Some aspects of interaction between diphenylhydantoin and digoxin by simultaneous administration to dogs.

Diphenylhydantoin, 1.1 mg/kg/min, and digoxin, 2.78 μg/kg/min, were infused separately and simultaneously in anesthetized dogs. Diphenylhydantoin lowered mean arterial pressure and heart rate after 30–40 min of infusion. Its average lethal dose was 127 mg/kg. All animals died in cardiac arrest. The hypotensive effect of diphenylhydantoin was associated with a decrease in cardiac output, stroke volume, peripheral vascular resistance, and maximum left ventricular dpdt. Diphenylhydantoin increased mean right atrial and left ventricular end-diastolic pressures. Digoxin, 2.78 μg/kg/min, infused for 40 min, increased mean aortic pressure, peripheral vascular resistance, and maximum left ventricular dpdt. It decreased cardiac output and heart rate. After 20–30 min of infusion, digoxin caused the usual ECG effects of digitalis: A-V block, premature beats, and paroxysmal ventricular tachycardia. The average lethal dose of digoxin was 0.26 mg/kg. All animals died in ventricular fibrillation. Digoxin given simultaneously with diphenylhydantoin protected animals from diphenylhydantoin-induced hypotension and myocardial depression. The decrease in mean aortic pressure, cardiac output, stroke volume, total peripheral vascular resistance, and maximum left ventricular dpdt as well as the increase in the left ventricular end-diastolic pressure after diphenylhydantoin and digoxin were less pronounced than after diphenylhydantoin alone. Digoxin did not antagonize diphenylhydantoin-induced cardiac slowing. The peripheral vasoconstrictor as well as the positive inotropic effects of digoxin are thought to be responsible for the protection of animals from the diphenylhydantoin-induced hypotension. Diphenylhydantoin, in the doses employed, prevented digoxin-induced elevation of mean arterial pressure, peripheral vascular resistance and maximum left ventricular dpdt; it increased the dose of digoxin which caused ventricular arrhythmias but had no significant effect on the lethal dose of digoxin. Most animals which received both drugs, died in sudden cardiac arrest, which occurred at a time when the mean arterial pressure was only slightly decreased.