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Antiarrhythmic drugs Part IV. Diphenylhydantoin in cardiac arrhythmias
Appraisal therapy
and reappraisal Edited by Arthur
C. DeGraff
Antiarrhythmic drugs Part IV. Diphenylhydantoin
of cardiac
and Alan F. Lyon
in cardiac
arrhythmias
Gerald C. Ruthen, M.D.* New York, N. Y.
D
iphenylhydantoin was introduced some 30 years ago for the control of epileptic seizures, but it was not until 1950, that it was suggested that it might also have some usefulness in the treatment of cardiac arrhythmias. Pharmacology. Diphenylhydantoin (Dia water-soluble powder lantin, (DPH), analogous in structure to the barbiturates, is available as lOO-mg. tablets and as a powder which can be dissolved for intravenous use. When administered orally, it is absorbed almost quantitatively from the gastrointestinal tract. It is metabolized in the liver by hydroxylation and subsequent conjugation with glucuronic acid, and is then excreted via the bile into the intestinal tract, from whence a small amount is excreted directly in the feces, but the greater part is reabsorbed into the blood and excreted in the urine. The rate of metabolism is such that after a single .intravenous dose there is an hourly decline of 10 per cent in the plasma level. After a single oral dose of 400 mg. of diphenylhydantoin, maximum levels in the blood (2 to 5 pg per milliliter) are achieved in approximately 8 hours, with a drop of 50 per cent in 18 to 24 hours. Chronic oral administration of diphenylhydantoin leads to plasma levels of 0.9 to 10.5 pg per milliliter in 6 to 13 days. The level is fairly constant in any given individual but varies widely from one patient to another. At all Received for publication April 20, 1965. *MedicaI Service and Cardiac Therapy Research Road, Bronx. N.Y.. 10468.
275
dosages, tissue concentrations are, in general, higher than plasma levels. Studies of the action of diphenylhydantoin on the cellular level have been generally oriented toward the central nervous system. In normal rats, DPH decreases the total, as well as the intracellular, concentrations of sodium in brain tissue. It also increases the rate of transport of Na** across the cell membrane in both directions. The decrease in intracellular sodium results in an increased ratio of extracellular to intracellular sodium concentration. The same changes occur in skeletal and cardiac muscle, but to a lesser degree. In addition, a direct correlation has been demonstrated between electroshock seizure threshold (EST) and the ratio of extracellular to intracellular sodium concentration; the potassium ratio demonstrates no such relationship. It seems likely that DPH acts to suppress or modify seizure activity by stimulating metabolic processes involved in the active extrusion of sodium from the cell, thereby raising the membrane threshold and decreasing the susceptibility to seizure activity. By inference, then, the same processes can be invoked as the mechanism of decreasing the excitability of myocardial tissue, thus interfering with arrhythmic activity. Interestingly, it has been found that the combination of DPH and desoxycorticosterone acetate (DCA) elevates the EST Unit,
Bronx
Veterans
Administration
Hospital,
130 West
Kingsbridge
276
Ruthen
even more that the sum of the effects of the two drugs given singly. It is postulated that the tendency of DPH to deplete the intracellular sodium, as well as the tendency of DCA to elevate the extracellular sodium, act to increase the ratio of extracellular to intracellular sodium concentration, thereby stabilizing the cell membrane at a higher threshold. Use in experimental arrhythmias. An early experimental study tested the premise that the area surrounding an acute myocardial infarction, the potential source of ectopic arrhythmias, being similar to the area of hyperexcitability surrounding an epileptogenic focus in the cerebrum, might be suppressed by DPH. By occlusion of a ramus of the left coronary artery in dogs, ventricular tachycardia could be predictably produced after a latent period of from 4% to 8 hours. It was noted that when intravenous DPH was given during the latent period, the frequency of ventricular premature contractions was markedly decreased, and that when ventricular tachycardia occurred, doses of DPH in the range of 12.5 to 200 mg. per kilogram produced rapid conversion of the tachycardia, which recurred after brief periods. Further doses of the drug produced prolonged suppression of the arrhythmia. Orally administered doses produced the same effect, but with a delay in the onset of action. The prevention of the onset of ventricular tachycardia in dogs made toxic with ouabain has also been reported. Dogs were given ouabain until the onset of ventricular tachycardia. While 10 per cent glucose showed no effect, DPH caused reversion to normal rhythm. Similar good results were obtained with procaine, procainamide, and quinidine, but the incidence of side effects and mortality was greater with these agents. Aconitine and delphinine, applied directly to the atria, produces atria1 flutter or fibrillation by increasing vagal tone. Although the effects of the two drugs may be abolished with atropine, or by the local application of cold, quinidine and other antiarrhythmic agents have generally been unsuccessful in the treatment of the arrhythmias so produced. When, in another study, a dose of DPH, 5 mg. per kilogram,
Am. He&J.
Augwt,
1965
was infused into dogs with flutter or fibrillation induced by aconitine and delphinine, the arrhythmia stopped abruptly in all of the dogs treated with aconitine, and in 6 of 8 of the dogs treated with delphinine. In the other 2 dogs the atria1 rate gradually slowed until regular sinus rhythm was resumed. In most cases the arrhythmia disappeared within 2 minutes, the shortest period of time being 10 seconds after the infusion of DPH. In all cases the arrhythmia recurred from 2 to 14 minutes after the single dose. Injections of DPH were repeated in the same animal up to five times, with the same result in each instance. No dilation or weakening of myocardial contractility was observed in these dogs. Clinical experience. In 1958, the successful clinical use of DPH for ventricular tachycardia was first reported in a woman who had received procainamide and quinidine without success. Procainamide was discontinued when the QRS group widened after the intravenous infusion of 2,300 mg. The patient was in extremis when 250 mg. of DPH was given intravenously. Within 2 minutes, a sinus mechanism with atria1 bigeminy was re-established and lasted for 20 minutes. The arrhythmia was successfully repressed with further doses at intervals of 4 to 6 hours. It was not until early 1965 that two large series describing the clinical use of diphenylhydantoin appeared. In one series, the drug was administered as initial therapy intravenously for acute arrhythmias. An initial dose of 250 mg. was given over a period of 1 to 3 minutes with electrocardiographic monitoring, and repeated every 5 to 10 minutes until an effect could be established. When there was a change toward normal, the patient was observed for recurrence of the arrhythmia, in which event additional doses were given. After the response was firmly established, the patient was placed on maintenance doses of 200 to 400 mg. orally daily, until resolution of the problem, or until other drug therapy was established. The cases described included 12 patients with arrhythmias suspected of being secondary to digitalis toxicity and 14 in whom there \vas no prior history of digitalis administration. Among the patients
Volume Number
70 2
with digitalis-induced arrhythmias, only 1 with atria1 flutter did not respond, whereas 2 with paroxysmal atria1 tachycardia, 1 with a complex atrioventricular rhythm, 1 with paroxysmal atria1 tachycardia (PAT) with wandering pacemaker, 2 with ventricular bigeminy, and 4 with multifocal ventricular premature contractions all responded promptly. In one of the patients with PAT the response was an increase in block rather than a reversion to sinus rhythm. Among the other patients, responses were achieved in 2 cases of atria1 tachycardia after cardioversion, 2 cases of ventricular bigeminy, 2 cases of multifocal ventricular premature contractions, and a single case of ventricular tachycardia. In 2 patients with atria1 flutter, 2 with atria1 fibrillation, 1 with ventricular bigeminy, and 1 with atria1 tachycardia secondary to severe electrolyte imbalance, there was no response. All responses occurred within 30 seconds to 4 minutes, or not at all. Duration of response varied from 5 minutes to 4 to 6 hours. A second series gives the results of the oral use of DPH in patients with recurrent arrhythmias who had had inadequate response to conventional modes of therapy. Conventional doses of oral DPH were used. Of 37 patients with frequent ventricular premature contractions, 26 maintained regular sinus rhythm for an average of 16.7 months, 7 had a significant decrease in the number of ventricular premature contractions, and 4 showed no response. Ten of 13 patients with paroxysmal atria1 tachycardia were maintained in regular sinus rhythm without evidence of recurrence for an average of 18 months, 2 had some decrease in the frequency of paroxysms, and 1 showed no response. All of 6 patients with atria1 fibrillation showed no recurrences for an average of 13 months. Two patients with frequent atria1 premature contractions and 1 patient with frequent A-V nodal premature contractions had no recurrences, for an average of 19 months in the first 2 patients and for 16 months in the other patient. One treated patient with atria1 flutter had no response. Both of these studies should be considered to be preliminary because there were no control cases, and comparison
Antiarrhythmic
drugs. Part IV
277
with other modes of treatment was largely inferential. They do suggest, however, that DPH may have some beneficial effect on cardiac arrhythmias. Toxicity. Original early studies on the toxic side effects of DPH in laboratory animals showed that large doses were tolerated and that no histologic changes were noted in animals receiving ten times the clinical dose for a period of 6 months. In early studies, large doses of DPH, or rapid injection intravenously, occasionally produced respiratory arrest, but with conventional doses, or when given over a few minutes, this is not a problem. The various toxic and hypersensitivity manifestations of DPH have been covered exhaustively in the literature, encompassing extensive numbers of patients on longterm therapy for neurological problems, and need not be repeated here. Among the patients treated for cardiac arrhythmias in the two series discussed above, toxic manifestations were as fohows: skin reactions varying from urticaria to purpura, drowsiness, depression or nervousness, arthralgias, gingival hypertrophy, and transient eosinophilia. Among those receiving the medication intravenously there was transient hypotension in 1 patient, and block with bradycardia in 1 patient. All responded to cessation of therapy and supportive measures. Conclusions. The electrophysiologic evidence that diphenylhydantoin stabilizes cell membranes, the controlled animal studies showing a favorable effect on some arrhythmias, and the preliminary clinical studies suggesting its effectiveness in the arrhythmias of patients warrant further controlled studies of the range and consistency of action of diphenylhydantoin and of its value in comparison to established treatment. Until these studies are done, it should probably not be used as initial therapy for any arrhythmia. In view of the drug’s relative safety, however, employment of it in clinical situations in which other drugs have been ineffective does not appear to be unreasonable at this time. REFERENCES 1.
Harris, A. S., and diphenylhydantoin
Kokernot, sodium
R. H.: (Dilantin
Effects of sodium)
278
2.
Am. Heart I. August, 1965
Ruthen
and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction, Am. J. Physioi. 163:505, 1950. Woodbury, D. M.: Effect of DPH on electrolytes and radiosodium turnover in brain and other tissues of normal, hyponatremic, and postictal rats, J. Pharmacol. & Exper. Therap. 115:74, 1955.
3.
4.
Bernstein, H., Gold, H., Lang, T. W., Pappelbaum, S., Bazika, V., and Corday, E.: Therapy of recurrent cardiac arrhythmias, J.A.M.A. 191:695, 1965. Conn, R. D.: Diphenylhydantoin sodium in cardiac arrhythmias, New England J. Med. 272:2X’, 196.5.
and reappraisal Edited by Arthur
C. DeGraff
Antiarrhythmic drugs Part IV. Diphenylhydantoin
of cardiac
and Alan F. Lyon
in cardiac
arrhythmias
Gerald C. Ruthen, M.D.* New York, N. Y.
D
iphenylhydantoin was introduced some 30 years ago for the control of epileptic seizures, but it was not until 1950, that it was suggested that it might also have some usefulness in the treatment of cardiac arrhythmias. Pharmacology. Diphenylhydantoin (Dia water-soluble powder lantin, (DPH), analogous in structure to the barbiturates, is available as lOO-mg. tablets and as a powder which can be dissolved for intravenous use. When administered orally, it is absorbed almost quantitatively from the gastrointestinal tract. It is metabolized in the liver by hydroxylation and subsequent conjugation with glucuronic acid, and is then excreted via the bile into the intestinal tract, from whence a small amount is excreted directly in the feces, but the greater part is reabsorbed into the blood and excreted in the urine. The rate of metabolism is such that after a single .intravenous dose there is an hourly decline of 10 per cent in the plasma level. After a single oral dose of 400 mg. of diphenylhydantoin, maximum levels in the blood (2 to 5 pg per milliliter) are achieved in approximately 8 hours, with a drop of 50 per cent in 18 to 24 hours. Chronic oral administration of diphenylhydantoin leads to plasma levels of 0.9 to 10.5 pg per milliliter in 6 to 13 days. The level is fairly constant in any given individual but varies widely from one patient to another. At all Received for publication April 20, 1965. *MedicaI Service and Cardiac Therapy Research Road, Bronx. N.Y.. 10468.
275
dosages, tissue concentrations are, in general, higher than plasma levels. Studies of the action of diphenylhydantoin on the cellular level have been generally oriented toward the central nervous system. In normal rats, DPH decreases the total, as well as the intracellular, concentrations of sodium in brain tissue. It also increases the rate of transport of Na** across the cell membrane in both directions. The decrease in intracellular sodium results in an increased ratio of extracellular to intracellular sodium concentration. The same changes occur in skeletal and cardiac muscle, but to a lesser degree. In addition, a direct correlation has been demonstrated between electroshock seizure threshold (EST) and the ratio of extracellular to intracellular sodium concentration; the potassium ratio demonstrates no such relationship. It seems likely that DPH acts to suppress or modify seizure activity by stimulating metabolic processes involved in the active extrusion of sodium from the cell, thereby raising the membrane threshold and decreasing the susceptibility to seizure activity. By inference, then, the same processes can be invoked as the mechanism of decreasing the excitability of myocardial tissue, thus interfering with arrhythmic activity. Interestingly, it has been found that the combination of DPH and desoxycorticosterone acetate (DCA) elevates the EST Unit,
Bronx
Veterans
Administration
Hospital,
130 West
Kingsbridge
276
Ruthen
even more that the sum of the effects of the two drugs given singly. It is postulated that the tendency of DPH to deplete the intracellular sodium, as well as the tendency of DCA to elevate the extracellular sodium, act to increase the ratio of extracellular to intracellular sodium concentration, thereby stabilizing the cell membrane at a higher threshold. Use in experimental arrhythmias. An early experimental study tested the premise that the area surrounding an acute myocardial infarction, the potential source of ectopic arrhythmias, being similar to the area of hyperexcitability surrounding an epileptogenic focus in the cerebrum, might be suppressed by DPH. By occlusion of a ramus of the left coronary artery in dogs, ventricular tachycardia could be predictably produced after a latent period of from 4% to 8 hours. It was noted that when intravenous DPH was given during the latent period, the frequency of ventricular premature contractions was markedly decreased, and that when ventricular tachycardia occurred, doses of DPH in the range of 12.5 to 200 mg. per kilogram produced rapid conversion of the tachycardia, which recurred after brief periods. Further doses of the drug produced prolonged suppression of the arrhythmia. Orally administered doses produced the same effect, but with a delay in the onset of action. The prevention of the onset of ventricular tachycardia in dogs made toxic with ouabain has also been reported. Dogs were given ouabain until the onset of ventricular tachycardia. While 10 per cent glucose showed no effect, DPH caused reversion to normal rhythm. Similar good results were obtained with procaine, procainamide, and quinidine, but the incidence of side effects and mortality was greater with these agents. Aconitine and delphinine, applied directly to the atria, produces atria1 flutter or fibrillation by increasing vagal tone. Although the effects of the two drugs may be abolished with atropine, or by the local application of cold, quinidine and other antiarrhythmic agents have generally been unsuccessful in the treatment of the arrhythmias so produced. When, in another study, a dose of DPH, 5 mg. per kilogram,
Am. He&J.
Augwt,
1965
was infused into dogs with flutter or fibrillation induced by aconitine and delphinine, the arrhythmia stopped abruptly in all of the dogs treated with aconitine, and in 6 of 8 of the dogs treated with delphinine. In the other 2 dogs the atria1 rate gradually slowed until regular sinus rhythm was resumed. In most cases the arrhythmia disappeared within 2 minutes, the shortest period of time being 10 seconds after the infusion of DPH. In all cases the arrhythmia recurred from 2 to 14 minutes after the single dose. Injections of DPH were repeated in the same animal up to five times, with the same result in each instance. No dilation or weakening of myocardial contractility was observed in these dogs. Clinical experience. In 1958, the successful clinical use of DPH for ventricular tachycardia was first reported in a woman who had received procainamide and quinidine without success. Procainamide was discontinued when the QRS group widened after the intravenous infusion of 2,300 mg. The patient was in extremis when 250 mg. of DPH was given intravenously. Within 2 minutes, a sinus mechanism with atria1 bigeminy was re-established and lasted for 20 minutes. The arrhythmia was successfully repressed with further doses at intervals of 4 to 6 hours. It was not until early 1965 that two large series describing the clinical use of diphenylhydantoin appeared. In one series, the drug was administered as initial therapy intravenously for acute arrhythmias. An initial dose of 250 mg. was given over a period of 1 to 3 minutes with electrocardiographic monitoring, and repeated every 5 to 10 minutes until an effect could be established. When there was a change toward normal, the patient was observed for recurrence of the arrhythmia, in which event additional doses were given. After the response was firmly established, the patient was placed on maintenance doses of 200 to 400 mg. orally daily, until resolution of the problem, or until other drug therapy was established. The cases described included 12 patients with arrhythmias suspected of being secondary to digitalis toxicity and 14 in whom there \vas no prior history of digitalis administration. Among the patients
Volume Number
70 2
with digitalis-induced arrhythmias, only 1 with atria1 flutter did not respond, whereas 2 with paroxysmal atria1 tachycardia, 1 with a complex atrioventricular rhythm, 1 with paroxysmal atria1 tachycardia (PAT) with wandering pacemaker, 2 with ventricular bigeminy, and 4 with multifocal ventricular premature contractions all responded promptly. In one of the patients with PAT the response was an increase in block rather than a reversion to sinus rhythm. Among the other patients, responses were achieved in 2 cases of atria1 tachycardia after cardioversion, 2 cases of ventricular bigeminy, 2 cases of multifocal ventricular premature contractions, and a single case of ventricular tachycardia. In 2 patients with atria1 flutter, 2 with atria1 fibrillation, 1 with ventricular bigeminy, and 1 with atria1 tachycardia secondary to severe electrolyte imbalance, there was no response. All responses occurred within 30 seconds to 4 minutes, or not at all. Duration of response varied from 5 minutes to 4 to 6 hours. A second series gives the results of the oral use of DPH in patients with recurrent arrhythmias who had had inadequate response to conventional modes of therapy. Conventional doses of oral DPH were used. Of 37 patients with frequent ventricular premature contractions, 26 maintained regular sinus rhythm for an average of 16.7 months, 7 had a significant decrease in the number of ventricular premature contractions, and 4 showed no response. Ten of 13 patients with paroxysmal atria1 tachycardia were maintained in regular sinus rhythm without evidence of recurrence for an average of 18 months, 2 had some decrease in the frequency of paroxysms, and 1 showed no response. All of 6 patients with atria1 fibrillation showed no recurrences for an average of 13 months. Two patients with frequent atria1 premature contractions and 1 patient with frequent A-V nodal premature contractions had no recurrences, for an average of 19 months in the first 2 patients and for 16 months in the other patient. One treated patient with atria1 flutter had no response. Both of these studies should be considered to be preliminary because there were no control cases, and comparison
Antiarrhythmic
drugs. Part IV
277
with other modes of treatment was largely inferential. They do suggest, however, that DPH may have some beneficial effect on cardiac arrhythmias. Toxicity. Original early studies on the toxic side effects of DPH in laboratory animals showed that large doses were tolerated and that no histologic changes were noted in animals receiving ten times the clinical dose for a period of 6 months. In early studies, large doses of DPH, or rapid injection intravenously, occasionally produced respiratory arrest, but with conventional doses, or when given over a few minutes, this is not a problem. The various toxic and hypersensitivity manifestations of DPH have been covered exhaustively in the literature, encompassing extensive numbers of patients on longterm therapy for neurological problems, and need not be repeated here. Among the patients treated for cardiac arrhythmias in the two series discussed above, toxic manifestations were as fohows: skin reactions varying from urticaria to purpura, drowsiness, depression or nervousness, arthralgias, gingival hypertrophy, and transient eosinophilia. Among those receiving the medication intravenously there was transient hypotension in 1 patient, and block with bradycardia in 1 patient. All responded to cessation of therapy and supportive measures. Conclusions. The electrophysiologic evidence that diphenylhydantoin stabilizes cell membranes, the controlled animal studies showing a favorable effect on some arrhythmias, and the preliminary clinical studies suggesting its effectiveness in the arrhythmias of patients warrant further controlled studies of the range and consistency of action of diphenylhydantoin and of its value in comparison to established treatment. Until these studies are done, it should probably not be used as initial therapy for any arrhythmia. In view of the drug’s relative safety, however, employment of it in clinical situations in which other drugs have been ineffective does not appear to be unreasonable at this time. REFERENCES 1.
Harris, A. S., and diphenylhydantoin
Kokernot, sodium
R. H.: (Dilantin
Effects of sodium)
278
2.
Am. Heart I. August, 1965
Ruthen
and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction, Am. J. Physioi. 163:505, 1950. Woodbury, D. M.: Effect of DPH on electrolytes and radiosodium turnover in brain and other tissues of normal, hyponatremic, and postictal rats, J. Pharmacol. & Exper. Therap. 115:74, 1955.
3.
4.
Bernstein, H., Gold, H., Lang, T. W., Pappelbaum, S., Bazika, V., and Corday, E.: Therapy of recurrent cardiac arrhythmias, J.A.M.A. 191:695, 1965. Conn, R. D.: Diphenylhydantoin sodium in cardiac arrhythmias, New England J. Med. 272:2X’, 196.5.