Protection Against Digitalis Toxicity

Helfant, Scherlag and Damato, Circulation (1967),155 and Clinical Research (1967),685 demonstrated that intravenous PHT (5 mg/kg), given prophylactically to dogs, protected against digitalis toxicity. With PHT, 72 to 224% more digitalis was required to produce toxic arrhythmias. The authors state that PHT's effect on the toxic-therapeutic ratio of digitalis has important clinical implications.

155. Helfant, R. H., Scherlag, B. J., and Damato, A. N., Protection from digitalis toxicity with the prophylactic use of diphenylhydantoin sodium: an arrhythmic-inotropic dissociation, Circulation, 36: 119-124, 1967.
685. Helfant, R., Scherlag, B., and Damato, A. N., Protection from digitalis toxicity with prophylactic Dilantin: an electrophysiological-inotropic dissociation, Clin. Res., 15: 206, 1967.

Lüllmann and Weber, Arztliche Forschung (1968),233 and Naunyn-Schmiedebergs Archiv fur Pharmakologie (1968),403 found that PHT (20-80 mg/kg) given intravenously to guinea pigs almost doubled the amount of intravenous digoxin necessary to produce death. The normalization of rhythm by PHT occurred without interfering with the beneficial effects of digitalis.

233. L.kllmann, H. and Weber, R., On the action of Phenytoin on digitalis-induced arrhythmia, Arztliche Forschung, 22: 49-55, 1968.
403. Laliman, H. and Weber, R., Inhibition of cardiac glycoside-induced arrhythmia by Phenytoin, Naunyn-Schmiedeberg Arch. Pharm., 259: 182-183, 1968.

Scherlag, Helfant, Ricciutti and Damato, American Journal of Physiology (1968),1507 observed that, in dogs, PHT (5 mg/kg, intravenously) consistently converted digitalis-induced ventricular tachycardia to sinus rhythm with a corresponding reversal of the digitalis-induced potassium efflux. Improvement in myocardial contractility with digitalis was not altered by PHT. With PHT pretreatment, the toxicity of digitalis was markedly delayed and the rate of myocardial potassium efflux slowed.

1507. Scherlag, B. J., Helfant, R. H., Ricciutti, M. A., Damato, A. N., Dissociation of the effects of digitalis on myocardial potassium flux and contractility, Am. J. Physiology, 215: 1288-1291, 1968.

Baskin, Dutta and Marks, British Journal of Pharmacology (1973),801 in a study of the guinea pig heart, showed that PHT (30-100 µM) and potassium significantly prevent ouabain intoxication without interfering with its inotropic benefits.

801. Baskin, S. I., Dutta, S., and Marks, B. H., The effects of diphenylhydantoin and potassium on the biological activity of ouabain in the guinea-pig heart, Brit. J. Pharmacol., 47: 85-96, 1973.

Watson and Woodbury, Archives Internationales de Pharmacodynamie et de Therapie (1973),1663 studying ouabain intoxication in guinea pigs, observed that PHT prevented ouabain-induced electrolyte changes and arrhythmias. Under some conditions, pretreatment with PHT (80 mg/kg) reduced the lethality of ouabain from 90% to 34%. The authors found that PHT normalized plasma potassium, as well as intracellular concentrations of sodium, potassium and chloride, in cardiac muscle. They suggest that the antiarrhythmic effect of PHT is due to an action on active transport of electrolytes across cell membrane.

1663. Watson, E. L. and Woodbury, D. M., The effect of diphenylhydantoin and ouabain, alone and in combination, on the electrocardiogram and on cellular electrolytes of guinea-pig heart and skeletal muscle, Arch. Int. Pharmacodyn., 201: 389-399, 1973.

Hansen and Wagener, Zeitschrift fur Kardiologie und Angiologie (1974),1122 by using both isolated atrium and barbiturate-damaged heart-lung preparations of guinea pigs, showed that the toxic arrhythmogenic side effects of digoxin are prevented by PHT (3-5 µg/ml), without affecting its inotropic benefits. The authors suggest that by the addition of PHT, glycoside dosages can be beneficially increased in patients with cardiac failure.

1122. Hansen, H. W. and Wagener, H. H., Experimental studies an the influence of diphenylhydantoin glycoside effects on the heart, Herz Kreislauf Zeitschrift Fur Kardiologie und Angiologie in Klinik und Praxis, 6: 69-72, 1974.

Takeya, Hotta and Yajima, Journal of Aichi Medical University Association (1980),3001 reported that PHT (30-50 µM) inhibited both chronotropic and inotropic effects of grayanotoxin, and chronotropic effects of G-strophanthin on spontaneous pacemaker activity in isolated guinea-pig right atrial preparations. The authors conclude that PHT reduced grayanotoxin and G-strophanthin induced sodium influx.

3001. Takeya, K., Hotta, Y., Yajima, M., Effect of phenytoin on the positive inotropic actions of grayanotoxin-I and C-strophanthin in the isolated guinea pig atria under contraction-frequency change, J. Aichi Med., Univ. Assoc., 8(2): 96-104, 1980.

Garan, Ruskin and Powell, American Journal of Physiology (1981),2525 in a study evaluating the role of PHT's central nervous system effects in its control of cardiac arrhythmias, found that PHT (10 mg) administered directly into the cerebrospinal fluid (cisterna magna) protected against digoxin-induced arrhythmias in ten anesthetized dogs. Time to onset of ventricular arrhythmias was significantly longer in the PHT-treated animals (50 minutes compared to 19 minutes in controls). Five of the PHT-treated dogs remained free of ventricular fibrillation for the entire three-hour observation period, compared to one of ten in the control group. PHT, administered by an intra-venous route, had a similar, but slightly less, protective effect. The protective action of PHT was less under conditions of bilateral vasectomy, confirming PHT's regulatory effect on the heart via the nervous system.

2525. Garan, H., Ruskin, J. N., Powell, W. J., Centrally mediated effect of phenytoin on digoxin-induced ventricular arrhythmias, Am. J. Physiol., 241: h67-h72, l981.

Rhee, Fourth International Symposium on Calcium-Binding Proteins in Health and Disease (1983),2904 studied the effects of PHT, as well as dimethylpropanolol (DMP) and quinidine, on radioisotopic rubidium and calcium uptake in specialized canine cardiac tissues including sinoatrial node, Purkinje fibers, left ventricular muscle and aorta. An arrhythmogenic dose of ouabain significantly reduced rubidium uptake in all tissue types. Both PHT and DMP, at doses sufficient to control the ouabain-induced arrhythmias, significantly increased rubidium uptake in the left ventricle and Purkinje fiber samples. In the sinoatrial node PHT decreased rubidium uptake, while DMP had no effect. Neither drug affected uptake in aortic tissue. In a second series of experiments, PHT, DMP and quinidine were found to reduce calcium uptake by membrane vesicles prepared from the left ventricle. The author concludes that PHT's effects on monovalent cation flux, and its antiarrhythmic actions, are due to its regulation of calcium channels or binding.

2904. Rhee, H. M., Effects of some antiarrhythmic agents on 45Ca++ transport in dog heart membrane vesicles and 86Rb+ transport in specialized cardiac tissues, Calcium-Binding Proteins 1983, DeBernard, B., et al., Eds., Elsevier Science Publishers, Amsterdam, 293-5, 1983.