Quinidine enhancement of digoxin toxicity in rats and minipigs

The combined use of digoxin and quinidine has been associated with potentially fatal toxic reactions. The mechanisms involved in this drug interaction were investigated in Wistar rats and Hormel miniature pigs (minipigs). Infusions of digoxin alone (0.013 mg/min) and in combination with quinidine (0.051 mg/min) demonstrated that quinidine pretreatment significantly decreases the time of onset of arrhythmias and death in these animals as compared with digoxin alone. Similarly, when administered as a slow, bolus intravenous (i.v.) injection to either anesthetized or unanesthetized minipigs, quinidine pretreatment (10 mg/kg, i.v.) led to the rapid development of arrhythmias and death. Quinidine administration in both species also causes a dramatic reduction in blood pressure, and it appears that this hypotension may trigger the irregular rhythms of the heart once digoxin is administered. Electrocardiographic (ECG) evidence showed that the toxicity associated with digoxin administration alone was characterized by bradyarrhythmias and death was attributed to cardiac arrest. In contrast, quinidine pretreatment led to severe tachyarrhythmias and earlier death by ventricular fibrillation. These studies demonstrate the usefulness of these two species, particularly the minipigs, in assessing the magnitude of this drug interaction and also confirm the risks involved when these two drugs are combined.