlcular tachycardis despite administration of Ildocaine, 100 mg intravenously, and requiring electrical countershock (CS). Recordings C through E, obtained several hours later, indicate the salutary response to Intravenous administration of disopyramlde, 150 mg, part of which was given during record C. D and E are continuous.

June 1977

The American Journal of CARDIOLOGY

Volume 39

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F I G U R E 5. Case 6. Continuous electrocardiographic monitoring records. A and B s h o w f r e q u e n t p r e m a t u r e v e n t r l c u l a r c o n t r a c t i o n s a n d p a r o x y s m a l v e n t r i c u l a r t a c h y c a r d i a 4 5 m i n u t e s after the final d o s e o f Ildoc a i n e , 3 0 0 m g i n t r a v e n o u s l y . In C a n d O ( r e c o r d i n g s n o t c o n t i n u o u s ) , d i s o p y r a m l d e , 170 mg i n t r a v e n o u s bolus injection (given 4 5 minutes a f t e r Ildocalne), p r o m p t l y t e r m i n a t e s ventricular tachycardia and m a r k e d l y d i m i n i s h e s the f r e q u e n c y o f p r e m a t u r e v e n t r i o u l a r c o n t r a c tions (E t h r o u g h G r e c o r d e d c o n t i n u o u s l y ) .

Subsequently, frequent multifocal premature ventricular contractions were unresponsive to orally administered procainamide, which was discontinued because of skin rash and arthritis. Diphenylhydantoin was also ineffective and quinidine was proscribed because of severe diarrhea. At the time •of the current hospitalization he was receiving propranolol, 40 mg every 6 hours, the last dose 3 hours before admission. Paroxysmal ventricular tachyeardia persisted after a total of 300 mg lidocaine was administered over 20 minutes as three injections of a 100 mg intravenous bolus dose; dizziness was induced by the last dose. Thus, 45 minutes after the last dose of lidocaine, disopyramide was administered intravenously: a 170 mg bolus dose over 5 minutes and then infusion, 35 rag/hour, for 2 hours (Fig. 5). Intravenously administered disopyramide demonstrated marked antiarrhythmic efficacy with only an occasional unifocal premature ventricular contraction (average l/rain) without ventricular tachycardia. Further, this therapeutic response was extended by oral administration of disopyramide, 300 mg every 6 hours. Subsequent cardiac catheterization confirmed the diagnosis of cardiomyopathy with diffuse left ventricular hypokinesia (left ventricular end-diastolic pressure 12 mm Hg, cardiac index 3.2 liters/rain per m 2) without valve dysfunction or coronary artery disease.

1032

Case 7 : A 78 year old man was hospitalized for congestive heart failure with pulmonary edema. Despite the resolution of heart failure with medical therapy, he manifested frequent multi/coal premature ventricular contractions and 10 episodes of paroxysmal ventricular tachycardia concurrent with standard antiarrhythmic therapy (Table I). During these arrhythmias serum drug levels included: digoxin 1.2 ng/ml, quinidine 5.1 ~g/ml and procainamide 6.2 ~g/ml. After this ineffective antiarrhythmic regimen disopyramide was administered: a 172 mg bolus dose intravenously over 5 minutes with 35 rag/hour infused intravenously for the next 2 hours and then 200 mg orally every 6 hours on a long-term basis. With both oral and intravenous administration of disopy. ramide, which was well tolerated, continuous electrocardiographic monitoring detected only a rare unifocal premature ventricular contraction (average 1/hour) and•established that ventrieular tachycardia was completely abolished with this antiarrhythmic agent.

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The American

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Discussion

Our data emphasize the potential therapeutic efficacy of d i s o p y r a m i d e p h o s p h a t e for the t r e a t m e n t of ventricular a r r h y t h m i a s . A l t h o u g h p r e v i o u s s~udies12.1,~ have n o t e d the efficacy of oral a d m i n i s t r a t i o n of this agent in suppressing v e n t r i c u l a r ectopy, the present s t u d y is u n i q u e in its evaluation of i n t r a v e n o u s adm i n i s t r a t i o n of the drug in p a t i e n t s w i t h life-threatening ventricular t a c h y a r r h y t h m i a s u n r e s p o n s i v e to extensive standard medical a n t i a r r h y t h m i c therapy, Thus, the p r o m p t and effective response o b s e r v e d n o t only indicates an i m p o r t a n t new t h e r a p e u t i c use f o r disop y r a m i d e p h o s p h a t e b u t also suggests t h a t it m a y provide an additional and distinctive m e c h a n i s m of ant i a r r h y t h m i c action for p a t i e n t s w i t h r e f r a c t o r y ventricular tachycardia. P r e v i o u s studies on a n t i a r r h y t h m i c e f f e c t s of d i s o p y r a m i d e : D i s o p y r a m i d e is a b u t y r a m i d e - t y p e . c o m p o u n d whose chemical s t r u c t u r e differs f r o m that of o t h e r a n t i a r r h y t h m i c agents. 14 Initial animal studies 15 established its a n t i a r r h y t h m i c properties a n d also indicated t h a t its efficacy p o t e n t i a l l y e x c e e d e d t h a t of s t a n d a r d a n t i a r r h y t h m i c agents. 15 In anesthetized dogs i6 d i s o p y r a m i d e p h o s p h a t e in similar oral or intravenous doses was two to three times more active than quinidine and four to five times m o r e p o t e n t t h a n procainamide in suppressing electrically or aconitineinduced atrial tachyarrhythmias. T h e same results were also d e m o n s t r a t e d in suppression of e x p e r i m e n t a l ventricular ectopic beats i n d u c e d in dogs by ouabain toxicity, catecholamine s t i m u l a t i o n or myocardial ischemia.15,16 T h e a n t i a r r h y t h m i c efficacy of d i s o p y r a m i d e in man has also been established. 17-19 E v a l u a t i o n with serial 10 h o u r portable electrocardiographic m o n i t o r i n g during a 16 week s t u d y with oral d i s o p y r a m i d e and placebo a d m i n i s t r a t i o n indicated not only a m a r k e d reduction with disopyramide t h e r a p y in cardiac e c t o p y in 59 p e r c e n t of patients, but also a r e d u c t i o n in the prevalence of complicated v e n t r i c u l a r ectopic beats (5 or more/rain, multi/coal, paired, R on T p h e n o m e n o n ) and ventricular tachycardia (58 a n d 7 p e r c e n t of patients, respectively). 11 In a study of 64 p a t i e n t s with organic

39

DISOPYRAMIDE PHOSPHATE FOR VENTRICULAR ARRHYTHMIA--VISMARA ET AL.

heart disease Mizgala and Huvelle 17 noted that intravenous infusion of disopyramide in doses of 2 mg/kg abolished premature ventricular contractions in 24 of 28 and ventricular tachycardia in 9 of 10 patients. More recent clinical investigationslS,19 have shown the prophylactic benefit of orally administered disopyramide in suppressing ventricular ectopy after acute myocardial infarction. In a randomized double-blind trial 19 disopyramide therapy resulted in significant reduction in complicated premature ventricular contractions (13 percent of patients) and ventricular tachycardia (5 percent of patients) in comparison (P <0.05) with the placebo-treated group (complicated premature ventricular contractions 33 percent of patients and ventricular tachycardia 26 percent of patients). Electrophysiologic properties of disopyramide: The results of electrophysiologic studies both in man and in animal preparations suggest that disopyramide is best classified as a type I antiarrhythmic agent because its actions include: (1) decreased rate of phase 4 depolarization; (2) diminished myocardial conduction velocity; and (3) prolonged effective and functional refractory periods in the atria, atrioventricular node and ventricles. 2°,21 Thus, these multiple actions on the myocardial ionic current indicate potential mechanisms for the suppression of tachyarrhythmias due to either reentry or enhanced automaticity. In this regard, the electrophysiologic effects of disopyramide are similar to those of quinidine. 22 Further, disopyramide and quinidine share other properties, including an anticholinergic action and absence of beta-receptor block.ade and neuromuscular and ganglionic inhibition. 1~,1s However, disopyramide potentially possesses additional antiarrhythmic properties, which may explain its efficacy of abolishing ventricular tachycardia refractory to quinidine therapy in our study. Recent investigations by Naylor 22 suggest that disopyramide may act on the myocardial cell membrane to inhibit partially the transcellular calcium influx normally occurring during phase 2 of the action potential. Another important possible mechanism of action is suggested by the local anesthetic activity of disopyramide, the potency of which approaches that of lidocaine. 2'~Thus, despite the current classification of disopyramide as a type I antiarrhythmic agent, further electrophysiologic evaluation of disopyramide is needed because our study has established that this agent can suppress life-threatening ventricular tachyarrhythmias refractory to all currently available antiarrhythmic drugs. Clinical effects: Another potential explanation for the salutary effects of disopyramide is that its antiarrhythmic properties were additive to the effects of the standard agents previously administered. Because of the potentially lethal clinical circumstances, sufficient delay to enable elimination of other agents was not possible. Nevertheless, it is emphasized that recurrent ventricular tachycardia, which was present for days to weeks in all patients, had previously been refractory to maximal doses of combinations of the standard an-

tiarrhythmic agents. Further, ventricular tachycardia was promptly terminated within minutes after the initial intravenous disopyramide bolus injection in all patients. Moreover, sustained suppression of ventricular tachycardia was achieved in four patients using longterm oral disopyramide administration as the sole antiarrhythmic measure, thereby providing additional evidence that disopyramide has potent unique actions in the sustained abolition of life-threatening ventricular ectopy. Potential adverse effects: Although our study and previous investigations 12,1~,25-27suggest that disopyramide possesses a favorable ratio between therapeutic efficacy and serious toxic manifestations, its potentially adverse effects merit careful consideration. This agent can depress myocardial contractile force and pump performance. In recent study 2v of 15 patients with chronic coronary artery disease undergoing left heart catheterization, bolus infusion of disopyramide, 2 mg/kg, resulted in a 13 percent elevation of left ventricular end-diastolic pressure and a 12 percent reduction in cardiac index. These hemodynamic alterations were most pronounced 5 to 10 minutes after disopryamide but returned to essentially control levels within 30 minutes. Similarly, Willis2s reported transient decreases of 18 percent in cardiac output and of 6 to ].2 percent in left ventricular rate of pressure rise after disopyramide. Thus disopyrarnide must be utilized cautiously in patients with depressed ventricular activity. Nevertheless, intravenous disopyramide was well tolerated in our seven patients, all of whom had congestive heart failure. Although possible cardiac depression by the agent could not be excluded with certainty in Patient 5 with acute myocardial infarction, it is likely that this patient's death was due to extensive myocardial necrosis. In addition, orally administered disopyramide was well tolerated in the four patients who received this agent for ]ong-tsrm suppression of arrhythmias. Before this agent was administered, all four of these men had congestive heart failure and two also had myocardial infarction. In one patient with extensive coronary heart disease and severely abnormal left ventricular dysfunction (Case 2), it was necessary to reduce the long-term dose of disopyramide because of probable worsening of pump function by the agent. Therefore, although disopyramide has a potentially negative inotropic effect, it appears that neither prior cardiac decompensation nor myocardial infarction is an absolute contraindication to its administration. The other side effects of disopyramide are primarily related to its anticholinergic effects. Thus, nausea, vomiting, retention of urine and blurred vision have occasionally been reported. Dryness of the eyes and mouth is frequent but mild in degree and readily tolerated; in our seven patients this side effect occurred transiently and subsided within 1 to 2 hours after completion of the drug infusion. The other anticholinergic actions were not observed. Although the precise incidence of side effects with disopyramide is currently

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The American Journal of CARDIOLOGY

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DISOPYRAMIDE PHOSPHATE FOR VENTRICULAR ARRHYTHMIA--VISMARA ET AL.

undergoing evaluation, a recent comparative study 13 reported that toxic reactions were both less severe and less frequent with disopyramide (9.6 percent) than with quinidine (35.5 percent). Disopyramide has fewer adverse effects on atrioventricular (A-V) conduction than quinidine, 28 and no increase in severity of preexisting A-V block has been observed. 2s The therapeutic plasma range of disopyramide is 2 to 4 gg/ml, is After intravenous administration, the drug is rapidly distributed from the blood with a half-time of 3 to 5 minutes and then eliminated from the body tissues with a half-time of 5 to 6 hours. 24 The agent is completely absorbed orally, with peak plasma levels obtained in 30 minutes to 3 hours and subsequently maintained for 3 to 4 additional hours. 24 Binding of disopyramide to plasma proteins is reported as 21 to 33 percent. Elimination of the agent is renal. 24 Implications: Although this study has established

that disopyramide is a potentially highly effective antiarrhythmic agent, use of the drug is currently re* stricted to investigational administration. Therefore the precise role of disopyrarnide in future clinical antiarrhythmic therapy and its scope of employment remain to be clarified. However, it now appears to offer a valuable and effective alternative to other antiarrhythmic agents, especially quinidine and procainamide, in the treatment of arrhythmias unresponsive to conventional therapy and in instances of toxic manifestations developing with standard antiarrhythmic agents. Acknowledgment We gratefully acknowledgethe support and cooperation of W. Scott Smith, MD and Daniel McDermott, PhD of SearIe Laboratories for their assistance and provision of disopyramide phosphate (Norpace);and the technical assistance of David Janzen, Nancy Carston and Leslie Silvernail.

References 1. Hlnkte LE, Mayer J, Stevens M, et ah Tape rec~dings of the'ECG of active men: limitations and advantages of the Holter.-AvIonics iqstruments. Circulation 36:752-765, 1967 2. Harrison DC, Fitzgerald JW, Winkle RA" Ambulatory electrocardiography for diagnosis and treatment of cardiac arrhythmlas. N Engl J Med 294:373-376, 1975 3. Vlsmara LA, DeMarla AN, Hughes JL, et ah Evaluation of arrhythmias In the late hospital phase of acute myocardial infarction compared to coronary care unit ectopy. Br Heart J 37:598-603, 1975 4. Vismara LA, Amsterdam EA, Mason DT: Relation of ventricular arrhythmlas in the latehospital phase of acute myocardial infarction to sudden death after hospital discharge. Am J Med 59:6-12, 1975 5. Vlsmara LA, DeMarlaAN, Amsterdam EA, et al: The suddendeath problem: evaluation of ventrlcular arrhythmias in coronary artery disease. In, Recent Advances in Heart Disease, Vol I (Mason DT, ed). New York, Grune & Stratton, in press 6. Kotler MN, Tabatznlk B, Mower MM, et at: Prognostic significance of ventrlcular ectopic ~ats with respect to sudden death in the late postlnfarction period. Circulation 47:959-966, 1973 7. DeMarla AN, Amsterdam EA, Vismara LA, et al: Arrhythmlas in the mltral valve prolapse syndrome: prevalehce, nature and frequency. Ann Intern Mad 84:656-660, 1976 8. Ingham RE, Rossen RM, Goodman DJ, et al. Ambulatory electrocardiographic monitoring in Idiopathic hypertrophic subaortic stenosis (abstr). Circulation 52:Suppl Ih11-93, 1975 9. Koch-Weser J: Antiarrhythmic prophylaxis in ambulatory patients with coronary heart disease. Arch Intern Med 129:763-770, 1972 10. Vismara LA, Miller RR, DaMarla AN, et ah The treatment of ventricular arrhythmias: evaluation of standard therapy and recent advances. Heart and Lung 5:485-492, 1976 11. Arzbaocher R, Collins S: An analysis of the pharmacokinetlcs profile of Norpace administered Intravenously in man. Report submitted to GD Searle, Chicago, March 1974 12. Vlsmara LA, Mason DT, Amsterdam EA: Dlsopyramlde phosphate: clinical efficacy of a new oral antiarrhythmic drug. Clin Pharmacol Ther 16:330-335, 1974 13. Danllo P Jr, Rosen MR: Cardiac effects of disopyramide. Am Heart J 92:532-536, 1976 14. Ranney RE, Dean RR, Karlm A, el el: Dlsopyramlde phosphate:

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15, 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

28. 29.

Volume 39

pharmacokinetlc and pharmacologic relationships of a new antlarrhythmic agent. Arch Int Pharmacodyn Ther 191;162-167, 1971 Mokler CM, Van Arman CG: Pharmacology of a new antlarrhythmic agent, 3,-dllsopropyl-amino-c~-phenyl-~-(2-pyrldyl)-butyramlde (SC-7031). J Pharmacol Exp Ther 136:114-117, 1962 Dean RR" The pharmacology of Norpace. Anglology 25:$uppl 1, Part 2:67, 1975 Mlzgala HF, Huvelle PR: Acute termination of cardiac arrhythmlas with intravenous dlsopyramlde, a new antlarrhythmlc agent. J Int Med Res 4:Suppl 1:6, 1976 Zalnal N: Dlsopyramide In the treatment and prevention of arrhythmias following myocardial infarction. J Int Med Res 4:Suppl 1:8, 1976 Besterman EMM: A double-blind study on the effect of oral dlaopyramide in the prophylaxis of arrhythmias following acute myocardial infarction. Br J Clin Pharmaool 2:186-189, 1975 Dean RR, Ferguson DM: Effects of disopyramide on the A-V conduction system. Arch Int Pharmacodyn Thor 190:183-186, 1971 Dreifus LS, Filip Z, Sexton DM, et ah Electrophysiologlcal and clinical effects of a new antlarrhythmic agent: disopyramlde (abstr). Am J Cardiol 31:129, 1973 Naylor WG: Pharmacology of dlsopyramide. In, Disopyramlde Symposium. London, Royal College of Physicians, 1975, p 1 Dean RR: Myocardial metabolism of disopyramlde. In Ref 22, p 20 Karlm A: The pharmacoklnetics of Norpace. Anglology 26:Suppl 1, Part 2:85, 1975 Jensen G: Haemodynamlc effects of intravenous dlsopyramldo in heart failure. Eur J Clin Pharmacol 8:167-171, 1975 Willis PW: The hemodynamic effects of Norpace. Angiology 26: Suppl 1, Part 2:102, 1975 Vlsmara LA, OeMarla AN, Miller RR, et ah Effects of intravenous disopyramide phosphate on cardiac function and peripheral circulation in ischemic heart disease (abstr). CIIn Res 23:87A, 1975 Mathur P: Cadlovascular effects of a newer antlarrhythmlo agent, disopyramlde phosphate. Am Heart J 84:764-770, 1972 Befeler B, Castellanos A Jr, Wells DE, et ah ElectrophysloJogtc effects of the antiarrhythmic agent disopyramlde phosphate. Am J Cardiol 35:282-287, 1975