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Serum digoxin concentrations have been reported to increase in two patients taking daily doses of trazodone. However, in a canine model, no elevation in serum digoxin concentration was found with combined trazodone-digoxin administration. The authors suggest that serum digoxin concentrations should be monitored in patients receiving trazodone and digoxin concomitantly.
Quinidine has been reported to reduce clearance and the distribution volume of digoxin. Data are presented indicating that serum digoxin concentration (SDC) is increased throughout the coadministration of quinidine. This strongly suggests that the quinidine-induced reduction of digoxin clearance is the main mechanism underlying this drug interaction. It has been suggested that beside renal clearance quinidine also reduces non-renal clearance of digoxin. Direct evidence is provided by a study in patients with impaired renal function. Irrespective of the degree of renal impairment, quinidine increases SDC to about the same amount as found in patients with normal renal function. Since quinidine does not interfere with plasma protein binding of digoxin, this implies a decrease in non-renal clearance. In all patient groups the incidence of this drug interaction is rather high; however, pronounced interindividual differences occur as regards the extent of the increase in SDC. Regardless of the state of renal function careful monitoring of digitalized patients is mandatory once quinidine therapy is initiated. Since it may take a week or more until a new steady state is established in patients with impaired renal function, this period of close monitoring should be extended correspondingly.
The effects of digoxin have been studied on PRA of 11 hypertensive patients treated with a single oral administration of the glycoside or submitted to a prolonged treatment. The experiments performed with a single oral administration (0,5 mg) showed that digoxin induces a significant decrease of the hyperreninemic response induced by furosemide. This effect of digoxin develops very quickly and is well evident when plasma levels of the glycoside are still low. However, in the patients pretreated with a beta blocker, digoxin was completely ineffective in preventing the response to furosemide. In view of the results, the hypothesis is put forward that digoxin mainly acts at renal level through an antiadrenergic activity.
An elderly woman allegedly ingested oleander leaves and died. Ventricular arrhythmias and asystole were unresponsive to cardiopulmonary resuscitation, pharmacologic agents, and cardioversion. The patient, who had no access to digoxin, had an initial serum digoxin concentration of 5.8 ng/mL. Cross-reactivities between oleander extract and pure oleandrin and digoxin in the digoxin radioimmunoassay were 100:1 and 29,000:1, respectively. We postulate that glycosides in oleander leaves produced the elevated serum digoxin concentration. Based on an assumed volume of distribution of the oleander glycosides of 1 L/kg, the calculated lethal dose absorbed by our patient was 200 times greater than lethal doses in several animal species and corresponded to the absorption of 4 g of oleander leaves.
The influence of haemolysis, uraemia and hyperbilirubinaemia on the radioimmunoassay for both digoxin and insulin has been investigated for five separation techniques (dextran/charcoal; coated tube; polyethyleneglycol 4000; sodium sulphite; double antibody). Recoveries, and intra- and interassay precision were calculated. It was demonstrated that even in serum samples with a rather high degree of haemolysis (haemoglobin up to 50 g/l)digoxin can be measured by using each of the five separation techniques without any significant interference. Visible haemolysis (haemoglobin above 200 mg/l) leads either to disturbance or to a complete failure of insulin radioimmunoassays with all separation techniques. This effect can be largely neutralized, and precision improved, by using N-ethylmaleimide. With the exception of the coated tube separation technique the intraassay precision has a CV of less than 10%, and the interassay CV is between 10 and 20%. Elevated urea concentrations interfered in the digoxin radioimmunoassay only when the coated tube technique was used. The insulin radioimmunoassay, however was affected by high urea when either the double antibody or the coated tube technique was used. Here the intraassay precision also has a coefficient of variation less than 10%, the interassay CV lying between 10 and 20%. Bilirubin influenced the digoxin test when the sodium sulphite separation was used, and it affected the insulin determinations with polyethyleneglycol 4000 and sodium sulphite. The intra- and interassay precision were however also around 10% and between 10 and 20% respectively. Compared with the interassay precision of 15% CV for digoxin and 13% for insulin for a pool-serum from blood donors, the decrease of interassay precision caused by haemolysis, uraemia and hyperbilirubinaemia was insignificant.
The effect of progressive digoxin administration (20 micrograms/kg/15 min, i.v.) on cardiac contractile force, cardiac output, heart rate, arterial blood pressure and total peripheral resistance was examined in chloralose anesthetized cats with and without central nervous system control of the heart. In neurally intact animals, the inotropic response (i.e., a sustained increase of 0.5 g-tension in contractile force) occurred with 83 +/- 22.1 micrograms/kg digoxin. The peak change in force occurred immediately prior to the development of ventricular arrhythmias and attained a value of + 1.88 +/- 0.84 g-tension above the control level. Toxicity (i.e., ventricular arrhythmias) occurred with 158 +/- 8.0 micrograms/kg and death occurred with 188 +/- 8.4 micrograms/kg digoxin. The toxic to inotropic, and lethal to inotropic dose ratios were 3.62 +/- 1.28 and 4.28 +/- 1.50, respectively. Elimination of central nervous system control to the heart by bilateral cervical vagotomy and spinal section at the atlanto-occipital junction significantly (p less than 0.05) improved the toxic to inotropic and lethal to inotropic dose ratios to 6.66 +/- 1.00 and 8.72 +/- 1.29, respectively. In addition, the inotropic response attained in these animals (+ 5.30 +/- 0.70 g-tension above control level) was significantly higher than the inotropic response attained in the neurally intact animals. These results suggest that when the central nervous system actions of digoxin are prevented from influencing the heart, greater increases in cardiac contractility are obtained with less likelihood of digoxin-induced toxicity.
In three cases of attempted suicide by massive digoxin ingestion, a therapeutic attempt was undertaken to shorten the duration of toxicity of the drug by accelerating the removal of the glycoside from the body. Early administration of intravenous (IV) furosemide and fluids appeared to increase digoxin excretion in one case, which resulted in a substantially shortened digoxin half-time of eight hours. In two cases this therapy, initiated after a delay of 12 and eight hours was ineffective. The half-times were 51 and 43 hours, respectively. At an early preequilibrium stage, higher serum-tissue ratios of digoxin are present; thus, greater amounts of free digoxin are available for glomerular filtration and excretion. The prompt treatment by IV furosemide may be beneficial in the management of massive digitalis overdose.
We investigated the age and dose-specific quantitative electrocardiographic effects of digoxin in the rat. Adult female rats (n = 26) and one-day-old newborns (n = 20) were anesthetized with pentobarbital and injected subcutaneously with varying doses of digoxin. Electrocardiograms (ECG) were monitored continuously for four and one-half hours following digoxin administration. PR, QT, and RR intervals, QRS duration (msec), and T amplitude (mm) were measured every 15 minutes in all animals. QTc and PTQ index using the method of Joubert were calculated. Newborns demonstrated significant prolongation of the PR, QT, and RR intervals, an increase in the PTQ index, and a decrease in QTc when compared to adults (receiving the same dosage of digoxin) (P less than or equal to 0.05). In addition they developed toxic changes at much lower doses. Adults developed various tachycardias (tachyarrhythmias) compared to severe sinus bradycardias in the newborns. In conclusion, the newborn rat is much more sensitive to digoxin toxicity than the adult as demonstrated by ECG criteria. The newborns seem to be primarily "parasympathetic" responders as compared to adults who seem to be mainly "sympathetic" responders.
Symptomatic sinus bradycardia developed in two patients while they were taking methyldopa and digoxin. In one patient, bradycardia did not occur with either digoxin or methyldopa alone. The other patient, who had never taken methyldopa alone, did not demonstrate bradycardia with digoxin alone. In each patient, normal sinus node function was demonstrated after methyldopa and digoxin therapy was discontinued. Both patients continued to receive digoxin without recurrence of bradycardia.
The ability of family physicians to predict patients' compliance with a regimen of digoxin therapy was studied by an analytic survey. Compliance was assessed by a pill count at a home visit and measurement of the serum digoxin level in a blood sample obtained at that visit. Of 74 patients 70% were found to be taking more than 80% of their pills and 86% had a therapeutic serum digoxin level. The 10 physicians were unable to predict compliance better than chance, even for the 58 patients they had known for 5 or more years. Physicians should be cautious in predicting compliance, and when they prescribe oral digoxin therapy they should monitor the patient's compliance by means of the serum digoxin levels.
The renal clearances of digoxin and creatinine were determined in seven premature neonates (mean gestational age = 29.9 wk, range = 26 to 36 wk) at a postnatal age of 1 to 9 days (mean = 4.1 days). The corrected renal digoxin clearance (mean, 10.4 ml/min/1.73 m2; range, 2.5 to 36.7) was highly dependent on gestational age and body weight, r being 0.95 and 0.96, respectively (exponential curve). The linear slope of corrected renal digoxin clearance vs. creatinine clearance plot approached unity (r = 0.99), indicating that digoxin and creatinine were handled similarly by the kidney in these premature neonates (i.e. glomerular filtration with some degree of tubular secretion). Our finding of slower renal digoxin clearance helps to explain the higher serum levels and longer half-life of this drug in premature neonates.
We investigated the age-specific arrhythmogenic effects of digoxin in the rat. Adult female rats (n = 26) and one-day-old newborns (n = 20) were anesthetized with pentobarbital and injected subcutaneously with varying doses of digoxin. Electrocardiograms (ECG) were monitored continuously for four and one-half hours following digoxin administration. The arrhythmogenic dose 50 (AD50) and lethal dose 50 under anesthesia (LD50) were determined using the method of Litchfield and Wilcoxon. AD50 in adults was 13.0 +/- 1.0 mg/kg (X +/- SD) compared with 2.9 +/- 0.3 mg/kg in the newborns (P less than 0.01), and LD50 in adults was 30.0 +/- 1.9 mg/kg compared with 5.0 +/- 0.2 mg/kg in the newborns (P less than 0.01). Arrhythmias appeared earlier in adults (54 +/- 11.5 minutes after digoxin, X +/- SEM) than in newborns (132.2 +/- 11.0 minutes, P less than 0.01). Paroxysmal atrial tachycardia was the predominant arrhythmia in adults (73%), while transient sinus bradycardia appeared in only 9%. In contrast, all newborns with arrhythmias had severe sinus bradycardia and 69% had profound first degree heart block as well. In conclusion, the newborn rat is more sensitive to digoxin toxicity and develops lethal arrhythmias much more readily than the adult.
Eighteen neonates in heart failure were investigated to assess whether high or low serum digoxin levels had differing effects on left ventricular function as determined by systolic time intervals obtained by echocardiography. Nine patients had digoxin levels of 1.99 +/- 0.35 ng/ml (group 1). Nine others had levels of 3.62 +/- 0.95 ng/ml (group 2). Systolic time intervals were obtained by echocardiography before and at 5 days after digoxin and correlated with serum levels. The heart rate, preejection period (PEP), left ventricular ejection time (LVET), electromechanical systole (QS2) and the PEP/LVET ratio were measured. LVET and electromechanical systole were indexed. These measurements were analyzed and the two groups were compared using Student's t test. The clinical improvement in both groups was similar and no difference in ECG changes were noted. Therapy with digoxin produced changes in heart rate and systolic time intervals in both groups. Both showed significant shortening of electromechanical systole index; group 1 significantly shortened the LVET index and PEP/LVET ratio, whereas group 2 significantly shortened the PEP. Statistical analysis comparing the two groups showed no difference between them. Digoxin produces measurable changes in the indices of left ventricular function. The magnitude of these changes suggests no therapeutic advantage to the higher levels.
Plasma digoxin level and digoxin excretion were studied in 5 pat. suffering from cardiovascular diseases who had to be digitalized because of acute states of congestive heart failure. One of the patients took quinidine simultaneously. In the "quinidine" patient digoxin level was elevated to the 2--2.5 fold, as compared with "control" patients. Digoxin excretion of the "quinidine" patient was slightly increased. Following the results, a reduction in digoxin dosage to half of the dose is recommended.
The effect of left renal artery infusion of quinidine, 37.5 microgram (base)/kg/min on the renal clearance of ultrafilterable digoxin was studied in eight dogs given 0.06 mg/kg digoxin 24 hr previously. Digoxin was measured by 125I RIA, whose specificity was confirmed by HPLC. Within 15 min of the start of the infusion, the digoxin clearance decreased on the left 7.3 +/- 5.8 ml/min and on the right 6.1 +/- 6.4 ml/min, p < 0.02 and 0.05, respectively, compared to control. Quinidine infusion did not alter Cin. CDIG returned toward prequinidine infusion values after the infusion was stopped. We conclude that quinidine has a prompt and direct effect on the renal clearance of digoxin.
Digoxin, 30 micrograms/kg, was given by IV injection and orally, in the forms of pediatric elixir and tablet, on three separate occasions to six healthy dogs. Multiple serum samples were collected at timed intervals and assayed by radioimmunoassay. Data were analyzed, using nonlinear least squares regression analysis. The mean serum digoxin-time relationship was triexponential. Rapid and slow distributive phases with half lives of 9 minutes and 4.7 hours were followed by a biological disposition phase with a half life of 30.1 hours. Mean volume of distribution by extrapolation was 15.6 L/kg. When calculated by the area method, mean volume of distribution was 12.4 L/kg. Digoxin elixir was rapidly absorbed, with a mean bioavailability estimate of 71.4 +/- 8.2% SD. Digoxin tablets were less rapidly and less completely absorbed, with a mean bioavailability estimate of 58.0 +/- 11.6%. Data collected in this series of experiments and data from the literature were applied to standard pharmacokinetic equations to formulate loading and maintenance doses of digoxin for the IV injection, the elixir, and the tablet. Mean loading doses were, in micrograms/kg/24 hours: 27, 38, and 45 for the IV injection, elixir, and tablet, respectively. Corresponding mean maintenance doses were 13, 18, and 23.
The mechanism of reduced sensitivity to digitalis in patients with hyperthyroidism has been attributed to a change of intrinsic myocardial function and/or to altered pharmacokinetics of cardiac glycosides. Digoxin kinetics have been studied in hyperthyroid and 8 euthyroid patients after a single oral and i.v. dose at steady-state. Plasma and urinary digoxin concentrations were determined by radioimmunoassay. A significantly mean lower serum digoxin concentration was found in hyperthyroid patients, both after a single oral drug administration and at the steady-stage. A decreased digoxin absorption could not account for this finding, since both the percentage of gastrointestinal uptake of the drug and maximal serum concentration did not differ in hyperthyroid patients as compared to controls. Hyperthyroid subjects showed, on the contrary, an expended distribution volume and a significantly higher excretion, as documented by a lower drug half-life, by the increase of the elimination constant and urinary digoxin output.
In isolated guinea-pig left atria driven by rates of 0.5, 1,2, 3 and 4 Hz digoxin was infused continuously until cardiac arrest occurred. The experiments were performed in Tyrode solution with normal and twice the calcium content. Calculated was the toxic concentration of digoxin as that concentration which caused arrest of the preparation. In normal Ca2+-content (1.8 mM) an increase of the driving frequency decreased significantly the toxic concentration of digoxin, i.e. elevated the toxicity of this cardiac glycoside. The elevation of the Ca2+-content of the Tyrode caused a further diminution of the toxic concentrations of digoxin in dependence of the driving rate, thus demonstrating a synergism of Ca2+ and digoxin with regard to its toxicity.