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PubMed1980

Therapeutic and toxic plasma concentrations of digoxin in the cat.

Nonanesthetized cats of both sexes were given oral digoxin (0.011 mg/kg of body weight) 3 forms: elixir, tablet, and crushed tablet mixed with food. Mean peak plasma concentrations of digoxin were highest with the elixir (1.89 +/- 1.02 ng/ml) and lowest with the crushed tablet mixed with food (0.66 +/- 0.35 ng/ml). Male cats had significantly higher (P less than 0.10) mean plasma digoxin concentrations than did female cats. A 2nd group of nonanesthetized cats of both sexes was given digoxin elixir orally at therapeutic amounts (0.011 mg/kg) once a day for 4 consecutive days. The cumulative effect of digoxin resulted in 62% increase in the mean peak plasma concentration and 231% increase in the 24-hour plasma concentration of digoxin over the 4-day period. Male cats had a significantly (P less than 0.05) higher mean plasma digoxin concentration than did the female cats. Significant changes in the ECG were not recorded. A 3rd group of nonanesthetized cats of both sexes was given a single toxic dose (0.11 mg/kg) of digoxin elixir orally. All cats showed clinical signs of digitalis toxicosis (depression, vomiting, salivation, and anorexia) before ECG changes appeared. Alterations in the ECG were minimal; the most important changes were a slight increase in the PQ interval, an elevated ST segment, and decreased heart rate. Plasma concentrations of digoxin at the time of vomition ranged from 4.45 to 12.12 ng/ml with a mean peak plasma value of 7.37 +/- 3.61 ng/ml. The cats were clinically ill for 48 to 96 hours. A plasma digoxin concentration of 2.3 ng/ml was not toxic.

Animals↗
PubMed1980

Digoxin pharmacokinetics, bioavailability, efficacy, and dosage regimens in the horse.

The pharmacokinetics of IV administered digoxin and the bioavailability of intragastrically administered powdered digoxin tables suspended in water were investigated in 6 clinically normal adult horses by 125I radioimmunoassay. The effect of 3 to 5 sequential IV doses of 5 micrograms of digoxin/kg of body weight at 2-hour intervals on a left ventricular index of contractility (Vmax) was assessed in 5 clinically normal horses. Standard pharmacokinetic equations and mean pharmacokinetic variables were used to derive parenteral and oral (loading and maintenance) doses for digoxin in horses. The calculated dosage regimens were administered and resulting plasma digoxin concentrations were monitored in 5 horses and 1 pony. Digoxin disposition after IV injection was triexponential. A rapid distributive phase with a half life (t 1/2 of 15 minutes was followed by a slow distributive phase with a t 1/2 of 4.1 hours. The biological disposition t 1/2 was 23.1 hours. The volume of distribution by extrapolation was 6.79 L/kg of body weight and 4.89 L/kg by the area method. The average bioavailability estimate for intragastrically administered digoxin was 19.2%. The Vmax increased significantly (P < 0.01) after IV digoxin administration. Greatest changes in Vmax were recorded after the first 2 injections (5 micrograms of digoxin/kg) corresponding to plasma digoxin concentrations of 0.83 and 1.68 ng/ml. Doses of digoxin were calculated as follows: IV loading 14, IV maintenance 7, oral loading 70, and oral maintenance 35 micrograms/kg/24 hours. When these doses were given to a group of horses, plasma digoxin concentrations measured 12 and 24 hours after administrated were mostly in the proposed therapeutic, nontoxic range of 0.5 to 2.0 ng/ml.

Administration, Oral↗
PubMed1994

Incidence of digoxin toxicity in outpatients.

The incidence of digoxin toxicity among patients in hospitals has declined in recent years. To evaluate whether a similar decline has occurred in ambulatory care, we reviewed randomly selected medical records for 183 outpatients receiving ongoing treatment with digoxin at 10 urban and rural Department of Veterans Affairs Medical Centers in the Rocky Mountain region. The prevalence of traditional risk factors for digoxin toxicity--elevated serum digoxin and serum creatinine levels, hypokalemia, and a new prescription of an interacting drug-was established from computerized laboratory and pharmacy records. Of the 183 patients, 50 (27.3%) had one or more risk factors for digoxin toxicity: serum digoxin levels were elevated in 13.6% of patients in whom a level was obtained, with hypokalemia in 14.3%, elevated creatinine levels in 17.9%, and possible drug interactions in 5.5% of patients over a 1-year period. Nevertheless, digoxin toxicity occurred in only 2 persons (1.1% or 1.4 per 100 patient-years of treatment). We conclude that digoxin toxicity was rare in this group of outpatients, even in persons presumed to be at high risk because of metabolic abnormalities, increased digoxin concentrations, or the use of interacting drugs. The low rate of digoxin toxicity in outpatients parallels the decline in the incidence of toxicity observed in hospital-based studies.

Aged↗
PubMed1995

[Digoxin concentration in blood].

Immunoreactive digoxin-like activity was found in the Chinese medicine, KYUSHIN tablet, taken popularly in Japan without prescription. The antibodies used in the assays of digoxin reacted with Ch'an-su, the major effective component of KYUSHIN, which contained cardiotonic steroids with a chemical structure similar to that of digoxin. One tablet of KYUSHIN had digoxin-like immunoreactivity equivalent to 1.9 micrograms. (TDx analyzer), 1.5 micrograms (Du Pont aca analyzer) and 72 micrograms digoxin (Enzymun-Test, Boehringer). These different equivalencies may be attributed to differences in cross-reactivity of the antibody used in the immunoassays. Two healthy volunteers took two KYUSHIN tablets three times a day, a typical dose, and digoxin-like immunoreactivity reached almost 0.4 microgram/l in 0.5 day. Recently, a competitive digoxin chemiluminescent immunoassay has been developed by Ciba Corning ACS 180. The assay utilizes an acridinium-ester labelled mouse monoclonal digoxin antibody as the tracer. In the extracted solution of KYUSHIN and serum after administration of two tablets, the digoxin-like immunoreactivity value on the Ciba Corning ACS 180 digoxin assay was < 0.10 microgram/l (off-range low). Therapeutic drug monitoring should be interpreted carefully in patients taking Chinese medicines, many of which contain the Ch'an-su component.

Digoxin↗
PubMedDate not supplied

Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension.

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (Cmax), mean time to maximum concentration (Tmax), concentration at 24 hours after the dose (C24), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and Cmax for digoxin increased by 14% and 32%, respectively (p < 0.05), with no change in Tmax. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p < 0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.

Administration, Oral↗
PubMed1994

Effects of concurrent administration of flosequinan and digoxin on the pharmacokinetics of each drug.

The pharmacokinetic and pharmacodynamic effects of co-administration of flosequinan (BTS 49465, CAS 76568-02-0) and digoxin (CAS 20830-75-5) were investigated in 12 healthy volunteers. A 4-day, open, lead-in phase established the pharmacokinetics of flosequinan (100 mg on the first day and 50 mg for the next 3 days) and was followed by a 24-day open interaction phase. Digoxin was administered alone (0.75 mg for the first 3 days and 0.5 mg for the next 4 days) to establish steady-state pharmacokinetics and in combination with flosequinan (100 mg on the 8th day and 50 mg for the next 14 days with 0.5 mg digoxin daily), and finally digoxin alone (0.5 mg for the remaining 3 days). No statistically significant differences were observed for any of the pharmacokinetic parameters for flosequinan, its major metabolite BTS 53554, or digoxin when flosequinan and digoxin were administered alone or concomitantly, but the confidence intervals for differences were relatively wide. Overall diastolic blood pressure was significantly lowered by 10% with concomitant treatment compared with flosequinan monotherapy. There were no significant effects on overall heart rate or systolic blood pressure, although pre-dose heart rate was increased by 6% during concomitant administration compared with digoxin alone, and remained high and digoxin alone. Adverse events (headache, nausea and vomiting) were reported by 2 volunteers on digoxin and 5 on concomitant therapy. One volunteer was withdrawn during concomitant therapy because of severe headache and vomiting. The results from this study indicate that no pharmacokinetic interaction occurred during concomitant administration of flosequinan and digoxin in healthy volunteers.

Adult↗
PubMed1976

[Blood digoxin and treatment of heart failure in aged patients].

Serum digoxin level was determined by radioimmunoassay in 76 elderly in-patients (age: 76.1 +/- 1.0) which were treated by digoxin without any evidence of toxicity. Digoxin levels was related to blood nitrogen (p less than 0,01); on the other hand, no relationship between others factors influencing the digoxin bioavailability (age, body weight, associated drug) and digoxin levels could be found. Therapeutic effectiveness, as estimated by ventricular rate and signs and symptoms, was not dependent of digoxin levels. In patients with higher functional class (III and IV NYHA), however, digoxin level was generally demonstrated to be increased. Digoxin levels were lower in patients with coronary heart disease (1.71 +/- 0,22 ng/ml; n = 16) than in patients with right ventricle overload (2.94 +/- 0,74 mg/ml; n + 7 - p less than 0.05). Because of the very large scattering of digoxin levels, digoxin determination seems to be useful in measuring individual bioavailability and therapeutic effectiveness, and leading to the best base line of any individual treatment.

Age Factors↗
PubMed1997

[Modification of transplacental digoxin transfer in the isolated placental lobule].

Digoxin is widely used in the transplacental therapy of fetal tachyarrhythmia. Unfortunately, in cases with severe cardiac insufficiency and hydrops fetalis, transplacental passage of digoxin is often hampered and therapy therefore ineffective. The present study was designed to establish the isolated placental lobule to quantify transplacental digoxin passage under different experimental conditions. Ten human placentas were obtained immediately after delivery, and a lobule was dually perfused after cannulating a small artery and vein of the chorionic plate and piercing four catheters through the corresponding basal plate. Flow rates were 12 ml/min in the maternal circuit and 6 (I) respectively 3 ml/min (II) in the fetal circuit. The maternal circuit was spiked with digoxin to 6.18 +/- 0.40 ng/ml, and transplacental passage was calculated from repeated fetal and maternal perfusate samples (Fluorescence-Polarization-Immunoassay; TDx, Abbott Laboratories). Within three hours of recirculating perfusion with a fetal flow rate of 6 ml/min (I), digoxin concentrations in the maternal circuit (400 ml) declined to 3.56 +/- 0.09 ng/ml, whereas digoxin levels in the fetal compartment (200 ml) increased to 2.58 +/- 0.37 ng/ml. With a fetal perfusion rate of 3 ml/min (II), the efflux of digoxin out of the maternal circuit was lower (p < 0.05) and the influx in the total compartment was reduced (fetal digoxin concentrations reached only 26.9 +/- 10.6% vs. 39.1 +/- 5.5% of the initial maternal digoxin concentrations). These data suggest that severe fetal cardiac insufficiency with reduced placental perfusion may be in part responsible for the decrease of transplacental digoxin passage in fetuses with hydrops.

Anti-Arrhythmia Agents↗
PubMed1976

Neuroexcitatory effects of digoxin in the cat.

The effect of intravenous injections of digoxin (20 mug/kg every 15 minutes) on spontaneously occurring activity in autonomic efferent nerves, motor nerves, afferent nerves, electrocardiogram and on arterial blood pressure was evaluated in chloralose-anesthetized cats. Administration of digoxin enhanced neural activity in pre- and postganglionic cardiac synpathetic nerves and this enhancement occurred near the time the disturbances in ventricular rhym were noted. Neural activity continued to increase during ventricular tachycardia and maximum enhancement was observed just proir to ventricular fibrillation. Similar results were observed when digoxin was administered to animals in which neural activity was recorded from preganglionic splanchnic and superior cervical nerves. Digoxin administration also increased discharge frequency from vagus (efferent fibers), phrenic and carotid sinus nerves. Denervation of cardiovascular reflexogenic areas prevented the increased discharge in vagus nerves, reduced it in phrenic nerves, but did not affect nerve discharge in sympathetic nerves. These results suggest that digoxin-induced hyperactivity in synpathetic nerves was related to a central nervous system effect of the drug, whereas the mechanism for the digoxin-induced hyperactivity in vagus nerves involved a peripheral reflex effect of the drug. Both sites were involved in the digoxin-induced hyperactivity in phrenic nerves. Enhancement of cardiac sympathetic nerve activity appeared to be responsible for the ventricular arrhythmias provoked by digoxin as 1) a temporal relationship was observed between augmented nerve activity and arrhythmia development, 2) a centrally acting sympathetic nervous system depressant drug, clonidine, converted the ventricular arrhythmia to normal rhythm, and 3) removal of sympathetic influence to the heart by spinal cord transection decreased the sensitivity of the heart to the arrhythmogenic effect of digoxin. These results suggest that digoxin partially responsible for its cardiotoxic effects.

Adrenal Glands↗
PubMed1999

Digoxin in the critically ill patient.

OBJECTIVE: To review the pharmacodynamic and pharmacokinetic properties of digoxin in health and disease and the potential use and toxic effects of digoxin in the critically ill patient. DATA SOURCES: A review of studies reported from 1966 to 1998 and identified through a MEDLINE search of the literature on digoxin and the use of digoxin in critical illness. SUMMARY OF REVIEW: Digoxin inhibits the sarcolemmal NaK-ATPase in many tissues with the effects on myocardial contractile and conducting tissue, neural tissue and smooth muscle providing the major physiological effects in health and disease. Currently the major indications for its clinical use include systolic heart failure, where, in addition to angiotensin conversion enzyme inhibitors and diuretics, it reduces the incidence of pulmonary oedema, and in the management of patients with supraventricular tachycardia, where it reduces the ventricular rate. In the critically ill patient, digoxin is used infrequently as there are other agents that have a superior inotropic effect, a greater ability to control and reverse supraventricular tachyarrhythmias, have a larger therapeutic window and are easier to regulate. As the myocardial depression associated with septic shock is manifest by ventricular dilation and reduction in ejection fraction, it would seem that digoxin may be of some therapeutic benefit in this disorder, particularly as early experimental and clinical studies have reported an improvement in the myocardial dysfunction associated with sepsis with the use of intravenous digoxin (750 - 1000 mug/70 kg). However, large prospective randomised controlled trials are lacking. CONCLUSIONS: Digoxin is a therapeutic agent with unique effects. It should be considered in all patients with systolic heart failure, supraventricular tachycardia, and, in association with other treatment, as a single dose of 750 -1000 mug/70 kg in patients not treated previously with digoxin who have septic shock. It should be avoided in patients with critical coronary artery disease and ischaemic or hypertrophic diastolic failure.

Journal Article↗
PubMed1999

Evaluating the appropriateness of digoxin level monitoring.

BACKGROUND: Digoxin level determinations can be useful clinically in patients receiving digoxin therapy but are sometimes misused. METHODS: Explicit appropriateness criteria were adapted from previously published criteria and revised using local expert opinion. They were then used to evaluate the appropriateness of random samples of inpatient and outpatient serum digoxin levels. Overall agreement between reviewers regarding appropriateness was good (K = 0.65). Patients in the study included 162 inpatients in whom 224 digoxin levels were measured and 117 outpatients in whom 130 digoxin levels were measured during a 6-month period. The main outcome measure was the proportion of digoxin levels with an appropriate indication. RESULTS: Among inpatient levels, only 16% (95% confidence intervals [CI], 11%-20%) were appropriate. Of the 189 digoxin levels considered inappropriate, only 26 (14%) had a result of 2.3 nmol/L or more (> or =1.8 ng/ mL). None of these levels resulted in an important change in therapy, and no patient had a toxic reaction to the therapy. Among inappropriate levels, daily routine monitoring accounted for 78%. Of the 130 outpatient levels, 52% (95% CI, 44%-61%) were appropriate. Of 62 inappropriate levels, only 4 (6%) had a result of 2.3 nmol/L or more (> or =1.8 ng/mL). One result led to a change in therapy, but none of the patients were believed to experience a toxic reaction. Among the inappropriate levels, 87% of patients underwent early routine monitoring before a steady state was achieved. CONCLUSIONS: A high proportion of digoxin levels were inappropriate, particularly among inpatients. In both groups, the primary reason tests were judged inappropriate was early routine monitoring. Few inappropriate tests resulted in important data. Interventions to improve the use of digoxin levels could potentially save substantial resources without missing important clinical results.

Aged↗
PubMed1982

Myocardial vs serum digoxin concentrations in infants and adults.

To establish whether there is a difference between infants and adults in the relationship of serum levels of digoxin to dosage or the ratio of myocardial to serum digoxin levels, the concentrations of digoxin in right atrial appendage (RAA) and serum were measured in 12 infants and 17 adults undergoing open heart surgery. Although the daily digoxin dose per weight for the infant was significantly greater than that for adults, there was no difference in the serum digoxin levels for the two groups. We found, however, a considerable difference in myocardial digoxin levels. The RAA digoxin levels were 211.8 +/- 72.1 ng/g of wet weight in infants and 35.1 +/- 7.7 ng/g of wet weight in adults. Similarly, the RAA-serum digoxin ratio was much higher in infants (149 +/- 30) than in adults (28 +/- 5). These data indicate discrepancies between infants and adults in the pharmacokinetics of digoxin, especially with respect to myocardial uptake.

Adult↗
PubMed1985

Autoradiographic localization of 3H-digoxin binding by neural cells in the medulla.

The purpose of this investigation was to localize binding sites for the cardiac glycoside digoxin in the medulla of the rat in vivo. Adult male Sprague-Dawley rats were injected (IV) with 3H-digoxin and killed 30 minutes later. Autoradiographs of medullas showed evidence of 3H-digoxin binding to small- and medium-sized neural cells in the regions of the nucleus solitarius, dorsal motor nucleus of the vagus, area postrema, and in the zone between the area postrema and the underlying neuropil. However, the parasympathetic preganglionic neurons of the dorsal motor nucleus were not labeled. The 3H-digoxin-labeled cells in the medulla were located mainly in the commissural and medial portions of nucleus solitarius at the level of the area postrema. Animals injected with unlabeled digoxin followed by 3H-digoxin showed reduced binding of radioactivity. The small- and medium-sized neurons of the caudal portions of the nucleus solitarius are internuncial in position with respect to cardiovascular afferents of the glossopharyngeal and vagus nerves and sympathetic and parasympathetic cardiovascular efferent neurons of the medulla. The results of this study suggest that these 3H-digoxin-labeled cells, presumably neurons of nucleus solitarius, may possess high affinity binding sites for digoxin. Further, the area postrema, which lacks a blood-brain barrier, may provide a portal of entry for 3H-digoxin into regions of the medulla known to contain neurons that play a role in the regulation of cardiac rhythm.

Animals↗
PubMed2004

Comparative evaluation of digoxin concentrations determined by three assay systems: TDx, IMx and OPUS.

Digoxin concentrations measured by three automated immunoassay systems, i.e. OPUS, TDx and IMx assays, were compared in order to evaluate precision and accuracy performance, and data compatibility. Coefficients of variation for all methods in within-run and between-run precision were less than 10% at weighed-in concentrations of 0.545, 1.090 and 2.180 ng/ml. The accuracy relative to the three weighed-in concentrations ranged from 97% to 123% for all methods. One hundred and three plasma samples from 60 patients receiving digoxin were used to evaluate the data compatibility. Digoxin concentrations measured by the three immunoassay systems correlated well with one another. These results suggest that there are few problems when switching between digoxin assay methods, and that IMx and OPUS are more useful than TDx because they do not require sample pretreatment. The digoxin concentrations of the plasma samples from one patient receiving both digoxin and potassium canrenoate were investigated as a case report. The digoxin concentrations measured by TDx and IMx became higher than those measured by OPUS after starting the combination treatment. In another patient suffering from bilirubinaemia, the digoxin concentrations measured by TDx or IMx were higher than those measured by OPUS. These results suggest that OPUS has a higher specificity for measuring the plasma digoxin concentrations compared with TDx or IMx.

Analysis of Variance↗
PubMed1976

Effect of sulfasalazine on digoxin bioavailability.

Low levels of digoxin were noted in a patient receiving digoxin and sulfasalazine (SSA). Discontinuation of SSA resulted in a significant increase in serum digoxin levels. To determine whether or not SSA consistently interfered with the therapeutic effect of digoxin, both drugs were administered to 10 normal subjects in a crossover study. Each received 2 doses of digoxin (0.5 mg, elixir): one dose given alone, and a second dose after 6 days of treatment with SSA. When digoxin was given with SSA, the average area under the serum digoxin curve fell from the control value of 8.79 ng-hr-ml(-1) to 6.66 ng-hr-ml(-1) (p less than 0.05), fell and total urinary excretion decreased from 278 mcg/10 days to 228 mcg/10 days (p less than 0.025). These changes suggest interference with the bioavailability of digoxin by SSA. Studies were conducted to determine whether SSA inhibited digoxin absorption by physically absorbing the glycoside from solution. In vitro tests failed to reveal any significant adsorptive properties for SSA.

Absorption↗
PubMed1976

Effect of furosemide on the renal excretion of digoxin.

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin

Adult↗
PubMed1977

Digoxin in hyperthyroidism.

A patient with chronic atrial fibrillation developed hyperthyroidism. Increasing doses of digoxin were required to maintain satisfactor ventricular rate control. The systemic availability of oral digoxin was decreased in this patient. The metabolism of digoxin was studied in the hyperthyroid rats. The plasma digoxin concentrations were significantly decreased in the hyperthyroid rats. A threefold increase in digoxin excretion in the bile of the hyperthyroid rats was associated with these changes in plasma digoxin concentrations. Conversely, hypothyroid rats excreted less digoxin in the bile when compared with control and hyperthyroid rats. Thus, changes in digoxin absorption and its biliary excretion result, in part, in a decreased therapeutic effect of digoxin based on dose in hyperthyroidism.

Animals↗
PubMed1987

Esmolol-digoxin drug interaction.

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.

Adolescent↗