SUMMARYTo study the mechanism of the renal handling of digoxin, simultaneous measurements of digoxin and inulin clearances were performed in 13 digitalized patients with congestive heart disease. The renal digoxin clearances exceeded inulin clearances, indicating an active tubular secretion of digoxin. No Several authors have demonstrated that the renal clearance of digoxin calculated from the total plasma digoxin concentration is equal to the endogenous creatinine clearance,7~1' which, in man, approximates the glomerular filtration rate (GFR). However, about 25% of plasma digoxin is bound to protein'2' 13 and not available for filtration, suggesting that digoxin is subject to tubular secretion.The present study was undertaken for a closer evaluation of the mechanism of the renal handling of digoxin in digitalized patients. Simultaneous determinations of digoxin and inulin clearance were performed since inulin is the accepted standard for measurement of the GFR. The observation of a significantly reduced digoxin clearance in a patient (not included in this series) who received spironolactone caused me to repeat the clearance determinations, when possible, after treatment with spironolactone. None of the patients gave a history of renal disease. Five had slightly elevated serum creatinine levels, but none had proteinuria, and the urinary sediments were normal.All the patients had been on a stable oral maintenance digoxin dose (table 1) for more than one month prior to the study and presented no clinical or electrocardiographic evidence of digitalis toxicity. The bioavailability of the tablets was not studied; however, each patient received tablets from the same batch throughout the study. In addition to digoxin all the patients received only furosemide (40-160 mg daily) and supplemental potassium to maintain the serum concentration of potassium within normal limits. Medication was withheld 24 hours before the study. At the time of the investigation none of the patients had clinical signs of cardiac incompetence.Simultaneous measurements of inulin and digoxin clearances were performed in all 13 patients. Nine of the patients were subsequently treated with 100 mg spironolactone (Aldactone) daily for ten days, and the measurements of inulin and digoxin clearances were repeated. Inulin ClearancePriming doses of 10% inulin solution of 100 mg per kg body weight were given followed by a constant infusion of 30 ml 10% inulin solution per hour. Sixty minutes were allowed for equilibration, and no clearance was used unless plasma inulin was 20-50 mg/100 ml and urine flow at least 1 ml per minute. Three periods of about 60 to 90 minutes voided urine were used.Inulin was determined by the method of Heyrovsky:14 duplicate determinations varied 1.0 mg ± 2.5% for both plasma and urine. The inulin clearance was calculated as a mean of the three computed clearance rates. Patients whose separate clearance rates varied more than ± 5% of the mean were excluded.

Twelve patients with congestive heartfailure receiving maintenance therapy with digoxin and potent diuretics were followed closely during development of hypokalaemia and potassium loss. Cardiac arrhythmias compatible with digoxin toxicity developed in 6 patients in the presence of stable, normal serum digoxin concentrations. The mechanisms involved in the development of the rhythm disturbances are discussed with regard to hypokalaemia, intracellular potassium loss, intra-/extracellular potassium gradients and digoxin, and the significance of maintaining a normal potassium balance in this setting is stressed.It is generally accepted that hypokalaemia and diuretics were subjected to a potassium depleting potassium loss may promote digitalis toxicity in regimen and followed closely for development of patients with congestive heart failure receiving cardiac arrhythmias while serum digoxin concenmaintenance treatment with digitalis. However, trations were controlled. while this situation was frequent in earlier studies of digitalis toxicity (Lown and Levine, 1954; Jorgensen and Sorensen, 1970), hypokalaemia and Methods potassium loss were not observed as causes of Twelve patients with advanced congestive heart failure digitalis intoxication in more recent reports (Belier admitted to Medical Department B, Rigshospitalet et al., 1971; Evered and Chapman, 1971). Though Copenhagen, were selected for study according to the this new trend may reflect better treatment with following criteria: 1) The subjects had received mainregard to maintenance of potassium balance during tenance digoxin therapy for at least one month and digitalis therapy in particular in patents on chronic showed normal serum digoxin levels, 2) the patients diuretic therapy, it seems also possible that the were in a stable situation on maintenance diuretic diu i ttreatment, and 3) the subjects presented normal serum risks involved m hypokalaemia and potassium loss potassium concentrations and were apparently in a in this setting have been overestimated in the past. stable potassium balance while receiving a standard In earlier studies of digitalis toxicity in man the supplement of potassium chloride of 3 g daily or a relative role of digitalis overdosage and of acute potassium sparing drug as additional diuretic if required. or chronic hypokalaemia or potassium loss have The series consisted of 5 men and 7 women; mean age not been precisely defined, and more recent studies 57,7 years. The clinical diagnoses were rheumatic in dogs have not supported the concept that valvular disease in 6 patients, ischaemic heart disease hypoksaaemia sensitizes the myocardim to digi-in 4, and cardiomyopathy in 2. The patients received talis during condition representinmamtenance treatment with digoxin in a dose range tallsdunrng conditions representing tne nearest from 0.125 to 0 50 mg daily and frusemide 80 to 160 mg practical approximation to the situation of patients or bumetanide 4 to 6 mg per day. on chronic diuretic therapy (Kleiger, Vitale, and With their inform...

A kinetic and dynamic study of digoxin was performed in 6 healthy subjects, and repeated in the same subjects after administration of quinidine for 1 wk. Myocardial performance evaluated by systolic time intervals increased in parallel with plasma digoxin concentration, whereas left ventricular end-diastolic diameter on echocardiography and arterial blood pressure remained constant. The positive inotropic effect of digoxin was abolished during concomitant treatment with quinidine. Quinidine has been reported to increase the risk of digitoxicity, and therefore the treatment with digoxin and quinidine in combination should be reconsidered.