Effective termination of reentrant supraventricular tachycardia by single dose oral combination therapy with pindolol and verapamil

Effective termination of reentrant supraventricular tachycardia by single dose oral combination therapy with pindolol and verapamil We evaluated the efficacy of single oral dose combining 20 mg pindolol and 120 mg verapamil in termination of paroxysmal supraventricular tachycardia (SVT) in 12 patients with recurrent symptomatic tachycardia. All had electrically inducible SVT lasting longer than 30 minutes. Patients were administered placebo or crushed pindolol and verapamil on 2 consecutive days after tachycardia was electrically induced and allowed to sustain for 30 minutes. With placebo, SVT lasted 186 + 18 minutes (mean +- SEM); five patients converted spontaneously within 121 to 180 minutes. With pindolol and verapamil, g of 12 patients (responders) converted to sinus rhythm within 8 to 74 minutes. The mean duration of SVT in the nine responders was 28 f 8 minutes compared with 168 + 20 minutes on placebo (p < 0.001). Before termination, tachycardia rate on pindolol and verapamil slowed significantly from 182 +- 5 to 164 i 7/min (p < 0.05) compared with no significant change in the rate of SVT on placebo. The mean systolic blood pressure during tachycardia was 97 rt 5 mm Hg with placebo and 101 f 7 mm Hg with pindolol and verapamil. Serum levels of pindolol and verapamil obtained in seven patients at time of spontaneous termination of tachycardia were 66 f 13 and 56 + 14 rig/ml, respectively. The side effects with ptndolol and verapamil included lightheadedness in one patient and symptoms of rapid palpitations in three. A single oral dose of pindolol and verapamil is safe and effective in termination of acute paroxysmal SVT and may be the initial therapy of choice in selected patients. (AM HEART J 1986;112: 759.)

Jeffrey S. Rose, M.D., Anil Bhandari, M.D., Shahbudin H. Rahimtoola, M.B., F.R.C.P., and Delon Wu, M.D. Los Angeles, Calif., and Taipei, Taiwan

Patients with paroxysmal supraventricular tachycardia (SVT) (Bouveret’s syndrome)’ often engage in a variety of mechanical tricks designed to stimulate vagal efferent activity and interrupt their tachycardia. These activities, which might include direct pressure on the carotid sheath, dunking the head in iced water. assuming the yoga position and selfinduced vomiting, are usually uncomfortable and frequently unsuccessful. As an alternative, these patients must seek costly emergency parenteral treatment or attempt prophylaxis with daily maintenance therapy. Wood noted that “when attacks From the Section County/University Calif., and Puget Memorial Hospital,

of Cardiology, Department of Medicine, of Southern California Medical Center, Sound Cardiology Consultants, P.S., WA, Taipei, Taiwan.

Received accepted

for publication Oct. February 25, 1986.

Supported Research Institutes

in part by Grant No. GCRC Centers Program of the Division of Health, Bethesda, Md.

Reprint Section Angeles.

24, 1985;

revision

received

RR-43 from of Research

Los Angeles Los Angeles, Chang Gung Jan.

the General Resources,

requests: Anil K. Bhandari, M.D., Department of Cardiology, LAC-USC Medical Center, 2025 CA 90033.

1, 1986; Clinical National

of Medicine, Zonal Ave., Los

are infrequent and not disabling, maintenance therapy is not advised for all drugs may have undesirable effects on the patient’s health and well being.“* Iliescu and Sebastiani suggested that a single oral dose of quinidine might terminate these tachycardias; however, this idea was neglected for nearly 50 years largely because of inefficacy and potential toxicity. In 1980 Margolis et al. used single dose oral therapy for a variety of well tolerated supraventricular and ventricular arrhythmias in 32 patients and reported success in 24 as measured by a reduced need for hospitalization and drug prophylaxis.4 Their investigation was not systematic and did not take into account the likely possibility of spontaneous termination. Accordingly, we designed this study to evaluate a specific therapy for a specific arrhythmia and suggest that this approach may be the therapy of choice in selected patients with paroxysmal SVT. METHODS Patient selection. From July 1983 to June 1984, 37 patients with documented SVT were referred to the Clinical Electrophysiology Service of the Los Angeles 759

760

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Rose et al.

County-University of Southern California Medical Center for electrophysiologic stimulation studies, and they were screenedfor this study. Twelve fulfilled the following criteria: (I) a history of clinically recurrent and electrocardiographically documented sustained SVT, (2) tachycardia determined at the time of electrophysiology study to be atrioventricular or atrioventricular nodal reentrant, (3) reproducible initiation and termination of SVT by programmed atria1 or ventricular stimulation, (4) relative patient comfort during sustained SVT, and (5) informed consent for electrophysiologic and electropharmacologic evaluation. Patients were excluded if they had (1) any form of organic heart disease,(2) specific contraindications to beta-adrenergic blockade, and (3) tachycardia that would not sustain for longer than 30 minutes. Their agesranged between 19 and 68 years with a mean ageof 42 years. Four patients were men and eight were women.The duration of history of symptomatic SVT was 1 to 50 years with a mean of 18 years. The frequency of symptomatic episodesdefined as the median number of clinical events in the 6 months preceding study was3.5. Previous antiarrhythmic therapy that had failed to control SVT in these patients included digoxin in two patients, propranolol in two, verapamil in two and diltiazem in one patient. The remaining five patients had no history of receiving prior antiarrhythmic therapy. Electrophysiologic studies. All cardioactive drugs were discontinued for the equivalent of at least five times the drug half-life before study. A No. 6 F. quadripolar electrode catheter (USC1Model 5656,USC1Div. of C.R. Bard, Billerica, Mass.) was introduced by percutaneous technique into the right femoral vein, advanced to the right atrium, and positioned across the tricuspid valve. The proximal two electrodeswere usedfor His bundle recording and the distal two electrodes for right ventricular pacing. A secondNo. 7 French hexapolar electrode catheter (USCI Model 5675, USC1 Div. of C.R. Bard) was introduced into either a left antecubital vein by cutdown or into the left subclavian vein by percutaneoustechnique. This catheter was used to cannulate the coronary sinus, thus electrodeswere available for recording or pacing the coronary sinusand the right atrium, and alsofor mapping the atria1 activation sequenceduring induced episodesof supraventricular tachycardia. Multiple surface and intracardiac electrograms were simultaneously recorded on a multichannel oscilloscopicrecorder (Model VR-16, Electronics for Medicine Honeywell Inc., Pleasantville, N.Y.) at a paper speedof 100 mm/set. Stimuli approximately twice the diastolic threshold and 2 msecin duration were provided by a programmable digital stimulator (Bloom and Associates,Reading, Pa.). The study protocol included an initial electrophysiologic study for definition of mechanisms,modesof initiation, and termination, aswell asreproducibility of induction of sustained SVT. The diagnosis of atrioventricular nodal reentrance and atrioventricular reentrance were made according to previously describedcriteria.5 On completion of the diagnostic study, the quadripolar catheter was removed while the hexapolar catheter was withdrawn

American

Heart

1986 .tournat

from the coronary sinus,advanced to the right ventricular apex, and then secured for subsequent studies.” The proximal two electrodes were kept at the junction of the superior vena cava and the right atrium while the distal two electrodeswere available for ventricular pacing. Study design. The study was approved by the institutional human investigation committee. On the first day of the study, called the placebo day, an ambulatory electrocardiographic monitor was placed and SVT was induced by programmed stimulation 2 hours after a light breakfast. The patient wasobservedon bed rest in the coronary care unit. After tachycardia wasobservedto sustain for 30 minutes, the placebo wasgiven by mouth. The cuff blood pressureswith the patient in the supine position were recorded every 30 minutes. The tachycardia was observed until spontaneous termination occurred, tachycardia symptoms were intolerable to the patient, or 240 minutes had elapsed.If it wasnecessaryto terminate the tachycardia for the patient, this was done by programmed stimulation After an overnight rest, on the trial day, tachycardia was again induced 2 hours after breakfast and allowed to sustain. After 30 minutes, crushed tablets of verapamil, 120mg, and pindolol, 20 mg, were given asan oral powder with water. The patient wasthen observedin the coronary care unit. On the trial day, just ason the first study day, if the tachycardia persisted as long as 240 minutes, it was terminated for the patient by programmed stimulation. Serum for verapamil and pindolol assay was collected every 30 minutes for 150 minutes and at the time of conversion to sinus rhythm using an indwelling heparin lock. Assays for verapamil were performed using a high performance liquid chromatographic procedure (Bioscience Laboratories, Los Angeles, Calif.) and for pindolol usingreversephasehigh performance liquid chromatography followed by fluorescencedetection (Sandoz, Inc., East Hanover, N.J.; and Clinical Research Associates, New York, N.Y.).7,” Data analysis. The data are presentedas mean _t SEM as the index of dispersion. Statistical analyseswere done using the Student t test and analysis of variance. RESULTS

Electrophysiologic studies identified the mechanism of tachycardia as atrioventricular reentry and atrioventricular nodal reentry in six patients each. Of the six patients with atrioventricular reentry, two had manifest pre-excitation (Wolff-ParkinsonWhite syndrome) on the surface ECG while the remaining four patients used a concealed accessory pathway for atrioventricular reentry. As located and defined by intracardiac mapping techniques, three pathways were found to be left lateral, one left paraseptal, and two right lateral. Of the six patients with atrioventricular nodal reentry, five had the “usual” form (i.e., antegrade slow pathway conduction, retrograde fast pathway conduction) and one

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Number

4

Table

I. Responseof SVT to placebo and single oral dose of pindolol and verapamil ____ _I_-. Rate Duration Patient NC:.

Responders 1 2 :i 4 5 6 7 8 9 Mean (n = 9) Nonresponders 10 11 12 Mean (n = 12) SVT = Suprwentricular *p < 0.001. tp < 0.05.

Type of SVT

AVN AV AV AVN AVN AVN AV

AVN AVN

AV AV A\ t.achycardia;

Placebo (minutes)

of SVT V&P (minutes)

Placebo (beats/minute)

8 10 12 14 18 22 32 65 74 28 + SC

164 2 14 220 181 197 156 184 192 172 187 i 7

154 200 192 155 174 139 163 151 144 163 t St

210 210 210 186 + 18

145 180 198 81 k 28*

184 174 170 188 * 5

184 158 175 164 it 7+

nodal reentry;

patient had the “unusual” or incessant form of atrioventricular nodal reentrance (antegrade fast pathway conduction, retrograde slow pathway conduction). Incidental findings included the induction of nonsustained intra-atrial reentrant tachycardia in a patient with atrioventricular nodal reentrant tachycardia, and the presence of dual atrioventricular nodal pathways in another patient with atrioventricular reentrant tachycardia. Duration of SVT. Following induction of SVT on the placebo day, tachycardia continued for 216 f 18 minutes with a range of 145 to 240 minutes. Thus, the placebo period derived by subtracting the 30minute observation period was 186 it 18 minutes. With placebo, five of 12 patients had spontaneous termination of tachycardia within 115 to 180 minutes and seven patients required electrical termination of tachycardia after 210 minutes of observation (Table I). Single oral dose combination therapy with pindo101and verapamil was administered 30 minutes after the induction of tachycardia in each patient; thus, the duration of tachycardia was measured from the time of administration of medication to the termination of tachycardia. With pindolol and verapamil, nine of 12 patients had spontaneous termination of tachycardia to sinus rhythm. The mean duration of tachycardia before termination in these nine patients was 28 k 8 (range, 8 to 74) minutes compared with 168 +- 20 (range, 115 to 210) minutes in

~~--

V&P (beatslminutri

210 180 210 115 175 210 131 121 210 168 k 20

AVN = Atrioventricular

--.

of SVT immediately before termination

AV = atriwentricular

-__ reentry;

\’ = verapamil:

1’ = p!m’1111~l

the same patients on placebo (p < 0.001) (Fig. 1). Of the nine patients called responders, seven showed termination to sinus rhythm within 32 minutes, and two patients converted at 65 and 74 minutes, respectively (Table I). In the remaining three patients (nonresponders), SVT was terminated by programmed stimulation because of symptoms of palpitations after 145, 180, and 198 minutes of observation, respectively (Table I). Systematic electrical induction studies immediately following termination were performed in five of the nine patients who converted to sinus rhythm on pindolol and verapamil. None of the responders who were tested had inducible sustained tachycardia, although two had brief salvos of 3 to 5 echo beats. Rate of supraventricular tachycardia. The surface electrocardiographic morphology of the induced tachycardia was identical to that recorded at clinical presentation. Also, the mean rates of the tachycardia (beats per minute) induced on the placebo day (183 _+ 5) and drug trial day (182 t 6) were not significantly different from that rate during clinical episodes (184 k 6). At the time of intervention with placebo, the mean heart rate (180 I 5) was nearly identical to the heart rate before administration of pindolol and verapamil (182 k 5). After placebo, there was a slight increase in the heart rate of 188 -+ 5 bpm before spontaneous or electrical termination of tachycardia, but the change was not

Roseet al.

762

American

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DURATION

A 250-

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October, 1986 Heart Journal

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1. A, Duration of paroxysmal SVT (PSVT) in all 12 patients on placebocomparedwith an oral combination of pindolol and verapamil. B, Duration of PSVT in nine patients who respondedby converting to sinus rhythm on the oral combination of pindolol and verapamil compared with placebo. Fig.

statistically significant. With pindolol and verapamil, the tachycardia rate significantly slowed to 164 + 7 before termination (p < 0.05). The tachycardia rate was slower before termination in all nine spontaneous converters on pindolol and verapamil, whereas only one of the three nonresponders showed slowing of the tachycardia rate (Table I). Plasma verapamil and pindolol levels. In the nine responders to single oral dose combination therapy, the mean plasma pindolol concentration (rig/ml) was 95 +- 18 at 30 minutes, 121 f 22 at 60 minutes, 105 + 17 at 90 minutes, 78 _+ 13 at 120 minutes, and 75 rt 11 at 150 minutes. The mean plasma verapamil concentration (rig/ml) in these patients was 68 * 25 at 30 minutes, 110 + 36 at 60 minutes, 112 f 22 at 90 minutes, 90 + 16 at 120 minutes, and 76 f 15 at 150 minutes (Fig. 2). The plasma levels of pindolol and verapamil at time of tachycardia termination were available in seven of these nine patients and were 73 f 31 rig/ml and 64 & 37 rig/ml, respectively. In the three nonresponders to oral dose combination therapy, the mean plasma concentration of pindolol was 15 -t 5 at 30 minutes, 51 + 9 at 60 minutes, 49 +- 12 at 90 minutes, 79 + 41 at 120 minutes and 100 (one patient) at 150 minutes; these concentrations were not significantly different from their corresponding values in the nine responders. However, the mean plasma verapamil concentrations in the three nonresponders were 21 f 10 at 30 minutes, 27 + 5 at 60 minutes, 30 -+ 8 at 90 minutes, 29 + 9 at 120 minutes and 5 (one patient) at 150 minutes, and these concentrations were significantly lower compared with the corresponding values in the nine responders (p < 0.001).

2. Serum concentrations of verapamil in nine respondersand three nonrespondersto single oral dose combination therapy. Numbers adjacent to data points indicate number of patients. Fig.

Other observations before and after termination of WT. The sinus nodal recovery time was measured

during spontaneous or electrical termination of SVT in nine patients on the placebo day and ranged from 430 to 1160 msec with a mean of 826 + 75 msec. On the trial day sinus nodal recovery time in these patients ranged between 500 and 1850 with a mean of 1021 f 128 msec. These differences were not significant. Following tachycardia induction, blood pressure (millimeters of mercury) on placebo was 108/68 + 4/5 and was not significantly different from that seen on pindolol and verapamil (106/70 +- 4/4). At the time of intervention with placebo, blood pressure of 105/69 f 7/8 was similar to that with pindo101 and verapamil at 101/73 _+ 5/4. No significant change in the supine blood pressure was noted from the time of intervention to the time immediately before termination on either the placebo day (106/ 68 f 7/8) or the trial day (108/70 + 8/8). The mode of termination of tachycardia after single oral dose of pindolol and verapamil could be determined in all three responders with atrioventricular reentrant tachycardia and appeared to be due to antegrade block in the atrioventricular conduction system. In the remaining six responders with atrioventricular nodal reentrant tachycardia, the direction of block causing termination could not be determined using the surface ECG findings as retrograde atria1 activity was buried in the QRS complexes. Side effects. Other than the unpleasant sensation of tachycardia, the most common side effect was polyuria, seen in six patients. Following pindolol and

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verapamil, three patients (patients Nos. 10, 11, 12) complained of severe palpitations requiring electrical termination of their tachycardia, and none had any significant accompanying change in the supine blood pressure. Dizziness was reported by two patients on both days, but was not intolerable. Only one patient had mild lightheadedness on pindolol and verapamil, which resolved spontaneously without any intervention. In one patient atrioventricular nodal reentrant tachycardia terminated following a salvo of three ventricular premature beats, a mechanism known to be an effect of verapamil.g The ambulatory electrocardiographic tapes were further scanned following tachycardia termination for unexpected electrocardiographic findings. In two patients transient first degree atrioventricular block was seen; however, no sinus pauses, high grade atrioventricular block, or significant ventricular arrhythmias were noted. The sinus rate (beats per minute) following termination was 87 r 4 compared with 96 _?:9 before induction (p = NS). DISCUSSION

For most patients paroxysmal SVT occurs infrequently and is well tolerated. These patients often attempt self termination by vagal maneuverslo and, if unsuccessful, will seek emergency treatment with parenteral medications. ‘I. l2 Digitalis and proprano101 have not been systematically investigated in the acute termination of paroxysmal SVT. However, they are less likely to be effective, particularly in patients with atrioventricular reentry using an accessory pathway.‘“,14 Verapamil has been carefully and repeatedly studied and has been shown to be safe and effective when given intravenously.153 l6 It stands as the treatment of choice for the termination of acute episodes of paroxysmal SVT.lfi Pharmacokinetics and electrophysiologic properties of oral verapamil. Although several investigators have

demonstrated the effectiveness of maintenance oral prophylaxis with verapamil in preventing recurrent episodes of paroxysmal SVT,17mz0no study has evaluated the efficacy and safety of a single oral dose of verapamil in terminating acute attacks of SVT. The absorption kinetics of orally administered verapamil have been studied. Schomerus et a1.2* studied the pharmacokinetic disposition of 80 mg of 14C-D, L-verapamil dissolved in water and found that both 14C activity as well as verapamil plasma concentration peaked within 30 to 45 minutes while the terminal phase of each half-life was similar to that of the intravenous preparation. Koike et a1.22 found that after a 120 mg tablet was given by mouth, the serum verapamil level peaked at 1.25 to 2.28 hours and then declined. The explanation for this differ-

ence in the time of absorption of verapamil in the two studies is most likely the effect of the specific form (liquid versus tablet) of the oral preparation used. The electrophysiologic actions of orally administered verapamil have not been adequately studied. Schlepper et al.“” found that. after a single oral dose of 240 mg of verapamil the effects on the atrioventricular node were seen at 2 hours and peaked at 5 hours. On the other hand, Wu et al.“” found that after multiple oral doses of verapamil, the peak effect on atrioventricular nodal function was seen at 1 hour after the last dose and this effect correlated well with the plasma verapamil concentration. The discrepancy in the observed effect,s on atrioventricular nodal conduction between the two studies may be accounted for as follows. With a single large oral dose of verapamil, peripheral vasodilatation occurs resulting in slighi.. hypotension. This can be expected to reflexly augment sympathetic tone, which would overcome or delay the electrophysiologic activity of the medication. With multiple oral doses the reflex augmentation in sympathetic tone may be minimized as evidenced by the data of Wu et al. in which heart rate and blood pressure did not change. Clinical efficacy of single pamil and pindolol. Since

oral dose combining

vera-

the bioavailability of a single large dose verapamil is good when given in liquid form, its efficacy in termination of paroxysmal SVT might be expected to increase if one could overcome any reflex increase in the sympathetic activity. Therefore, in our study we combined verapamil with pindolol hoping that the beta-adrenergic blockade produced by a single oral dose of pindolol would overcome any reflex augmentation of sympathetic activity produced by the use of verapamil alone. Pindolol was chosen because of its excellent bioavailability when given by mouth. It is rapidly and almost completely absorbed within 30 minutes, and unlike propranolol there is little hepatic “first pass” metabolism of pindolol.“” ?I’ Also, multiple clinical studies have shown pindolol to be probably as efficacious as propranolol for the treatment of supraventricular arrhythmias.:.’ ‘* A possible concern regarding pindolol is related t,o its intrinsic sympathomimetic activity, which may counteract its hetablockade effects on the atrioventricular node; the available evidence, however, does not, support this concern.2”-Lx In this study, we demonstrated that a single oral dose combination therapy with pindolol(20 mg) and verapamil (120 mg) was effective in terminating acute attacks of SVT in 75% of the studied patients (nine of 12 patients). The majority of patients tolerated this combination well without major unto-

764

Rose et al.

ward effects. Conceivably, the lack of efficacy in the three nonresponders might have been due to the low plasma levels of verapamil achieved in them. Clinical implications and limitations. The study has important clinical implications. The current approach of emergency parenteral therapy for an acute attack of paroxysmal SVT usually requires a visit to a hospital emergency department or a physician’s office; with frequent episodes, such visits become both inconvenient and expensive for the patient. The chronic maintenance therapy with oral antiarrhythmic agents is not only expensive but also associated with significant side effects. The use of single dose oral combination therapy with verapamil and pindolol provides an alternative approach in the management of selected patients with recurrent paroxysmal SVT and may significantly reduce the need for hospitalization and drug prophylaxis. However, there were limitations to this study. All patients received pindolol and verapamil under close monitoring in the intensive care area and no patient was discharged on this combination therapy. One must, therefore, be cautious in extrapolating these results to the outpatient management of patients with paroxysmal SVT. Furthermore, no firm conclusion can be drawn regarding the exact efficacy of this therapy because the patient population was highly selected. Patients with paroxysmal SVT and impaired left ventricular function would be unsuitable candidates as this drug combination could result in further deterioration of the left ventricular function.2g Because both verapamil and pindolol impair atrioventricular nodal conduction, the combination of two drugs may be of potential hazard if used in patients with Wolff-ParkinsonWhite syndrome and atrial fibrillation, particularly if the effective refractory period of the antegrade conducting accessory pathway is relatively short or unknown. Finally, this study evaluated only one particular combination of pindolol and verapamil, and it may be that there are better combinations of other calcium channel blockers and beta-adrenergic antagonists that could be used in this fashion.

American

We gratefully acknowledge the secretarial assistance Dione Fosdick and Alice Madrid, and the cooperation house staff of the Los Angeles County General Hospital.

of Mrs. of the

REFERENCES

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15. 16.

17.

18.

CONCLUSION

We have shown that a single oral dose of pindolol and verapamil is relatively safe and effective in terminating acute attacks of reentrant SVT. In most patients the effect of these medications was rapid enough to make it an agreeable method for selftermination of the tachycardia. As the therapy of choice in selected patients with well tolerated SVT, this method may avoid the inconvenience, side effects, and expense of the other available treatment programs.

October, 1966 Heart Journal

19. 20.

21.

22.

23.

Bouveret L: De la tachycardie essentielle paroxystique. Rev Med Par 1889;1X:753. Wood PH: Diseases of the heart and circulation. Philadelphia: Lippincott, 1950:246. Iliescu CC, Sebastiani A: Notes on the effects of quinidine upon paroxysms of tachycardia. Heart 1923;10:223. Margolis B, DeSilva RA, Lown B: Episodic drug treatment in the management of paroxysmal arrhythmias. Am J Cardiol 1980;45:621. Wu D, Denes P, Amat-y-Leon F, Dhingra R, Wyndham CR, Bauernfeind R, Latif P, Rosen KM: Clinical, electrocardiographic, and electrophysiologic observations in patients with paroxysmal SVT. Am J Cardiol 1978;41:1045. Wu D, Amat-y-Leon F, Simpson R, et al: Electrophysiologic studies with multiple drugs in patients with atrioventricular reentrant tachycardia utilizing an extranodal pathway. Circulation 1977;56:727. Pacha WL: A method for the fluorometric determination of 4-(2-hgdroxy-3 isopropylaminopropoxy)-indole, a B blocking agent,in plasma and urine. Experientia 1969;25:802. Harauut SR. Kates RE: Hieh nerformance liauid chromatographic analysis of verapam% Ii simultaneous quantitation of verapamil and its active metabolite norverapamil. J Chromatogr 1980;181:484. Vohra -1. Peter T. Hunt D. Sloman G: Verauamil induced premature ventridular beats before reversion of SVT. Br Heart J 1974;36:1186. Waxman MB, Wald RW, Sharma AD, Huerta F, Cameron DA: Vagal techniques for termination of paroxysmal tachycardia. Am J Cardiol 1980;46:655. Frieden J, Cooper JA, Grossman JI: Continuous infusion of in treating supraventricular edrophonium (Tensilon) arrhythmias. Am J Cardiol 1971;27:294. Goldberger E: Treatment of cardiac emergencies. St. Louis: The CVMosby Co, 1982:86. Denes P. Cummines JM. Simuson R, et al: Effects of propranoiol on anoialous pathway refractoriness and circus movement tachycardias in patients with pre-excitation. Am J Cardiol 19’78;41:1061. Barrett PA, Jordan JL, Mandel WJ, Yamaguchi I, Laks MM: The electrophysiologic effects of intravenous propranolol in the Wolff-Parkinson-White syndrome. Am Heart d 1979;98:213-24. Krikler DM, Spurrell ARJ: Verapamil in the treatment of paroxysmal SVT. Postgrad Med J 1974;50:447. Sung RK, Elser B, McAllister RG Jr: Intravenous verapamil for termination of reentrant SVT. Ann Intern Med 1980;93:682. Mauritsdn DR, Winniford MD, Walker WS, Rude RE, Cary JR, Hillis LD: Oral verapamil for paroxysmal SVT. Ann Intern Med 1982;96:409. Pritchett ELC, Hammill SC, Reiter MJ, McCarthy EA, Zimmerman JM, Shand D: Life table methods for evaluating antiarrhythmic drug efficacy in patients with paroxysmal atria1 tachycardia. Am J Cardiol 1983;52:1007. Yeh S, Kou H, Lin F, Hung J, Wu D: Effects of oral diltiazem in paroxysmal SVT. Am J Cardiol 1983;52:271. Lie KI, Duren DR, MangerCats DV, David GK, Durrer D: Long term efficacy of verapamil in the treatment of paroxysmal SVTs. Am Heart J 1983;105:688. Schomerus M, Spiegelhalder B, Stieren B, Eichelbaum M: Physiologic disposition of verapamil in man. Cardiovas Res 1976;10:605. Koike Y, Shimamura K, Shudo I, Saito H: Pharmacokinetics of verapamil in man. Res Commun Chem Path01 Pharmacol 1979;24:37. Schlepper M, Thormann J, Schwarz F: The pharmacodynamits of orally taken verapamil and verapamil retard as judged

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by their negative dromotropic effects. Arzneim-Forsch 1975;25:1452. 94. Wu D. Kou H. Yeh S, Lin F. Huna J: Effects of oral verapamil in patients with atrioventricular reentrant tachycardia incorporating an accessory pathway. Circulation 1983;67:426. 25. Meier .h Pharmacokinetic comparison of pindolol with other agents. Am Heart J beta-adrenoceptor-blocking 1983;104:364. 26. Frishman WH: Pindolol: a new B-adrenoreceptor antagonist with partial agonist activity. N Engl J Med 1983;308:940.

27. Frishman WH, Davis R, Strom J, et al: Clinrcal pharmacology of the new beta-adrenergic blocking agents. Part 5. Pindolol (LB-46) therapy for supraventricular arrhythmia: a viable alternative to propranolol in patients wit.h hronchospasm. Am Heart J 1979;98:393. 28. Aronow WS, Uyeyama RR: Treatment. ol arrhythmias with pindolol. Clin Pharmacol Ther 1972:1X:15. 29. Packer M, Meller J, Medina N, et al: Hemodynamic consequences of combined beta-adrenergic and slow calcium channel blockade in man. Circulation l!X?:ti~?:~~A~i

Differential interaction of adrenergic cholinergic effects on AV junctional and AV conduction

and automaticity

The effects of postsynaptic autonomic interactions on atrioventricular (AV) junctional automattcity and AV conduction were studied in six canine heart in situ using direct injections of norepinephrine (NE) and physostigmine (PSM) into the AV node artery. injection of NE (0.05 ).rg/ml, 2 ml) caused an AV junctional rhythm (AVJR) in every dog. After injection of PSM (10 pg/ml, 2 ml), the responses of AVJR to NE were virtually identical to those observed before cholinesterase inhibition (160 + 13 vs 162 + 12 bpm). In contrast, this moderate cholinesterase inhibition still had a readily demonstrable negative dromotropic effect. In any given dog, depressed AV conduction was characterized by one of two types (I and II) of retrograde atrial capture during AVJR. Before PSM in the AV junction, onset of atrial depolarization during AVJR preceded the onset of ventricular depolarization in both type I and type II responses. After PSM, atrial depolarization occurred later with respect to ventricular depolarization (i.e., during or mostly after ventricular activation) in type I, whereas in the type II responses atrial depolarizations began much earlier than before PSM, thus being completed long before the onset of ventricular activation. Because of such differential responsiveness of AV junctional automaticity and AV conduction and because of the two types of intranodal conduction observed after administration of PSM into the AV junction, we can postulate that under appropriate autonomic imbalance retrograde or antegrade AV block could readily develop in spite of preserved AV junctional automaticity. (AM HEART J 1986;112:765.)

Ferdinand

Urthaler,

Birmingham,

M.D., Brett H. Neely, Ph.D., and Gilbert

R. Hageman,

Ph.D.

Ala.

Several studies have shown that autonomic modulation of heart rate is largely determined by a pronounced interaction between sympathetic and

From the Division of Cardiology, Department of Medicine, University of Alabama at Birmingham. This work was supported hy the National Institutes of Health, Bethesda, Md. (National Heart, Lung, and Blood Institute Grant No. 31536 and SCOR on lschemir Heart Disease Grant No. 5P50HL17667). Received for publication 0~1. 24, 1985; revision received Jan. 6, 1986; accepted Feb. 10, 1986. Reprint requests: Ferdinand Urthaler, M.D., Division of Cardiology, 340 Zeipkr, I)ept. of Medicine. I’niversity of Alabama at Birmingham. Birmmgham. AI. Xi294

parasympathetic effects. ls2 Whereas accentuated parasympathetic-sympathetic antagonism’ (i.e., increase in the inhibitory effect of a given vagal stimulus when prevailing sympathetic activity increases) is typical for the control of the sinus rate,‘” similar autonomic interactions appear to be either virtually absent4a5 or even opposite, with accentuated sympathetic-parasympathetic antagonism prevailing for the control of atrioventricular conduction.’ To date, there are no published st,udies concerned with the simultaneous assessment of autonomic interactions on AV junctional automaticity and AV 765