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PubMed2004

[Symptoms of severe digoxin intoxication in patients hospitalized in geriatric wards].

Digoxin is a drug commonly used in geriatrics. The purpose of the study is to present cases of elderly patients hospitalized on the Geriatric Ward of the Provincial Neuro-Psychiatric Hospital "Dziekanka" in Gniezno with extremely high level of digoxin in the blood serum. The study was based on the case history of patients hospitalized on the ward from July 1998 to June 2003. During that time 83 patients (age: 77.4 +/- 8.1 years old, 60 females and 23 males) were suspected to suffer from digoxin intoxication on the basis of their morbid states, and their digoxin level in serum was measured. Furthermore, medical documentation of four patients with extremely high digoxin level was profoundly analyzed. Such is regarded, the level which exceeds by 100% the upper limit of concentration believed to be therapeutic (2 ng/ml) which is 4 ng/ml. The paper also includes a profile of clinical conditions of the patients at the time of their admission to the ward. While analyzing the patients' states, careful attention was drawn to the symptoms that might be caused by digoxin intoxication (changes in the ECG, central nervous system and gastrointestinal tract disturbances). However, because of typical for geriatrics polypathology and not clear characteristic clinical symptoms of majority of pathological syndromes, even severe intoxication may turn out to be impossible to diagnose. In the paper, coexistence of risk factors predisposing to appearance of toxic symptoms such as kidney failure, hypoproteinemia, dehydration, hypoxia, electrolyte abnormalities, drug interactions, and a possibility of improper taking medication were pointed out. It was concluded that lack of specific signs of severe digoxin intoxication among the elderly results in the fact that every worsening in a patient's state of health of an unknown reason treated with digoxin should be suspected as digitalis' glycosides intoxication.

Aged↗
PubMed1992

Effects of amiodarone on the pharmacokinetics and toxicity of digoxin in laboratory animals.

Some pharmacokinetic interactions between digoxin and amiodarone were studied in experiments on rabbits. An increase of digoxin serum levels was established in amiodarone-treated rabbits (amiodarone 30 mg/kg s.c. for five days alone or together with digoxin). The calculated elimination half-life (t 1/2) and the area under the curve (AUC) of digoxin were increased and the digoxin clearance was decreased, being most pronounced in animals receiving amiodarone-digoxin combination for five days. There were no changes either in digoxin toxicity in amiodarone-treated guinea pigs or in serum levels of T4, T3 and TTH. The possible mechanisms of digoxin-amiodarone interactions are discussed.

Amiodarone↗
PubMed1991

Effects of amiodarone on the pharmacokinetics and toxicity of digoxin in laboratory animals.

Some pharmacokinetic interactions between digoxin and amiodarone were studied in experiments on rabbits. An increase of digoxin serum levels was established in amiodarone-treated rabbits (amiodarone 30 mg/kg s. c. for five days administered alone or together with digoxin). The calculated elimination half-life(t1/2) and the area under the curve (AUC) of digoxin were increased and the digoxin clearance was decreased, being most pronounced in animals receiving a combination of amiodarone and digoxin for five days. Changes were observed neither in the digoxin toxicity in amiodarone-treated guinea-pigs nor in the serum levels of T4, T3 and TTH. The possible mechanisms of the digoxin-amiodarone interactions are discussed.

Amiodarone↗
PubMed1991

Clinical issues related to discontinuing digoxin therapy in elderly nursing home patients.

Digoxin is commonly used to treat congestive heart failure. Digoxin augments ventricular systolic performance, but does not benefit patients whose congestive heart failure is caused by poor diastolic function. We studied 47 elderly nursing home patients who were receiving long-term digoxin therapy. The left ventricular ejection fractions were measured using both a standard and a highly portable echocardiography machine. Thirty-five of 47 patients had normal ejection fractions (50% or greater). In this subgroup, 23 patients were in normal sinus rhythm. Digoxin was discontinued in 14 patients with good systolic function and normal sinus rhythm, but in nine cases physicians refused to stop the digoxin. Follow-up evaluations showed no deterioration off digoxin. Excellent correlations existed between estimated left ventricular ejection fractions from the two echocardiography machines. Many nursing home patients taking digoxin do not need it. Physician reluctance to discontinue digoxin may change with the availability of highly portable echocardiography.

Aged↗
PubMedDate not supplied

Amiodarone-digoxin interaction in rats. A reduction in hepatic uptake.

The interaction amiodarone-digoxin results in a marked increase in the digoxin serum concentrations. The mechanism of this interaction is still unexplained. The influence of amiodarone on digoxin hepatic extraction in rats was investigated. The digoxin hepatic extraction coefficients were determined using the isolated-perfused livers of control and amiodarone-treated (25, 50, and 100 mg/kg/day for 5 days) rats. When plotted as a function of time, an inverse relationship between the extraction coefficients and the dose of amiodarone was evident. Significant dose-related reductions were observed in hepatic clearances calculated after 16 and 20 min of digoxin infusion when steady state was achieved. Analysis of the hepatic effluent by HPLC revealed only digoxin in the effluent of both control and amiodarone-treated rats; no metabolites were detected. Using liver homogenates, no differences were found in the ability of control or amiodarone-treated (50 mg/kg/day for 5 days) rats to metabolize digoxin. These changes occur without significant lesion of the hepatocytes, inasmuch as the serum concentrations of glutamic-pyruvic and glutamic-oxaloacetic transaminases were not affected by the administration of amiodarone (50 or 100 mg/kg/day for 5 days). Furthermore, a microscopic study of the hepatocytes revealed light cytoplasmic vacuolization, normal Kupffer cells, and no evidence of macrophage proliferation. It was concluded that amiodarone increases digoxin serum concentrations by inhibiting its uptake into the hepatocytes.

Alanine Transaminase↗
PubMed1989

Serum digoxin concentrations in canine congestive heart failure.

Digoxin was administered to dogs (n = 10) in congestive heart failure, at an oral dosage rate of 0.01 mg kg-1 lean body mass twice daily. Lean body mass was determined by reducing gross mass by the estimated degree of ascites and body fat. The dose was further adjusted for factors such as renal and hepatic function, the bioavailability of different formulations, and the size of the patient. Trough and peak serum digoxin concentrations were determined after 10 days of digitalisation, or when signs of toxicity became apparent. Serum digoxin concentrations in 6 of the 10 dogs were found to be partially or completely in the toxic or subtherapeutic range. This indicates that an oral digoxin dosage rate of 0.01 mg kg-1 lean body mass administered twice daily, even when adjusted appropriately for factors that affect digoxin pharmacokinetics, provides no more than a rough approximation of the precise dose required to provide serum digoxin concentrations within the therapeutic range. The observations also lend support to a recent recommendation that the digoxin dosage rate should be based on body surface area, although even when administered on this basis, serum digoxin concentrations outside of the therapeutic range could be anticipated.

Animals↗
PubMed1988

Clinical pharmacokinetics of digoxin in Nigerians.

The pharmacokinetics of digoxin have been studied in eight healthy volunteers, 23 congestive cardiac failure and 10 chronic renal failure patients. The mean serum digoxin concentrations in the volunteers and the congestive cardiac failure patients were significantly different (P less than 0.001) from those in the chronic renal failure patients. The mean half-life of digoxin in the healthy volunteers (37.2 h +/- 8.6 s.d.) was comparable to the widely accepted 40 h for digoxin half-life in normal individuals. Half-life was significantly prolonged in renal failure patients. There was a good inverse correlation, in the three groups, between serum creatinine and creatinine clearance, but the expected close correlation between the renal clearance of digoxin and serum creatinine was not demonstrated, probably because this was an oral study. There was no statistically significant difference in the age and weight in all three groups. There was also no significant difference in all parameters, measured and derived, between the volunteers and the congestive cardiac failure patients. However, when the volunteers and/or the congestive cardiac failure patients were compared with the renal failure patients, there was a significant difference in all parameters except age and weight. Thus, in the absence of renal impairment and hypokalaemia, standard dosages of digoxin can be used in congestive cardiac failure patients, provided symptoms and signs of toxicity are constantly monitored. Therapeutic drug monitoring of digoxin is desirable in view of its low toxicity: therapeutic ratio, and its kinetics should be studied in detail in each community to establish correct dosages to prevent and manage digoxin toxicity.

Adolescent↗
PubMed1988

Digoxin-cyclosporine interaction: severe digitalis toxicity after cyclosporine treatment.

Digoxin toxicity developed in two patients awaiting cardiac transplantation upon the initiation of cyclosporine. Toxicity was associated with elevated digoxin concentrations (10.6 and 5.7 nmoles/L), gastrointestinal symptoms, and arrhythmias classic for digoxin toxicity (bidirectional ventricular tachycardia and AV nodal block with accelerated junctional rhythm respectively). A previously unreported drug interaction between cyclosporine and digoxin was suspected and digoxin pharmacokinetics were studied in two additional patients both before and after cyclosporine therapy prior to cardiac transplantation. The study confirmed a significant interaction between cyclosporine and digoxin; the apparent volume of distribution of digoxin decreased by 71% and its plasma clearance decreased by 53%. Until further information regarding the cyclosporine-digoxin interaction is available, this combination should be used with great caution.

Coronary Disease↗
PubMedDate not supplied

Pharmacokinetics of digoxin in the rat.

Previous studies on the pharmacokinetics of 3H-digoxin in the rat have been based on total radioactivity in the plasma, even though the drug is extensively metabolized in this species. A comparison of total radioactivity vs. unchanged drug in rat plasma after administration of 3H-digoxin clearly showed the need to separate digoxin from its metabolites. The pharmacokinetics of digoxin were therefore examined using solvent extraction and thin-layer chromatography to isolate unchanged drug. Digoxin levels after a 1 mg/kg iv dose were measured in the plasma and urine of adult male rats in which the bile duct or the ureters had been ligated, as well as in sham-operated controls. In all cases, digoxin concentrations were best described by a two-compartment open model. Digoxin was rapidly eliminated from the plasma of controls, with a half-life of 2.5 hr, a volume of distribution of 3.6 liter/kg, and a renal clearance somewhat lower than the glomerular filtration rate. No significant change in these parameters was observed in rats with bile duct ligation. The total body clearance of 5.77 ml/min in the controls was reduced by only 10% in the bile duct-ligated rats. In animals with bilateral ureter ligation, the body clearance was reduced by 30% and the plasma half-life of digoxin was increased to 4 hr, although no significant change in the apparent volume of distribution was noted. Approximately 60% of the total body clearance was unaffected by bile duct and ureter ligations, and was assumed to be due to biotransformation. Biliary excretion was found to be important for digoxigenin bisdigitoxoside, inasmuch as rats with bile duct ligation showed elevated metabolite levels in the plasma as well as a 3-fold increase in renal excretion of the bisglycoside.

Animals↗
PubMed1986

[What value do body weight, age and drug anamnesis have as an index of elevated digoxin level?].

A retrospective study of two groups of patients with a different plasma digoxin level (Group A: digoxin greater than or equal to 2 ng/ml, n = 32, Group B: digoxin less than 2 ng/ml, n = 34; total n = 66) showed a significantly lower creatinine clearance (p less than 0.05) in group A. This group also showed a weak correlation between the digoxin level and the length of observation (R = + 0.31, p less than 0.05, n = 29). Furthermore, a weak correlation between digoxin level and the ratio of average daily dosage to creatinine clearance was found for the total sample (R = + 0.30, p less than 0.05, n = 66). Patients treated for less than 7 days and with a higher digoxin level also had a higher dosage and worse renal function (p = 0.05, p = 0.01, respectively). A weak correlation also existed between the digoxin level and creatinine clearance and body weight for the whole sample (R = -0.29, p less than 0.05; R = -0.29, p less than 0.01, respectively; n = 66). The latter correlation was also found within each group. Apart from renal function, the medication taken and body weight seem to be useful variables in predicting impending elevation of the digoxin level. In this study these variables were found to be better suited for the said purpose than the ECG. These conclusions remain to be confirmed by means of a prospective study.

Acetyldigoxins↗
PubMed1986

Factors of importance for valid digitalis assays particularly for the determination of digoxin in plasma and urine.

Four commercial radioimmunoassay (RIA) kits for digoxin varied in precision (coefficient of variation, CV within-assays 5-14%) and accuracy (up to 40%). Thus it seems that such commercial RIA-kits can reach at best a CV within-assay of 5% and a similar variation between assays. Without a good control of the performance, the variation can increase 5-6 times. We found that the precision of digoxin RIA as performed at 27 Swedish laboratories using 10 different methods varied from 0.05 to 0.61 nmol/L in between-assay SD for a pool of 2.60 nmol/L. Up to 100% deviations between the highest and lowest reported concentration of a spiked plasma pool may occasionally occur. Such deviations mostly depend on the laboratory, but there are contributions from the kit and effects of the matrix as well. Matrix effects were observed in plasma samples from patients with uremia, acute myocardial infarction and treated with spironolactone to which digoxin was added to a concentration of 2.50 nmol/L. We found 10% underestimation by one method, 10% overestimation by two methods and 5% overestimation by a fourth method, respectively, with the above described samples. For a good judgement of a found plasma concentration value, calculation of a confidence interval is useful. This can be done by computer fitting of the standard curve after duplicate runs of standards and samples in random order. One source of error in RIA appears to be the use of inaccurate standards. We found that standards provided with different RIA-kits for digoxin varied up to 30%. Various physicochemical properties of cardiac glycosides, which could influence the assays were studied. Both digitoxin and digoxin are sparsely soluble in water (5.1 and 36 mumol/L, respectively). Methanol is a much better solvent, which dissolves 6.9 mmol/L of digoxin and 20-24 mmol/L of digitoxin. Chloroform is a good solvent for digitoxin (29-34 mmol/L) but not for digoxin (0.42 mmol/L). Partition of cardenolides between chloroform and water reflected their lipophilic or hydrophilic character. Thus, digitoxin had a high affinity to the organic phase (distribution constant KD = 10(3.65)), while the hydrophilic deslanoside was preferentially found in the aqueous phase (KD = 10(-3.08). Interestingly, the sugar moiety digitoxose in the digoxin molecule turned out to be a substituent that increased lipophilicity. Adsorption of cardiac glycosides occurs to plastics and glass from aqueous solutions. To overcome losses at low concentrations, the solutions must contain plasma, albumin, alcohol or similar solubility-increasing ingredients.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1986

Digoxin-like substance in term pregnancy, newborns, and renal failure.

Digoxin-like substance (DLS) is detected in pregnant women near term, newborns, and in patients with renal failure using RIAs for digoxin. We made "digoxin" measurements in such patients using three digoxin RIA kits (Nuclear Medical Laboratories (N), Clinical Assays (C), and Corning Magic (M]. At term mother DLS (micrograms/l digoxin) was 0-0.19 (N), 0.09-0.24 (C), 0.07-0.24 (M); cord blood DLS was 0.35-0.75 (N), 0.46-0.90 (C), 0.42-0.90 (M); infant DLS was 0.5-1.1 (N), 0.28-0.98 (C) and was not measured by M. DLS was detected at term in mothers and was essentially undetectable by 24 hr postdelivery. Cord levels fell in eight of ten infants to significantly lower levels by the second day of life. DLS in renal hemodialysis patients not receiving digoxin was 0.04-0.41 (N), 0.01-0.34 (C), 0.03-0.40 (M). While postdialysis levels by N tended to be lower than predialysis, they rose by C and M. Dilutions of cord blood yielded similar results by N, nonlinear decreases by C, and more nearly parallel decreases by M. In renal failure patients, dilutions yielded similar results by N and marked nonparallel results by M. Digoxin results obtained with immunoassays may be inaccurate in these patient populations. Digoxin immunoassays must be individually characterized as to the expected results.

Digoxin↗
PubMed1986

Pharmacokinetic studies of nifedipine and digoxin co-administration.

We have studied the possible interactions between nifedipine and digoxin in 8 healthy subjects in two ways: A. The effect of digoxin (0.25 mg, tablet q.d. for 8 days) on the pharmacokinetics of nifedipine following single-dose (10 mg capsule) administration. Mean values for peak concentration, area under the serum concentration time curve (AUC), total serum clearance and the half-life of elimination of nifedipine did not differ before and concomitantly with digoxin administration. B. The effect of nifedipine (30 mg t.i.d.p.o. for 6 days) on the pharmacokinetics of digoxin following single dose (0.5 mg i.v.) administration. No significant differences were found between the mean values of the half-life of the alpha and beta phases, the AUC and the apparent volume of distribution of digoxin before and concomitantly with nifedipine administration. However, during the later period, the mean cumulative 96 h urinary excretion of digoxin increased by 18% (p less than 0.05) and the renal clearance of digoxin by 26% (p less than 0.05). No change was found, however, in the total plasma clearance of digoxin.

Adult↗
PubMed1985

Effect of spironolactone on the renal clearance of digoxin in dogs.

The acute effect of i.v. spironolactone dissolved in ethanol on renal digoxin clearance was studied in 10 dogs. All dogs received i.v. digoxin (0.02 micrograms/kg/min) and 0.9% saline (30 ml/kg of bolus and 0.1 ml/kg/min for maintenance) throughout the study. After 2 hr of equilibration, four 15-min urine collections were made. The dogs then received, over 1 hr, a loading infusion of 4 mg/kg of spironolactone in ethanol (group 1, N = 6) or ethanol alone (group 2, N = 4). Thereafter the infusion was maintained at one-tenth the initial rate for eight 15-min periods. Three additional control dogs received ethanol plus spironolactone without digoxin. Digoxin radioimmunoassay of plasma and urine from these control animals did not reveal any significant cross-reactivity between spironolactone and the antibody of the digoxin radioimmunoassay. The digoxin clearance (CDIG) and ratio of CDIG to inulin clearance (CDIG/CIN) increased insignificantly with ethanol alone, but were respectively reduced by 21 and 28% with spironolactone (P less than .05). The reductions of CDIG and CDIG/CIN were observed immediately after the spironolactone loading infusion and were associated with a sudden rise in plasma digoxin. The changes in digoxin handling with spironolactone appeared to be temporally dissociated from the antimineralocorticoid activity of spironolactone. We conclude that spironolactone inhibits renal CDIG by a mechanism that may be independent of its antimineralocorticoid activity.

Aldosterone↗
PubMedDate not supplied

Color vision testing to assist in diagnosis of digoxin toxicity.

This report describes an initial step in the process of determining whether color vision changes might form the basis for testing to assist in diagnosis of digoxin toxicity. The research questions concerned the types of color vision deficiencies found in people with elevated digoxin levels, the types of color vision tests that could help identify color vision changes in these people, and the relationship between serum digoxin level and subjects' responses to color vision tests. Three groups of subjects with a minimum of one week on maintenance digoxin therapy were tested. Two groups who were free of selected known causes of abnormal color vision participated in a single test session: clinic women (N = 19) and hospitalized women (N = 30). A third group (N = 10) was initially tested at a time of elevated serum digoxin levels (greater than or equal to 2.5 ng/ml) and retested at therapeutic levels. The Farnsworth-Munsell 100-Hue Test was performed on the clinic women. All subjects were tested with the Ishihara; the Hardy, Rand, and Rittler (HRR) plates; and the Farnsworth Panel D-15. The 49 women who had a single test session demonstrated a positive relationship between digoxin level and failing the Ishihara (p less than .05). On retest at therapeutic levels, the group with initial high digoxin levels had a significant reduction in the number of Ishihara (p .005) and HRR (p less than .005) errors. The Panel D-15 lacked sensitivity. Most subjects with high digoxin levels would not have been able to perform a reliable 100-Hue test. Red-green deficiency was the most common defect.

Adult↗
PubMed1983

Serum digoxin level - determined or estimated?

In 108 patients on maintenance digoxin therapy the serum digoxin levels were determined by means of homogeneous enzymoimmunoanalysis and compared with those estimated by means of a commonly accepted nomogram and with those estimated by means of the equation derived from multiple regression analysis of variables. By using stepwise discriminant analysis and a jacknifed classification matrix, based on serum digoxin and potassium levels, 96% and 90% of the classification of patients with and without clinical signs of digoxin intoxication, respectively, was correct. Based on serum creatinine and potassium levels and the daily digoxin dose/kg only 83% and 78% of the classification, respectively, was correct. The direct determination of serum digoxin level provides, in real time, information of higher reliability than does the estimate of the serum digoxin level. It is of basic importance in patients with dysrhythmias, in persons with an implanted pacemaker and in persons in whom the estimated levels of serum digoxin are around 2.6 nmol/l.

Aged↗
PubMed1983

Interaction between digoxin and the calcium antagonists nicardipine and tiapamil.

The investigation was designed to test whether nicardipine and tiapamil interact with digoxin, resulting in increased plasma digoxin levels. Ten patients mean age, 67 years) taking 0.13 mg to 0.25 mg of digoxin daily were given nicardipine (20 mg TID), and eight patients (mean age, 77 years) taking 0.13 mg to 0.25 of digoxin daily were given tiapamil (200 mg TID). Plasma levels of digoxin and nicardipine, heart rate, blood pressure, weight, serum electrolytes, and serum enzymes were measured and the electrocardiogram was monitored twice before, four times during, and once after the intervention with a calcium antagonist. No measurements of plasma levels of tiapamil were made. A chest roentgenogram was taken before, during, and after use of nicardipine or tiapamil. Mean plasma digoxin levels increased significantly in patients receiving tiapamil (P less than 0.01), but the values returned to normal after treatment with the experimental drug was discontinued. A wide variation of plasma nicardipine levels was observed, but there was no proportionate correlation between these levels and changes in digoxin levels. Blood pressure decreased significantly (P less than 0.01) and heart rate increased significantly (P less than 0.05) in patients receiving nicardipine. Similar changes in blood pressure and heart rate were not seen in patients receiving tiapamil. Although the use of each calcium antagonist led to an increase in plasma digoxin levels, the effect of tiapamil was greater than that of nicardipine.

Aged↗
PubMed1984

Effects of indomethacin on digoxin pharmacokinetics in preterm infants.

Indomethacin is commonly coadministered with digoxin for the treatment of patent ductus arteriosus (PDA) in preterm infants. The combination of digoxin that is eliminated almost exclusively by the kidney and indomethacin, which tends to reduce renal function, has potential hazards. We report 11 preterm infants (gestational age 25-33 week) treated with digoxin for PDA in whom a standard indomethacin therapy (mean of total dose = 0.32 mg/kg) resulted in a significant elevation of serum digoxin to potentially toxic levels (from 2.2 +/- 0.7 ng/ml to 3.2 +/- 0.7) (P less than 0.001). This phenomenon correlated well with decreased urine output (from 86 +/- 34 ml to 43 +/- 24 per 24 hour) (P less than 0.001) following indomethacin. No significant change was found in serum creatinine concentration pre- and post-indomethacin. Digoxin half-life was significantly prolonged (mean 97 +/- 17 hour) following indomethacin therapy as compared with an age matched control group (mean half-life 43 +/- 19 hour) (P less than 0.05). Our data suggest that when indomethacin is added to digoxin therapy, the digoxin dosage should be reduced by 50% until urine output and digoxin serum levels can be better assessed.

Digoxin↗