- Email: [email protected]
Current status of diphenylhydantoin
Appraisal therapy
Current
status
and reappraisal Edited
by
Arthur
C. DeGraff
of cardiac and
Alan
F. Lyon
of diphenylhydantoin
Leonard S. Dreilfus, l4.D. Yoshio Watanabe, M.D. Philadel$hia, Pa.
iphenylhydantoin (DPH) has been in clinical use for more than twenty years. However, its precise role in the treatment of heart disease is still unsettled. Several clinical reports as early as 1939 suggested that DPH may exhibit effects on the heart.r In 1943, Scherf* was able to demonstrate changes in the electrocardiogram after the intravenous administration of DPH, while other investigators had already demonstrated bradycardia, ventricular premature beats, congestive heart failure, cardiac standstill, and death attributable to DPH administration.le5 Harris and Kokernot6 reasoned that the substances initiating the discharge of impulses in the area of a myocardial infarction may be similar to some fundamental property of the excitatory factors which produce epileptogenic spike discharges in boundary zones about posttraumatic cortical scars and certain other cerebral lesions. The results of these investigators demonstrating the survival of dogs through the initial period following occlusion of the anterior descending ramus of the left coronary artery suggested that DPH possessed but transient antiarrhythmic properties. More extensive studies by Mosey and Tyler’ established the effectiveFrom
the Division Philadelphia, Supported by the Reprint requests Broad Street,
Vol.
SO, No.
5, pp. 709-713
ness of this agent in abolishing ventricular tachycardia resulting from ouabain overdosage. Similar results in the presence of aconitine-induced atria1 fibrillation and flutter were obtained by Scherf.* However, most of these investigators emphasized the transient effect of this agent (2 to 30 minutes) and indicated that the short duration may preclude its clinical effectiveness. While these experimental observations and a pertinen-t clinical note by Leonard9 suggested that this agent may have potent antiarrhythmic effects, little clinical interest matured until the early 1960’s. The extensive clinical experience with this agent was summarizeId by Mercer and OsbornelO in 1967. Although DPH still appears to have only limited value in the therapy of cardiac arrhythmias, its unique electrophysiologic properties render it extremely useful as a pharmacologic tool. It now appears that antiarrhythmic agents can be generally classified into two groups according to their predominant electrophysiologic effects on automaticity and conduction. Agents such as quinidine, procaineamide, and propranolol depress automaticity and conduction and comprise the first group (Grow 11, while lidocaine, DPH, and
of Cardiology and the Department of Physiology and Biophysics, Pa. National Institutes of Health Grant HE 11281. to: Leonard S. Dreifus, M.D., Division of Cardiology, Hahnemann Philadelphia, Pa. 19102.
November,
1970
Hahnemann
Medical
Medical
College,
American Keart Journal
College,
230 North
709
bretylium depress automaticity but enhance conduction and are representative of a second group (Group 2).i1,12 This review will emphasize the present clinical status of DPH as well as recent electrophysiologic studies on DPH identifying the possible antiarrhythmic mechanisms of this agent. Pharmacology
DPH was introduced for the treatment of convulsive disorders by Merritt and Putnam.i3 This agent has gained wide acceptance for seizure therapy during the past twenty years. DPH is one of the most potent of all the antiepileptic drugs in its ability to modify the character of maximal (tonic-clonic) electroshock convulsions elicited in animals by supramaximal currents. Furthermore, DPH exerts antiepileptic activity without causing general depression of the central nervous system. The action of this agent on peripheral nerves is such as to stabilize the neuronal membrane and to decrease the intracellular content of sodium.‘j It is possible that the mechanism of action of certain antiepileptic drugs on heart muscle and nerve tissue is basically similar. Both anticholinergic and cholinergic actions have been described by different investigators mainly on the basis of the effects of DPH on” heart rate and atrioventricular conduction.l3-l7 There is some evidence for a direct central nervous system site of action of DPH. Hence, if in truth some cardiac arrhythmias are central in origin, this agent may successfully terminate such arrhythmias by its specific effects on the central nervous system. However, Lang and co-workers l8 failed to find a direct effect of this agent in the inhibition of arrhythmias when DPH was administered into the cerebral circulation. DPH produces a negative inotropic effect on the left ventricle which is similar to quinidine although its duration appears more transient.l$ Furthermore, these authors found that the left ventricular end-diastolic pressure (LVEDP) increased and dp/dt decreased. These effects were similar in both vagotomized and propranolol-blocked dogs. Administration of higher doses beyond 5 to 10 mg. per kilogram of body weight and subsequent injections further aggravate these
negative inotropic actions of this drug. Sowever, clinical studies by Conn, Kennedy, and Blackmon16 and Childress and associateszO indicate that DPH only transiently depresses left ventricular function.
Several diverse conclusions regarding the electrophysiologic effects of DPH on both the specialized and working myocardial cells have appeared in the literature within recent years. Group 1 drugs such as quinidine, propranolol, and procainamide can be contrasted to Group 2 drugs such as DPH, bretylium, and lidocaine, Bigger and coworkers2i demonstrated that DPH enhanced the rate of rise of phase 0 (dV/dtj of the action potential in canine Purkinje fibers. The duration of the transmembrane action potential shortened due to abbreviation of all phases of repolarization. The effective refractory period also shortened during exposure to DPH, but to a lesser extent than the action potential duration. Hence, the net effect was to relatively increase the refractory period. The earliest effective test stimulus propagated with a greater amplitude and dV/dt of phase 0 than under control conditions. Furthermore, DPH depressed the automaticity of Purkinje fibers by decreasing the slope of phase 4 depolarization. It should be pointed out that these effects were obtained in the rissue bath with concentrations of DPH irom 10T8 to IO+ moles. It would appear that the work of Helfant and associatesz2 and Scherlag and co-workersz3 using 5 mg. per kilogram intravenously confirms these findings as they showed a decrease of the P-R interval at various pacing rates. HOWever, Strauss and associates,24 using higher concentrations ( 10e5 moles)) showed a decrease in the slope of phase 4 depolarization in sinoatrial nodal and venous automatic tissue. DPH in concentrations of 1OF to 10M6 moles had no effect on transmembrane action potentials recorded from any cell studied.24 Furthermore, DPH markedly increased the dV/dt of phase 0 uf the action potential and membrane responsiveness of ordinary atria1 and specialized Bachmann’s bundle fibers under controlled conditions and produced more striking increases when these two variables
Current status
Table I. The efect oj DPH
711
on A-V condmtion”
I Control DPH (5 mg./L.) DPH (IO mg./L.) A = Intra-atria1 conduction: *Time in milliseconds.
qf diphenylhydantoin
A
i
25.4 28.0 28.6 N = intranodal
conduction:
N
IIP
/
30.8 28.6 27.5
30.4 30.4 33.4
HP = His-Purkinje
were decreased by ouabain. Hence, it was concluded by these authors that the unique ability of DPH to enhance membrane responsiveness and to improve conduction in the absence of significant effects on the effective refractory period and automaticity of atria1 cells may account for the antiarrhythmic activity of the drug in the lower concentrations.24 However, Sano and associatesz5 demonstrated a decrease in dV/dt over a wide range of concentrations and an increase in action potential duration in higher concentrations. Hence, it would appear that any particular action of the drug is essentially related to its concentration. Further studies in our laboratory utilizing microelectrode techniques may shed some light on this dilemma. In concentrations of 5 to 10 mg. per liter, which is essentially similar to clinical blood levels, DPH decreased intranodal conduction time (Table I). However, intra-atria1 conduction time was prolonged and, in a higher concentration of 10 mg. per liter, His-Purkinje conduction was also depressed. In contrast, the Scherlag group23 noted a decrease in His-ventricular activation time measured by intracardiac catheters. It is important to realize that effect on the A-V interval may vary with relative prolongation or shortening within the various regions along the A-V transmission system. However, there appears to be little doubt that in a concentration of 10 mg. per liter this agent will prolong A-V conduction time. It would be reasonable to suspect that in arrhythmias which are mainly a resuit of re-entry due to depressed conduction, DPH in low concentrations may be effective in terminating the mechanism by improving the conduction.11 Furthermore, the effect on phase 4 (diastolic) depolarization may also terminate automatic rhythms, particularly in the presence of digitalis excess. While
I
conduction;
A-V
= atriaventricular
A-P 86.6 87.8 89.5 conduction.
DPH and bretyliuml’ offer interesting electrophysiologic characteristics, lidocainez6 appears significantly more effective and safer in its clinical application. Finally, quinidine, procaineamide, and propranolol of Group 1 show many contrasting features to Group 2. All agents, except for possibly bretylium, favorably affect phase 4 depolarization and can terminate automatic rhythms. Clinical
use
Supraventricular arrhythmias. There appears to be little effect of DPH in either the termination or prophylaxis of atria1 fibrillation and flutter.IO Hence DPH has no practical value in the presence of these arrhythmias except prior to precordial shock when digitalis excess is suspected.10x32 Furthermore, attempts to terminate paroxysmal atria1 tachycardia by the intravenous administration of DPH have been generally unsuccessful. However, Mercer and Osbornelo were able to prevent 77 per cent of recurrent atria1 tachycardia by the oral prophylactic use of this agent. Ventricular arrhythmk. In contrast, the termination of ventricular arrhythmias by intravenous DPH is essentially successful in at least half of the instances in which it is attempted.‘O However, the precise etiologic factors underlying these ventricular arrhythmias appear to have pertinent significance. It seems that ventricular arrhythmias occurring during anesthesia and following cardioversion are particularly susceptible to intravenous DPH.lO Similarly, arrhythmias engendered by digitalis intoxication are quite sensitive to DPH administration. Helfant, Scherlag, and Damato”2 suggested that DPH may be of value in permitting adequate digitalization of patients having a low toxic to therapeutic ratio of digitalis. Hence, there appears to
be a more or less specific antagonism between DPH and the cardiac glycosides. On the other hand, ventricular arrhythmias associated with arteriosclerotic heart disease show only a fair response to either oral or intravenous DPH therapy.rO Administration of DPH in the presence of Type 2 A-V block would appear hazardous as intra-atria1 and subnodal conduction appears to be depressed (Table I), However, enhancement of conduction in Type 1 block may be possible because of increased conduction velocity within the node. However, one must consider the over-all effect on A-V conduction and the P-R interval and the interrelationship of DPH with other cardiac drugs which would affect A-V transmission in the same direction as DPH and engender higher grades of A-V conduction block. Cardiac toxicity of DPH. Although the administration of DPH appears to be relatively safe, side effects as well as sudden deaths have been reported by several investigators. Manifestations of toxicity have been described independent of sinusnode rhythmicity. Depression of atria1 and ventricular conduction and several instances of ventricular fibrillation have been described.27-29 DPH will reduce cardiac output and the maximum rate of rise of left ventricular pressure and myocardial contractile force and increase left ventricular end-diastolic pressure.17-20 Patients with hypothyroidism may be more sensitive to DPH than in the euthyroid state. 3o Congestive heart failure attributed to DPH administration appears to be rare. Occasionally significant hypotension has appeared in patients receiving this agent.14y31z32 Systemic manifestations of hypersensitivity have been reported.33 Recurrence of drug-induced hepatitis has been described by several authors,34z35 and diffuse lymphocytic thyroiditis and a generalized serum sickness have been reported as we11.36 Conclusion DPH is an effective antiarrhythmic agent particularly in the presence of transient ventricular arrhythmias, and it demonstrates potent antiarrhythmic effects in the presence of digitalis excess. It may affect certain arrhythmias which fail to respond to Group 1 agents such as quinidine, pro-
and procaineamide. Hence it would not seem unreasonable that if a particular arrhythmia did not respond to a Group 1 drug, selection of one or a combination of Group 2 agents such as DPH with different electrophysiologic actions would be important. However, its precise role in the pharmacologic armamentarium identifies DPH as a second order of drugs for both the control and prophylaxis of supraventricular and ventricular arrhythmias. One could imagine that in a patient with digitalis excess and with renal failure, potassium would be contraindicated and DPH could be selected as the drug of choice. However, most digitalis arrhythmias are best treated by the withdrawal of digitalis and adjustment of serum electrolytes rather than antiarrhythmic agents. If digitalis has produced A-V block, cardiac pacing is indicated until A-V conduction returns. Fina!ly, DPH offers no special protection from serious side effects. Its toxic manifestations have been well documented and sudden death due to this agent has also been reported. It is probably unwise to exceed daily doses of 10 mg. per kilogram of body weight and the agent should be given slowly intravenously with proper dilution. DPH is usually administered slowly in an intravenous bolus of 100 to 200 mg. initially. Additional doses of 100 mg. can be given every 5 to 10 minutes, but not to exceed 500 mg, in any 2 hour period. Still larger doses do not seem warranted as they are usually not effective and may be hazardous. An oral maintenance dose of DPH of 100 to 200 mg. every 6 hours can be continued after the rhythm is controlled. Finally, the experimental studies on DPH have suggested new electrophysiologic mechanisms that may offer possible clues concerning the action of antiarrhythmic drugs. This information will undoubtedly play a significant role in the development of more ideal antiarrhythmic agents. pranolol,
1.
2.
3.
REFEREKCES Williams, D.: Treatment of epilepsy with sodium diphenyl hydantoinate, Lancet 2:678, 1939. Scherf, D.: Changes in the electrocardiogram after intravenous administration of phenytoin sodium (Dilantin) in the acute experiment, Bull. IV. Y. Med. Coll. 6:82, 1943. Blair, D.: The modern treatment of epilepsy, Recent Progr. Psychiat. 86:888, 1940.
Current status of diphenylhydantoin
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Finkelman, I., and Arieff, A. J.: Untoward effects of phenytoin sodium in epilepsy, J.A.M.A. 118:1209, 1942. Mallach, J. F., Finkelman, I., Arieff, A. J., and Roberts, R. C.: Electrocardiographic changes resulting from Dilantin medication, Quart. Bull. Northwestern Univ. Med. School 17:97, 1943. Harris, A. S., and Kokernot, R. H.: Effects of diphenylhydantoin sodium (Dilantin sodium) and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction, Amer. J. Physiol. 163505, 1950. Mosey, L., and Tyler, M. D.: Effect of diphenylhydantoin sodium (Dilantin), procaine hydrochloride, procaine amide hydrochloride, and quinidine hydrochloride upon ouabain-induced ventricular tachycardia in unanesthetized dogs, Circulation 10:65, 1954. Scherf, D., Blumenfeld, S., Taner, D., and Uildiz, M.: The effect of diphenylhydantoin (Dilantin) sodium on atria1 flutter and fibrillation provoked by focal application of aconitine or delphinine, AMER. HEART J. 60:936, 1960. Leonard, W. A.: The use of diphenylhydantoin (Dilantin) sodium in the treatment of ventricular tachycardia, Arch. Intern. Med. 101:714, 1958. Mercer, E. hr., and Osborne, J. A.: The current status of diphenylhydantoin in heart disease, Ann. Intern. Med. 67:1084, 1967. Pamintuan, J. C., Dreifus, L. S., and Watanabe, U.: Comparative mechanisms of antiarrhythmic agents, Amer. J. Cardiol. In press. Davis, L. D., and Temte, J. V.: Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers, Circ. Res. 24:639, 1969. Merritt, H. H., and Putnam, T. J.: Sodium diphenyl hydantoinate in the treatment of convulsive disorders, J.A.M.A. 111:1068, 1938. Conn, R. D.: Diphenylhydantoin sodium in cardiac arrhythmias, New Eng. J. Med. 272:277, 1965. Haury, IJ. G., and Drake, M. E.: II. The effect of intravenous injections of sodium diphenyl hydantoin (Dilantin) on respiration, blood pressure, and the vagus nerve, J. Pharmacol. Exp. Ther. 68:36, 1940. Conn, R. D., Kennedy, J. W., and Blackman, J. R.: The hemodynamic effects of diphenylhydantoin, AnlEa. HEART J. 73:.500, 1967. Gupta, D. N., Unal, M. O., Bashour, F. A., and Webb, W. R.: Effects of diphenylhydantoin (Dilantin) on peripheral and coronary circulation and myocardial contractility in the experimental animal, Dis. Chest 51:248, 1967. Lang, T. W., Bazika, V., Pappelbaum, S., Gold, H., Bernstein, H., Herrold, G., and Corday, E.: Autotransplanted heart-lung and cerebra1 venous shunt preparation: Two new technics for pharmacologic assay of cardiovascular drugs, Amer. J. Cardiol. 16:695, 1965. Mierzwiak, D. S., Mitchell, J. H., and Shapiro, W.: The effect of diphenylhydantoin (Dilantin) and quinidine on left ventricular function in dogs, AMER. HEART J. 74:780, 1967.
20.
713
Childress, R. H., Higgs, L. M., Boyd, D. L., and Williams, J. F., Jr.: Effect of diphenylhydantoin on left ventricular function in patients with heart disease, Circulation 34 (Suppl. 3):73, 1966. (Abst.) 21. Bigger, J. T., Jr., Bassett, A. I,., and Hoffman, B. F. : Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers, Circ. Res. 22:221, 1968. 22. Helfant, R. H., Scherlag, B. J., and Damato, A. N.: The electrophysiological properties of diphenylhydantoin sodium as compared to procaine amide in the normal and digitalis-intoxicated heart, Circulation 36:108, 1967. 23. Scherlag, B., Helfant, R. H., and Damato, A. N.: The contrasting effects of diphenylhydantoin and procaine amide on A-V conduction in the digitalis-intoxicated and the normal heart, AMER. HEART J. 75:200, 1968. 24. Strauss, H. C., Bigger, J. T., Jr., Bassett, A. L., et al.: Actions of diphenylhydantoin on the electrical properties of isolated rabbit and canine atria, Circ. Res. 23:463, 1968. 25. Sano, T., Suzuki, F., Sato, S., and Iida, Y.: Mode of action of new antiarrhythmic agents, Jap. Heart J. 9:161, 1968. 26. Gianelly, R. E., Von der Geroeben, J. D., Spivack, A. P., and Harrison, D. C.: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease, New Eng. J. Med. 277:1215, 1967. 27. Unger, A. H., and Sklaroff, H. J.: Fatalities following intravenous use of sodium diphenylhydantoin for cardiac arrhythmias, J.A.M.A. 200:335, 1967. 28. Gellerman, G. L., and Martinez, C.: Fatal ventricular fibrillation following intravenous sodium diphenylhydantoin therapy, J.A.M.A. 200:337, 1967. 29. Bigger, J. T., Steiner, C., and Burris, J. 0.: The effects of diphenylhydantoin on atrioventricular conduction in man, Clin. Res. 15:196, 1967. 30. Fulop, M., Widrow, D. R., Colmers, R. A., and Epstein, E. J.: Possible diphenylhydantoin-induced arrhythmia in hypothyroidism, J.A.M.A. 196:454, 1966. 31. Rosen, M. R., Lisack, R., and Rubin, I. L.: Diphenylhydantoin in cardiac arrhythmias, Circulation 34 (Suppl. 3):201, 1966. (Abst.) 32. Karliner, J. S.: Intravenous diphenylhydantoin sodium (Dilantin) in cardiac arrhythmias, Dis. Chest 51:256, 1967. 33. Carlen, S. A.: Congestive heart failure caused by sensitivity to diphenylhydantoin (Dilantin sodium), Canad. Med. Ass. J. 80:725, 1959. 34. Harinasuta, ‘ii., and Zimmerman, H. J.: Diphenylhydantoin sodium hepatitis, J.A.M.A. 203:1015, 1968. 35. Pezzimenti, J. F., and Hahn, A. L.: Anicteric hepatitis induced by diphenylhydantoin, Arch. Intern. Med. 12.5:118, 1970. 36. Kuiper, J. J.: Lymphocytic thyroiditis possibly induced by diphenylhydantoin, J.A.M.A. 210:2370, 1969. 37. Dreifus, L. S., Rabbino, M. D., and Watanabe, Y.: Sewer agents in the treatment of cardiac arrhythmias, Med. Clin. N. Amer. 48:371, 1964.
Current
status
and reappraisal Edited
by
Arthur
C. DeGraff
of cardiac and
Alan
F. Lyon
of diphenylhydantoin
Leonard S. Dreilfus, l4.D. Yoshio Watanabe, M.D. Philadel$hia, Pa.
iphenylhydantoin (DPH) has been in clinical use for more than twenty years. However, its precise role in the treatment of heart disease is still unsettled. Several clinical reports as early as 1939 suggested that DPH may exhibit effects on the heart.r In 1943, Scherf* was able to demonstrate changes in the electrocardiogram after the intravenous administration of DPH, while other investigators had already demonstrated bradycardia, ventricular premature beats, congestive heart failure, cardiac standstill, and death attributable to DPH administration.le5 Harris and Kokernot6 reasoned that the substances initiating the discharge of impulses in the area of a myocardial infarction may be similar to some fundamental property of the excitatory factors which produce epileptogenic spike discharges in boundary zones about posttraumatic cortical scars and certain other cerebral lesions. The results of these investigators demonstrating the survival of dogs through the initial period following occlusion of the anterior descending ramus of the left coronary artery suggested that DPH possessed but transient antiarrhythmic properties. More extensive studies by Mosey and Tyler’ established the effectiveFrom
the Division Philadelphia, Supported by the Reprint requests Broad Street,
Vol.
SO, No.
5, pp. 709-713
ness of this agent in abolishing ventricular tachycardia resulting from ouabain overdosage. Similar results in the presence of aconitine-induced atria1 fibrillation and flutter were obtained by Scherf.* However, most of these investigators emphasized the transient effect of this agent (2 to 30 minutes) and indicated that the short duration may preclude its clinical effectiveness. While these experimental observations and a pertinen-t clinical note by Leonard9 suggested that this agent may have potent antiarrhythmic effects, little clinical interest matured until the early 1960’s. The extensive clinical experience with this agent was summarizeId by Mercer and OsbornelO in 1967. Although DPH still appears to have only limited value in the therapy of cardiac arrhythmias, its unique electrophysiologic properties render it extremely useful as a pharmacologic tool. It now appears that antiarrhythmic agents can be generally classified into two groups according to their predominant electrophysiologic effects on automaticity and conduction. Agents such as quinidine, procaineamide, and propranolol depress automaticity and conduction and comprise the first group (Grow 11, while lidocaine, DPH, and
of Cardiology and the Department of Physiology and Biophysics, Pa. National Institutes of Health Grant HE 11281. to: Leonard S. Dreifus, M.D., Division of Cardiology, Hahnemann Philadelphia, Pa. 19102.
November,
1970
Hahnemann
Medical
Medical
College,
American Keart Journal
College,
230 North
709
bretylium depress automaticity but enhance conduction and are representative of a second group (Group 2).i1,12 This review will emphasize the present clinical status of DPH as well as recent electrophysiologic studies on DPH identifying the possible antiarrhythmic mechanisms of this agent. Pharmacology
DPH was introduced for the treatment of convulsive disorders by Merritt and Putnam.i3 This agent has gained wide acceptance for seizure therapy during the past twenty years. DPH is one of the most potent of all the antiepileptic drugs in its ability to modify the character of maximal (tonic-clonic) electroshock convulsions elicited in animals by supramaximal currents. Furthermore, DPH exerts antiepileptic activity without causing general depression of the central nervous system. The action of this agent on peripheral nerves is such as to stabilize the neuronal membrane and to decrease the intracellular content of sodium.‘j It is possible that the mechanism of action of certain antiepileptic drugs on heart muscle and nerve tissue is basically similar. Both anticholinergic and cholinergic actions have been described by different investigators mainly on the basis of the effects of DPH on” heart rate and atrioventricular conduction.l3-l7 There is some evidence for a direct central nervous system site of action of DPH. Hence, if in truth some cardiac arrhythmias are central in origin, this agent may successfully terminate such arrhythmias by its specific effects on the central nervous system. However, Lang and co-workers l8 failed to find a direct effect of this agent in the inhibition of arrhythmias when DPH was administered into the cerebral circulation. DPH produces a negative inotropic effect on the left ventricle which is similar to quinidine although its duration appears more transient.l$ Furthermore, these authors found that the left ventricular end-diastolic pressure (LVEDP) increased and dp/dt decreased. These effects were similar in both vagotomized and propranolol-blocked dogs. Administration of higher doses beyond 5 to 10 mg. per kilogram of body weight and subsequent injections further aggravate these
negative inotropic actions of this drug. Sowever, clinical studies by Conn, Kennedy, and Blackmon16 and Childress and associateszO indicate that DPH only transiently depresses left ventricular function.
Several diverse conclusions regarding the electrophysiologic effects of DPH on both the specialized and working myocardial cells have appeared in the literature within recent years. Group 1 drugs such as quinidine, propranolol, and procainamide can be contrasted to Group 2 drugs such as DPH, bretylium, and lidocaine, Bigger and coworkers2i demonstrated that DPH enhanced the rate of rise of phase 0 (dV/dtj of the action potential in canine Purkinje fibers. The duration of the transmembrane action potential shortened due to abbreviation of all phases of repolarization. The effective refractory period also shortened during exposure to DPH, but to a lesser extent than the action potential duration. Hence, the net effect was to relatively increase the refractory period. The earliest effective test stimulus propagated with a greater amplitude and dV/dt of phase 0 than under control conditions. Furthermore, DPH depressed the automaticity of Purkinje fibers by decreasing the slope of phase 4 depolarization. It should be pointed out that these effects were obtained in the rissue bath with concentrations of DPH irom 10T8 to IO+ moles. It would appear that the work of Helfant and associatesz2 and Scherlag and co-workersz3 using 5 mg. per kilogram intravenously confirms these findings as they showed a decrease of the P-R interval at various pacing rates. HOWever, Strauss and associates,24 using higher concentrations ( 10e5 moles)) showed a decrease in the slope of phase 4 depolarization in sinoatrial nodal and venous automatic tissue. DPH in concentrations of 1OF to 10M6 moles had no effect on transmembrane action potentials recorded from any cell studied.24 Furthermore, DPH markedly increased the dV/dt of phase 0 uf the action potential and membrane responsiveness of ordinary atria1 and specialized Bachmann’s bundle fibers under controlled conditions and produced more striking increases when these two variables
Current status
Table I. The efect oj DPH
711
on A-V condmtion”
I Control DPH (5 mg./L.) DPH (IO mg./L.) A = Intra-atria1 conduction: *Time in milliseconds.
qf diphenylhydantoin
A
i
25.4 28.0 28.6 N = intranodal
conduction:
N
IIP
/
30.8 28.6 27.5
30.4 30.4 33.4
HP = His-Purkinje
were decreased by ouabain. Hence, it was concluded by these authors that the unique ability of DPH to enhance membrane responsiveness and to improve conduction in the absence of significant effects on the effective refractory period and automaticity of atria1 cells may account for the antiarrhythmic activity of the drug in the lower concentrations.24 However, Sano and associatesz5 demonstrated a decrease in dV/dt over a wide range of concentrations and an increase in action potential duration in higher concentrations. Hence, it would appear that any particular action of the drug is essentially related to its concentration. Further studies in our laboratory utilizing microelectrode techniques may shed some light on this dilemma. In concentrations of 5 to 10 mg. per liter, which is essentially similar to clinical blood levels, DPH decreased intranodal conduction time (Table I). However, intra-atria1 conduction time was prolonged and, in a higher concentration of 10 mg. per liter, His-Purkinje conduction was also depressed. In contrast, the Scherlag group23 noted a decrease in His-ventricular activation time measured by intracardiac catheters. It is important to realize that effect on the A-V interval may vary with relative prolongation or shortening within the various regions along the A-V transmission system. However, there appears to be little doubt that in a concentration of 10 mg. per liter this agent will prolong A-V conduction time. It would be reasonable to suspect that in arrhythmias which are mainly a resuit of re-entry due to depressed conduction, DPH in low concentrations may be effective in terminating the mechanism by improving the conduction.11 Furthermore, the effect on phase 4 (diastolic) depolarization may also terminate automatic rhythms, particularly in the presence of digitalis excess. While
I
conduction;
A-V
= atriaventricular
A-P 86.6 87.8 89.5 conduction.
DPH and bretyliuml’ offer interesting electrophysiologic characteristics, lidocainez6 appears significantly more effective and safer in its clinical application. Finally, quinidine, procaineamide, and propranolol of Group 1 show many contrasting features to Group 2. All agents, except for possibly bretylium, favorably affect phase 4 depolarization and can terminate automatic rhythms. Clinical
use
Supraventricular arrhythmias. There appears to be little effect of DPH in either the termination or prophylaxis of atria1 fibrillation and flutter.IO Hence DPH has no practical value in the presence of these arrhythmias except prior to precordial shock when digitalis excess is suspected.10x32 Furthermore, attempts to terminate paroxysmal atria1 tachycardia by the intravenous administration of DPH have been generally unsuccessful. However, Mercer and Osbornelo were able to prevent 77 per cent of recurrent atria1 tachycardia by the oral prophylactic use of this agent. Ventricular arrhythmk. In contrast, the termination of ventricular arrhythmias by intravenous DPH is essentially successful in at least half of the instances in which it is attempted.‘O However, the precise etiologic factors underlying these ventricular arrhythmias appear to have pertinent significance. It seems that ventricular arrhythmias occurring during anesthesia and following cardioversion are particularly susceptible to intravenous DPH.lO Similarly, arrhythmias engendered by digitalis intoxication are quite sensitive to DPH administration. Helfant, Scherlag, and Damato”2 suggested that DPH may be of value in permitting adequate digitalization of patients having a low toxic to therapeutic ratio of digitalis. Hence, there appears to
be a more or less specific antagonism between DPH and the cardiac glycosides. On the other hand, ventricular arrhythmias associated with arteriosclerotic heart disease show only a fair response to either oral or intravenous DPH therapy.rO Administration of DPH in the presence of Type 2 A-V block would appear hazardous as intra-atria1 and subnodal conduction appears to be depressed (Table I), However, enhancement of conduction in Type 1 block may be possible because of increased conduction velocity within the node. However, one must consider the over-all effect on A-V conduction and the P-R interval and the interrelationship of DPH with other cardiac drugs which would affect A-V transmission in the same direction as DPH and engender higher grades of A-V conduction block. Cardiac toxicity of DPH. Although the administration of DPH appears to be relatively safe, side effects as well as sudden deaths have been reported by several investigators. Manifestations of toxicity have been described independent of sinusnode rhythmicity. Depression of atria1 and ventricular conduction and several instances of ventricular fibrillation have been described.27-29 DPH will reduce cardiac output and the maximum rate of rise of left ventricular pressure and myocardial contractile force and increase left ventricular end-diastolic pressure.17-20 Patients with hypothyroidism may be more sensitive to DPH than in the euthyroid state. 3o Congestive heart failure attributed to DPH administration appears to be rare. Occasionally significant hypotension has appeared in patients receiving this agent.14y31z32 Systemic manifestations of hypersensitivity have been reported.33 Recurrence of drug-induced hepatitis has been described by several authors,34z35 and diffuse lymphocytic thyroiditis and a generalized serum sickness have been reported as we11.36 Conclusion DPH is an effective antiarrhythmic agent particularly in the presence of transient ventricular arrhythmias, and it demonstrates potent antiarrhythmic effects in the presence of digitalis excess. It may affect certain arrhythmias which fail to respond to Group 1 agents such as quinidine, pro-
and procaineamide. Hence it would not seem unreasonable that if a particular arrhythmia did not respond to a Group 1 drug, selection of one or a combination of Group 2 agents such as DPH with different electrophysiologic actions would be important. However, its precise role in the pharmacologic armamentarium identifies DPH as a second order of drugs for both the control and prophylaxis of supraventricular and ventricular arrhythmias. One could imagine that in a patient with digitalis excess and with renal failure, potassium would be contraindicated and DPH could be selected as the drug of choice. However, most digitalis arrhythmias are best treated by the withdrawal of digitalis and adjustment of serum electrolytes rather than antiarrhythmic agents. If digitalis has produced A-V block, cardiac pacing is indicated until A-V conduction returns. Fina!ly, DPH offers no special protection from serious side effects. Its toxic manifestations have been well documented and sudden death due to this agent has also been reported. It is probably unwise to exceed daily doses of 10 mg. per kilogram of body weight and the agent should be given slowly intravenously with proper dilution. DPH is usually administered slowly in an intravenous bolus of 100 to 200 mg. initially. Additional doses of 100 mg. can be given every 5 to 10 minutes, but not to exceed 500 mg, in any 2 hour period. Still larger doses do not seem warranted as they are usually not effective and may be hazardous. An oral maintenance dose of DPH of 100 to 200 mg. every 6 hours can be continued after the rhythm is controlled. Finally, the experimental studies on DPH have suggested new electrophysiologic mechanisms that may offer possible clues concerning the action of antiarrhythmic drugs. This information will undoubtedly play a significant role in the development of more ideal antiarrhythmic agents. pranolol,
1.
2.
3.
REFEREKCES Williams, D.: Treatment of epilepsy with sodium diphenyl hydantoinate, Lancet 2:678, 1939. Scherf, D.: Changes in the electrocardiogram after intravenous administration of phenytoin sodium (Dilantin) in the acute experiment, Bull. IV. Y. Med. Coll. 6:82, 1943. Blair, D.: The modern treatment of epilepsy, Recent Progr. Psychiat. 86:888, 1940.
Current status of diphenylhydantoin
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Finkelman, I., and Arieff, A. J.: Untoward effects of phenytoin sodium in epilepsy, J.A.M.A. 118:1209, 1942. Mallach, J. F., Finkelman, I., Arieff, A. J., and Roberts, R. C.: Electrocardiographic changes resulting from Dilantin medication, Quart. Bull. Northwestern Univ. Med. School 17:97, 1943. Harris, A. S., and Kokernot, R. H.: Effects of diphenylhydantoin sodium (Dilantin sodium) and phenobarbital sodium upon ectopic ventricular tachycardia in acute myocardial infarction, Amer. J. Physiol. 163505, 1950. Mosey, L., and Tyler, M. D.: Effect of diphenylhydantoin sodium (Dilantin), procaine hydrochloride, procaine amide hydrochloride, and quinidine hydrochloride upon ouabain-induced ventricular tachycardia in unanesthetized dogs, Circulation 10:65, 1954. Scherf, D., Blumenfeld, S., Taner, D., and Uildiz, M.: The effect of diphenylhydantoin (Dilantin) sodium on atria1 flutter and fibrillation provoked by focal application of aconitine or delphinine, AMER. HEART J. 60:936, 1960. Leonard, W. A.: The use of diphenylhydantoin (Dilantin) sodium in the treatment of ventricular tachycardia, Arch. Intern. Med. 101:714, 1958. Mercer, E. hr., and Osborne, J. A.: The current status of diphenylhydantoin in heart disease, Ann. Intern. Med. 67:1084, 1967. Pamintuan, J. C., Dreifus, L. S., and Watanabe, U.: Comparative mechanisms of antiarrhythmic agents, Amer. J. Cardiol. In press. Davis, L. D., and Temte, J. V.: Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers, Circ. Res. 24:639, 1969. Merritt, H. H., and Putnam, T. J.: Sodium diphenyl hydantoinate in the treatment of convulsive disorders, J.A.M.A. 111:1068, 1938. Conn, R. D.: Diphenylhydantoin sodium in cardiac arrhythmias, New Eng. J. Med. 272:277, 1965. Haury, IJ. G., and Drake, M. E.: II. The effect of intravenous injections of sodium diphenyl hydantoin (Dilantin) on respiration, blood pressure, and the vagus nerve, J. Pharmacol. Exp. Ther. 68:36, 1940. Conn, R. D., Kennedy, J. W., and Blackman, J. R.: The hemodynamic effects of diphenylhydantoin, AnlEa. HEART J. 73:.500, 1967. Gupta, D. N., Unal, M. O., Bashour, F. A., and Webb, W. R.: Effects of diphenylhydantoin (Dilantin) on peripheral and coronary circulation and myocardial contractility in the experimental animal, Dis. Chest 51:248, 1967. Lang, T. W., Bazika, V., Pappelbaum, S., Gold, H., Bernstein, H., Herrold, G., and Corday, E.: Autotransplanted heart-lung and cerebra1 venous shunt preparation: Two new technics for pharmacologic assay of cardiovascular drugs, Amer. J. Cardiol. 16:695, 1965. Mierzwiak, D. S., Mitchell, J. H., and Shapiro, W.: The effect of diphenylhydantoin (Dilantin) and quinidine on left ventricular function in dogs, AMER. HEART J. 74:780, 1967.
20.
713
Childress, R. H., Higgs, L. M., Boyd, D. L., and Williams, J. F., Jr.: Effect of diphenylhydantoin on left ventricular function in patients with heart disease, Circulation 34 (Suppl. 3):73, 1966. (Abst.) 21. Bigger, J. T., Jr., Bassett, A. I,., and Hoffman, B. F. : Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers, Circ. Res. 22:221, 1968. 22. Helfant, R. H., Scherlag, B. J., and Damato, A. N.: The electrophysiological properties of diphenylhydantoin sodium as compared to procaine amide in the normal and digitalis-intoxicated heart, Circulation 36:108, 1967. 23. Scherlag, B., Helfant, R. H., and Damato, A. N.: The contrasting effects of diphenylhydantoin and procaine amide on A-V conduction in the digitalis-intoxicated and the normal heart, AMER. HEART J. 75:200, 1968. 24. Strauss, H. C., Bigger, J. T., Jr., Bassett, A. L., et al.: Actions of diphenylhydantoin on the electrical properties of isolated rabbit and canine atria, Circ. Res. 23:463, 1968. 25. Sano, T., Suzuki, F., Sato, S., and Iida, Y.: Mode of action of new antiarrhythmic agents, Jap. Heart J. 9:161, 1968. 26. Gianelly, R. E., Von der Geroeben, J. D., Spivack, A. P., and Harrison, D. C.: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease, New Eng. J. Med. 277:1215, 1967. 27. Unger, A. H., and Sklaroff, H. J.: Fatalities following intravenous use of sodium diphenylhydantoin for cardiac arrhythmias, J.A.M.A. 200:335, 1967. 28. Gellerman, G. L., and Martinez, C.: Fatal ventricular fibrillation following intravenous sodium diphenylhydantoin therapy, J.A.M.A. 200:337, 1967. 29. Bigger, J. T., Steiner, C., and Burris, J. 0.: The effects of diphenylhydantoin on atrioventricular conduction in man, Clin. Res. 15:196, 1967. 30. Fulop, M., Widrow, D. R., Colmers, R. A., and Epstein, E. J.: Possible diphenylhydantoin-induced arrhythmia in hypothyroidism, J.A.M.A. 196:454, 1966. 31. Rosen, M. R., Lisack, R., and Rubin, I. L.: Diphenylhydantoin in cardiac arrhythmias, Circulation 34 (Suppl. 3):201, 1966. (Abst.) 32. Karliner, J. S.: Intravenous diphenylhydantoin sodium (Dilantin) in cardiac arrhythmias, Dis. Chest 51:256, 1967. 33. Carlen, S. A.: Congestive heart failure caused by sensitivity to diphenylhydantoin (Dilantin sodium), Canad. Med. Ass. J. 80:725, 1959. 34. Harinasuta, ‘ii., and Zimmerman, H. J.: Diphenylhydantoin sodium hepatitis, J.A.M.A. 203:1015, 1968. 35. Pezzimenti, J. F., and Hahn, A. L.: Anicteric hepatitis induced by diphenylhydantoin, Arch. Intern. Med. 12.5:118, 1970. 36. Kuiper, J. J.: Lymphocytic thyroiditis possibly induced by diphenylhydantoin, J.A.M.A. 210:2370, 1969. 37. Dreifus, L. S., Rabbino, M. D., and Watanabe, Y.: Sewer agents in the treatment of cardiac arrhythmias, Med. Clin. N. Amer. 48:371, 1964.