Effects on ventricular function of disopyramide, procainamide and quinidine as determined by radionuclide angiography

Effects on Ventricular Functionof Disopyramide, Procainamide and Quinidineas Determined by RadionuclideAngiography GERALD WISENBERG, MD, ANDREW G. ZAWADOWSKI,

MD,

VERNON A. GEBHARDT, MD, FRANK S. PRATO, PhD, MICHELE D. GODDARD, MD, PETER M. NICHOL, MD, PETER A. RECHNITZER, MD, and BRENDA GRYFE-BECKER, BSc Phm

To evaluate the effects of the 3 commonly used antiarrhythmic agents-disopyramide, procainamide and quinidine-on left ventricular (LV) function, these 3 agents were administered in random sequence after control radionuciide angiography performed at rest and during exercise in 17 patients. Drug dosages were tailored to achieve therapeutic blood levels 5 minutes before and 2 to 3 hours after drug administration. The mean dose of disopyramide was 141 f 26 mg every 6 hours, procainamide, 441 f 100 mg every 4 hours, and quinidine, 401 f 101 mg of the gluconate preparation every 6 hours. The patients received the appropriate dosage for 7 or more days before repeat radionuciide angiography was performed. The ejection fraction at rest was: control 60 f 13%, dlsopyramide 55 f 1 1%, procainamide 56 f 11% , and quinidine 59 f 12 %. The exercise ejection

fraction was: control 61 f 14%, disopyramide 56 f 13 % , procainamide 56 f 12 % and quinidine 61 f 13%. in neither case, at rest nor during exercise was there any significant difference observed between any of the agents or between any individual agent and control. However, at rest 6 subjects had a 5 % or more decrease from the control value with disopyramide, 5 had a 5% or more decrease with procainamide and 6 had a 5% or more decrease with quinidine, whereas during exercise the decreases were 8, 6 and 5 %, respectively. These values were not statistically different but suggest that caution should be taken in administering ail 3 agents, particularly to patients with impaired LV function, because individual sensittvity to a given agent may precipitate a significant decline in LV function. (Am J Cardioi 1984;53:1292-1297)

Since the addition of quinidine to the therapeutic armamentarium in the early 1950s it has been appreciated in the clinical setting that antiarrhythmic agents may have adverse effects on myocardial function, particularly in patients who have impaired left ventricular (LV) function before the institution of therapy. Although in recent years several new antiarrhythmic agents have been introduced, 3 agents remain the most

commonly used: quinidine, procainamide and disopyramide. Case reports have documented a serious negative inotropic effect of disopyramide therapy, in some cases leading to cardiogenic shock.1-3 There have been no similar case reports with regard to either quinidine or procainamide. Thus, it is believed that disopyramide has the most deleterious effect on ventricular function. Walsh and Horwitz4 compared the effect of i.v. disopyramide with that of i.v. quinidine in conscious dogs and found a potent negative inotropic effect with disopyramide that was not observed with quinidine, but no study has been performed comparing disopyramide, quinidine and procainamide in the same group of persons receiving routine clinical doses to achieve therapeutic concentrations. This study compares the effects of these 3 agents on LV function as monitored by radionuclide angiography.

From the Department of Medicine, St. Joseph’s Hospital, and University of Western Ontario, London, Ontario. This study was supported by grants from G. D. Searle & Co. of Canada, Limited, Oakville, Ontario, and the Ontario Heart Foundation, Toronto, Ontario, Canada. Manuscript received September 16, 1983; revised manuscript received January 9, 1984, accepted January 13, 1984. Address for reprints: Gerafd Wise&erg, MD, Department of Medicine, Division of Cardiology, St. Joseph’s Hospital, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada.

May I,1984

Met hods Patients: Patients were selected from those undergoing 24-hour ambulatory Holter monitoring for assessment of ventricular arrhythmias. Patients were asked to participate in the study if they manifested serious ventricular ectopic activity (Lown classification III or V), had markedly symptomatic ventricular ectopic activity (even in the absence of malignant forms) and were 3 or more months removed from an acute myocardial infarction. A history of episodes of heart failure and ongoing therapy with antifailure drugs were not considered criteria for exclusion as long as the patient was not in clinical heart failure at the time of entry into the study. Twenty-seven patients were thus entered into the study. However, because of noncardiac side effects, 9 patients could not complete the full protocol. Of the remaining 18 patients, 1 developed pulmonary edema within 24 hours of institution of disopyramide therapy and a radionuclide study was not obtained, although this subject tolerated both quinidine and procainamide well. The data on the remaining 17 patients were submitted for formal analysis. The 17 patients ranged in age from 34 to 73 years (mean 57 f 11) and consisted of 11 men and 6 women; 5 had had 1 or more myocardial infarctions. Six further patients had evidence of coronary artery disease without prior infarction, documented by typical angina and a positive stress test. Six patients had idiopathic ventricular ectopic activity. Two patients were receiving digoxin at the time of the study. All nonantiarrhythmic drugs were continued throughout the study without modification in dosage, including digoxin. Radionuclide angiography: In the postabsorptive state, after in vitro labeling of autologous red blood cells, radionuelide angiography was performed in the supine position. Images were acquired with a Picker 4/15 large field-of-view camera equipped with an all-purpose, parallel-hole collimator, and interfaced to a Digital Equipment Corporation PDP 11/34 computer. Images were acquired at rest and during graded ergometer exercise in all 17 patients using a protocol of 200 kg-m/min as the initial stage, with increases of 200 kg-m/min every 4 minutes to a symptom-limited maximum. No exercise study was terminated before the symptom-limited end point because of ventricular irritability. Exercise was performed to the same stage during the control study and all drug studies for each patient. Images at rest were acquired for a 4-minute period and the exercise images were acquired during the last 3 minutes of each 4-minute stage. The rest and maximal exercise data only were submitted to analysis. Routine gated equilibrium angiography was performed in the majority of patients in whom more than 95% of the beats observed were sinus beats. The software incorporated into the computer for this acquisition format calls for defining a baseline R-R interval before beginning acquisition, with confidence limits of 20% set around this predefined R-R interval. Thus, if an ectopic beat presented whose R-R interval did not fall within 20% of this, it, as well as the postextrasystolic beat, would not be included in data analysis. However, this method would have significantly reduced the number of beats included as a cohort for analysis during the respective periods of 4-minutes acquistion at rest and 3 minutes during exercise, in persons with frequent ventricular ectopic activity, and rendered any results thus obtained statistically suspect because of the low counts per image obtained. To circumvent this problem, in patients whose frequency of premature ventricular contractions was increased at the time of acquisition of the radionuclide angiogram, data were acquired in list mode directly onto disk with simultaneous recording of the physiologic marker, the QRS signal. Data were then reformatted by grouping together all cardiac cycles that had the same

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preceding R-R interval (as this affects end-diastolic volume) as the sinus rate. The data thus derived were separated into 16 frames, similar to the format used for the gated equilibrium studies, and ejection fraction (EF) was subsequently determined. Radionuclide angiograms were analyzed by 3 experienced observers blinded to patient identity, status of drug therapy and rest/exercise status, with the results derived by averaging. After g-point spatial and 3-point temporal smoothing and automated, interpolative background subtraction, EF was determined by manual assignment of LV regions of interest. This method has been shown in our laboratory to be superior to automated techniques in comparison with contrast angiography (r = 0.95 for manual method and 0.82 for the automated method). At rest and during exercise testing, heart rate and blood pressures were recorded (the latter determined by the cuff method) during the last minute of each stage, and continuous electrocardiographic recording of leads VJ, Vs and Vs was performed. Study protocol: The protocol is summarized in Figure 1. Each patient was administered all 3 agents in random sequence in a triple crossover design. Disopyramide was adminstered as disopyramide phosphate in capsules of 100 or 150 mg every 6 hours. Quinidine was administered as quinidine gluconate in tablets of 325 mg every 6 hours, which could be scored to provide half-tablet dosages, if necessary. Procainamide was administered as procainamide hydrochloride in capsules of 250 or 375 mg every 4 hours. Before initiation of any of the drugs, a control radionuclide angiogram was obtained. The patient was then randomly allocated to 1 of 6 possible drug sequences. The first drug in the

PRE-TREATMENT

24-HR. HOLTER MONITORING RADIONUCLIDE ANGIOGRAPHY

WITH

STRESS

TESTING

random t

I

I TREATMENT I

Treatment

allocation to treatment sequence

i 4 t

A

,

weekly serum level determinations

:

therapeutic

level

1 24-HR. HOLTER MONITORING RADIONUCLIDE ANGIOGRAPHY

one week changeover

I Treatment

to next

STRESS

TESTING

agent

B weekly serum level determinations

+

,

WITH

attained

4

therapeutic

24-HR. HOLTER MONITORING RADIONUCLIDE ANGIOGRAPHY

one week changeover

1 Treatment

level

WITH

to next

attained

STRESS

TESTING

agent

C 1

weekly serum level determinations

I therapeutic 1

level

attained

i 24-HR. HoLTER MONlTORING RADIONUCLIDE ANGIDGRAPHY

FIGURE 1. Study protocol.

WITH

STRESS

TESTING

1294

EFFECTS OF DISOPYRAMIDE,

TABLE I

PROCAINAMIDE

AND QUINIDINE ON VENTRICULAR

Individual Drug Doses and Serum Concentrations Quinidine

Disopyramide

Serum Concentration (pmol/liter) Case

Dose (mg)

Procainamide

Serum Concentration (pmol/liter) Dose

Before

325.0 487.5 325.0 487.5 487.5 487.5 487.5 325.0 325.0 325.0 325.0 325.0 325.0 650.0 325.0 325.0 487.5

After

(mg)

Before

After

7.8

6.9 10.2 6.9 7.5 6.0 9.3 6.0 12.6 6.0 7.5 a.4 7.8 6.6 7.5 6.7 6.2

a.4 12.3 11.1 9.3 6.8 11.1 9.6 6.9 15.3 9.3

7.7 1.7

814 13.3 9.0 6.5 9.9 6.8 9.6 7.1 6.8 9.9 6.2 a.7 6.5 6.6 a.4

6.8 10.0

150 150 150 150 200 150 100 100 150 150 150 100 150 150 100 150 150

a.2 7.8

10.1 2.5

141 26

9”fi

401 101

NAPA = N-acetyl procainamide;

TABLE II

FUNCTION

10.9 9.3 15.2 9.0 a.4

15.5 13.3 9.9 9.9 9.0 11.7 7.4 9.9 a.1

a.7

NAPA

Serum Concentration (I.Lmol/liter) Dose (mg)

Serum Concentration (~mollliter)

Before

After

Before

After

23.0 38.3 19.0 14.9 14.6 10.9 78.3 16.0 16.7 11.6

a.7

375 500 500

14.5 25.9 14.9 12.2 7.2 a.9 a.2 9.8 11.5 a.7 9.4 23.1 7.7 12.9 7.5 10.7 13.7

2::: 12.6 17.4 14.0 78.9 14.4

11.6 15.6 20.0 12.2 10.4 11.9 10.2 14.9 17.0 14.9 10.1 23.8 10.9 13.6 70.8 11.1 15.2

13.3 15.3 19.4 22.5 15.0 10.9 24.7 15.6 78.0 12.9 13.2 34.8 12.9 25.5 16.7 24.4 20.5

9.4 2.2

441 100

12.1 5.3

17.5 7.2

13.8 3.8

18.6 6.2

10.8

9.0 9.0

t.7 a:6

750 500 500 500 375 500 375 375 375 375 375 375 375

iii

SD = standard deviation.

Hemodynamic Effects of Disopyramide, Procainamlde and Quinldlne’ Heart Rate (beatsjmin) Rest

Control Disopyramide Procainamide Quinidine

66 66 68 69

f f f f

Exercise a 7 9 9

107 f 78 104 f 20 107 f 21 llOf20

Systolic Blood Pressure (mm Hg) Rest 127 129 124 122

f f f f

Exercise 13 11 15 10

161 158 157 159

f 20 f 16 f 21 f 17

Double Product (mm Hg/min X lo*) Best a4f a5f a4f a4f

77 13 16 14

Exercise 173 f 37 ::o”It’:z 778 f 45

Ejection Fraction (%) Best 60f 55f 5af 59f

13 11 77 12

Exercise 61 f 58 f 5af 61 f

14 13 12 13

Values are mean f standard deviation. No significant diferences were produced by any agent in any of the measurements, l

sequence was then administered in a dose estimated to produce therapeutic serum levels, both before and after administration. For the predose level, blood was drawn 5 minutes before the patient received his next tablet, and for the postdose level blood was drawn 2 hours after administration of procainamide and 3 hours after administration of both quinidine and disopyramide. Serum levels were defined as therapeutic for quinidine, 6.2 to 18.5 pmol/liter; disopyramide 6 to 18 pmol/liter; and procainamide 17 to 55 ~mol/liter of the combination of procainamide and its active metabolite, N-acetyl procainamide (NAPA). These assays were performed by the enzyme immunoassay technique.5 Blood samples were drawn at least 1 week after the initiation of therapy. If the serum levels before and after drug administration fell within the therapeutic range, radionuclide angiography was performed in the postabsorptive state, at the time interval after the previous dose at which the postdose serum levels had been drawn. If the dosage levels were not appropriate, the necessary adjustments in administered dosage were made, and repeat levels determined after an additional week. Radionuelide angiography was performed only when therapeutic serum concentrations of the antiarrhythmic agents were demonstrated. In addition to radionuclide angiography, repeat 24-hour Holter monitoring was performed. An agent was defined as being effective in controlling ventricular ectopy if it effected

a reduction of at least 85% of the total number of ventricular ectopic beats observed in the control 24-hour Holter study. The procedure was then repeated in sequence for each agent until the patient had received all 3 drugs. For the changeover period, the dosage of both the old and new agents were halved and administered concurrently to allow continuous antiarrhythmic protection. Statistical analysis: The results of heart rate, blood pressure, double product and EF were submitted to repeated measures analysis of variance to determine if there were any differences between the drugs and the control state and in addition to multiple regression analysis to determine if there were any differences between drugs. The frequency of 5% or more reduction in rest and exercise EF and the efficacy of ventricular arrhythmia suppression were compared by McNemar’s chi-square test.

Results Serum concentrations: The mean dose of quinidine administered was 401 f 101 mg every 6 hours, which achieved mean serum concentrations of 8.2 f 1.8 pmol/liter before and 10.1 f 2.5 pmollliter after administration. The mean dose of disopyramide was 141 f 26 mg every 6 hours, which achieved serum concentrations of 7.7 f 1.7 ~mol/liter before and 9.4 f 2.2 gmolfiter after administration. The mean dose of procainamide was 441 f 100 mg every 4 hours, which

May 1, 1984

TABLE III

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1295

Individual Ejection Fraction Results ( %) Rest

Case

P

Q

Control

53

50

49

56

;;

72 61

:s 68 64 43 59 69

::

48 f3:

D

Control

1

58

:

::

z66

4 5 6 B 9 10 11 12 13

43 72 ;: 45

40 59 z; 47

;: 67 42 59

:t :“5

l

5; 40 68

:;

::

42

i;f

16 17 Mean f SD

t

z

60f

:: 13

55f

t: 46

9: 11

58f

;: z

:: 68 67 ;:

65

62

3’:

;:

54 56 11

59f

:; 12

61 f

14

D = disopyramide; P = procainamide; 0 = quinidine; SD = standard deviation.

achieved serum concentrations of 12.1 f 5.3 pmol/liter of procainamide before and 17.5 f 7.2 pmol/liter after administration and 13.8 f 3.8 pmol/liter of NAPA before and 18.6 f 6.2 pmol/liter after administration. Individual doses and serum concentrations are presented in Table I. Hemodynamics: Mean values for hemodynamic parameters are presented in Table II and individual results in Table III and Figures 2 and 3. There were no significant differences observed in heart rate, systolic blood pressure, double product or EF, either at rest or during exercise between any of the drugs or any drug and the control state. However, both at rest and during exercise, the mean EF with disopyramide was the lowest of the 4 conditions: at rest EF was 55 f 11% with disopyramide vs 60 f 13% at control, 58 f 11% with procainamide and 59 f 12% with quinidine; during exercise, 58 f 13% with disopyramide vs 61 f 14% with control, 58 f 12% with procainamide and 61 f 13% with quinidine. At rest, 8 of 17 (47%) had 5% or more decline in EF from control to disopyramide vs 5 (29%) with procainamide and 6 (35%) with quinidine. There was no significant difference between these values. During exercise, 8 of 17 patients (47%) had 5% or more decrease in EF during disopyramide therapy, vs 6 (35%) during procainamide and 5 (29%) during quinidine therapy. Again, there was no significant difference between these values. Disopyramide produced the lowest EF in 9 patients at rest and 8 during exercise. The patient who developed pulmonary edema during disopyramide therapy and who was not included in the aforementioned results had a control EF at rest of 22%, vs 37% during procainamide and 21% during quinidine therapy. With exercise, the control EF was 17%, vs 24% during procainamide and 24% during quinindine therapy. This patient had had an extensive prior anterior myocardial infarction and was taking propranolol, 20 mg every 6 hours, at the time of entry into the study. Arrhythmia suppression: Ten of 17 patients (59%) had at least an 85% reduction in the number of ventricular ectopic beats per 24 hours compared to the control state on disopyramide vs 5 patients (29%) during

procainamide therapy (p <0.05), and 9 (53%) during quinidine therapy (p <0.05 vs procainamide). Discussion Antiarrhythmic agents have been available since the mid-1920s, and since then there has been ongoing clinical suspicion that some of these agents may induce depression of myocardial contractility of clinical significance. In vitro studies of quinidine have shown negative,7,8 positivelO or varying6,g inotropic effects, depending on drug dosage and timing of measurements after drug administration. Further, in vivo animal and human studiesll-ls have also yielded conflicting results. These divergent results may be due, in part, to the peripheral vasodilating effects of quinidine,lT-19 which will produce changes in volume-related indexes of ventricular function without affecting contractility as such. The majority of studies of disopyramide have suggested a negative inotropic effect. Mathur20 demonstrated a dose-dependent impairment in LV function after i.v. administration, with an accompanying increase in systemic vascular resistance. Other studies have suggested, however, that the duration of this effect may be relatively short-lived with noticeable improvement occurring 25 minutes after injection2’ or at 120 minutes,22 despite similar drug concentrations existing at the time of each measurement. Gottdiener et al23 demonstrated a significant negative inotropic effect after a single oral 300-mg dose. However, no effect was noted with chronic therapy of 150 mg every 6 hours, although serum levels were slightly lower with the latter regimen.23 Sutton24 reported that a differential response occurred depending on baseline EF, with no change in LV function if the EF was 50% or more. This finding is supported by the work of Podrid et a1,2who, in a series of 100 patients, found that 55% of those with prior cardiac decompensation had heart failure apparently induced by disopyramide vs only 3% having heart failure without such a history. In comparative studies of antiarrhythmic agents, Angelakos and Hastings I1 found that both quinidine

1296

EFFECTS OF DISOPYRAMIDE,

PROCAINAMIDE

AND QUINIDINE ON VENTRICULAR

and procainamide depressed LV function equally, although at doses higher than would be used clinically. Hammermeister et al25 found that dilantin, lidocaine and propranolol all produced more serious adverse effects than either quinidine or procainamide. Mathur20 and Walsh and Horwitz* both found that quinidine produced significantly less myocardial depression in dogs than disopyramide, and Cathcart-Rake et a126reported a consistently greater decline in EF in patients receiving disopyramide, 200 mg every 6 hours, vs those receiving propranolol, 80 mg every 8 hours. However, until the present study, no investigation has compared the effected of all 3 commonly used agents, quinidine, procainamide and disopyramide, in the same patients, with tailoring of drug dosages to achieve therapeutic concentrations. No significant differences were observed to occur in any hemodynamic variable. However, these 17 subjects can be considered to have normal or only moderately impaired LV function, with the lowest control rest EF being 41%. Patient 18, not included in data analysis, who had a control EF at rest of 22%, developed pulmonary edema during disopyr-

FUNCTION

amide therapy, but tolerated both quinidine and procainamide well. Futhermore, disopyramide produced the lowest mean EF of the 3 agents at rest and during exercise, and caused the largest number of subjects to have a 5% or more decrease in EF. The lack of statistical significance demonstrated may represent a p error caused by the limited total sample size and the lack of subjects with severely compromised LV function (EF <30%). Furthermore, the use of EF as an index of ventricular function is open to criticism because peripheral effects of these agents could cancel out any direct effects on contractility, producing little to no change in EF. However, the radionuclide angiographic method is convenient and practical to use in this ambulatory group and should be sensitive for clinically significant changes in LV function. With disopyramide, Patient 5 had a 13%decrease in EF from the control state at rest and a 21% decrease in EF during exercise; procainamide and quinidine both produced much smaller decreases of 4 and 5%, respectively, at rest, and 7 and 8% during exercise. Patient 15,

70 -

60-e

8

8

01

I

CONTROL

1

0

I

D

1

P

t

1

P

a

FIGURE 2. Responses of ejection fraction (EF) at rest to disopyramide (D), procainamide (P) and quinidine (a). The drugs were administered in random sequence after the control study.

FIGURE 3. Responses of exercise ejection fraction (EF). Abbreviations as in Figure 2.

01

1

CONTROL

I

D

I

D

I

P

I

P

May I. 1984

however, had a 30% decrease in EF while taking procainamide and a 25% decrease in EF during quinidine therapy at rest; EF decreased insignificantly (2%) with disopyramide, and during exercise the respective values were 17,16 and 4%. These 2 patients demonstrate that significant negative inotropic effects may occur with all 3 agents, depending on individual sensitivity. The data in the entire group suggests, however, that this may occur more frequently with disopyramide than with the other 2 agents. Thus, there is the potential for serious adverse effects on LV function with all agents, although clinically significant effects would be unlikely in most patients with normal or moderately impaired function. However, all 3 agents, particularly disopyramide, should be used with extreme function.

caution

in patients

with

severely

impaired

Acknowledgment: We gratefully acknowledge the expert technical assistance of Karon Mitton and the secretarial assistance of Madeleine Brucher.

References 1. Story JR, Abdulle AM, Frsnk MJ. Cardiogenic shock and disopyramide ohosphate. JAMA 1979:242:654-655. 2. Pod& PJ, S&emw&& A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614-617. 3. De& JM. !SdMwnan MM, Herechfekl D, Gonzalez R, Peters RW. Cardiovascular collapse associated with disopyramide therapy. Chest 1981; 79:545-551. 4. Wafsft RA, Horwb LD. Adverse hemodynamic effects of intravenous disopyramkfe compared with quinidine in conscious dogs. Circulation 1979;60:1053-1058. 5. Walberg CB, Won SH. Clinical evaluation of the EMIT procainamide and N-acetylprocainamide assay. Ther Drug Monit 1979;1:47-56. 6. Kruta V, Braveny P, Hfavkova-Stejskabva J. Resltiiion de la contractilite du myocarde et effets inotropas ouabaine. quinkfine. tyramine, theophilline et a&ylcholine chez la labaye et le rat. Crapta Medll Facultatum Medicina Universitatum Buinensis et Olomlcenses 1963;36: i-26. 7. Tomeda H, Chuck L, Parmley WW. Comparative myocardial depressant

a. 9.

10. 11. 12. 13. 14. 15. 16.

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effects of lidocaine, ajamline, propranolol, and quinidine. Jpn Circ J 1972;36:433-437. Hemori N, Taira N. Effects of quinidine on blood flow rate and developed tension in blood perfused canine papillary muscle. Clin Exp Pharmacol Physiol 1976;3:1-7. Chlba S. Effects of quinidine, procainamide, lidocaine and phenytoin on inotropic responses to acetylcholine and norepinephrine. Jpn J Pharmacol 1976;26:276-278. Kennedy BJ, West JC. Factors influencing quinidine-induced changes in excitability and contractility. J Pharmacol Exp Ther 1969;197:452-457. Angelakos ET, Hastings EP. Tha influence of quinidineand procaine amide on myocardial contractility in vivo. Am J Cardiol 1960;6:791-798. Prultt JK, Woods EF. The relationship of intracellular depolarization rates and contractility in tha dog ventricle in situ: effects of positive and negative inotropic agents. J Pharmacol Exp Ther 1967;257:1-7. Marklewlcz W, Winkle R, Benetti G, Kernoff R, Harrison DC. Normal myocardial contractile state in the presence of quinidine. Circulation 1976:53:101-106. Stern S. Hemodynamic changes following separate and combined administration of beta-blocking drugs and quinidine. Eur J Clin Invest 197I;l: 432-436. Sokolow M. The present status of therapy of the cardiac arrhythmias with quinidine. Am Heart J 1951;42:771-797. Samet JM, Surawl,cz B. Cardia! function in,patients treated with phenoFtazines. Comparison with quinidine. J Clan Pharmacol 1974;14:556-

_--.

17. Ferrer MJ, Harvey M, Warko L, Dresdale DJ, Cournand A, Richards DW. Some effects of quinidine sulfate on the hear-l and circulation in man. Am Heart J 1948;36:816-837. la. Mason JW, Winkle RA, lngels MB, Daughers GJ, Harrison DC, Stkwon EB. Hemodynamic effects of intravenously adminstered quinidine on the transplanted human heart. Am J Cardiol 1977;40:99-104. 19. Schmld PG, H&on LD, Mark AL. Inhibitionof adrenergic vasoconstriction by quinidine. J Pharmacol Exp Ther 1974; 188: 124- 134. 20. Mathur PP. Cardiovascular effects of a newer antiarrhythmic agent, Disopyramide phosphate. Am Heart J 1972;84:764-770. 21. Jensen 0, Slgurd B, Unhrenholt A. Circulatory effects of intravenous disopyramide in heart failure. J Int Mad Res 1976;4:suppl 1:42-45. 22. Polllck C, Glacomlni KM, Blasckke TF, Nelson WL, Turner-Tamlyasu K, B&ken U, Popp RL. The cardiac effects of d- and Idisopyramide in normal subjects: a noninvasive study. Circulation 1982;66:447-453. 23. Gottdlener JS, Dlblanco R, Bates R, Sauerbrunn BJ, Fletcher RD. Effects of disopyramide on left ventricular function: assessment by radionuclide cineangiography. Am J Cardiol 1983;51: 1554-1558. 24. Sutton R. Hemodynamics of intravenous disopyramide. J Int Med Res 1976;4:suppl 1:46-48. 25. Hammermetster KE, Boerth RC, Warbases JR. Tha comparative inotropic effects of six clinically used anti-arrhythmic agents. Am Heart J 1972;84: 643-652. 26. Carthcart-Rake WF, Coker JE, Atkins FL, Huffman DH, Hassaneln KM, Shen DD, Azarnoff DL. The effect of concurrent oral administration of propranololand disopyramldaon cardllc function in healthy men. Circulation 1980;61:938-945,