digitoxin and Kidney-Failure--Chronic

Patients with chronic renal failure develop a cardiomyopathy characterized by marked diastolic dysfunction and left ventricular hypertrophy. Interestingly, they also have substantial increases in the circulating concentrations of digitalis like substances. Digitalis like substances produce reactive oxygen species as part of the signal cascade induced by binding to the sodium pump and patients, and this signal cascade appears to induce hypertrophy of cardiac myocytes grown in culture. Also, patients with chronic renal failure develop an oxidant stress state without a known mechanism. From these data, we propose that it is these digitalis like substances which cause cardiomyopathy of renal failure as well as the systemic oxidant stress state.

Topics: Cardenolides; Cardiomyopathies; Digitalis; Humans; Kidney Failure, Chronic; Saponins; Uremia

Digitalis glycosides continue to place high on the list of prescribed drugs. Digoxin is 8th on prescriptions written in the United States in 1980, digitoxin 16th, and digitalis leaf 23rd. There is little doubt that most physicians continue to believe these drugs are useful. The application of more definite indications, smaller doses, and the recognition of the role of pharmacokinetics and drug interactions make use of the glycosides more challenging than ever before in 1985.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Age Factors; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Biological Availability; Bretylium Tosylate; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Failure, Chronic; Lidocaine; Metabolic Clearance Rate; Myocardial Infarction; Obesity; Phenytoin; Potassium; Pulmonary Heart Disease; Thyroid Diseases

Topics: Apazone; Bilirubin; Binding Sites; Carrier Proteins; Diazepam; Digitoxin; Fatty Acids, Nonesterified; Half-Life; Humans; Hydrogen-Ion Concentration; Indoles; Kidney Diseases; Kidney Failure, Chronic; Kinetics; Ligands; Liver; Methods; Protein Binding; Protein Conformation; Renal Dialysis; Serum Albumin; Toxins, Biological; Uremia; Warfarin

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Acid-Base Imbalance; Aged; Atropine; Cardiac Complexes, Premature; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Heart Block; Heart Failure; Heart Ventricles; Humans; Kidney Failure, Chronic; Phenytoin; Potassium; Tachycardia

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Heart Failure; Humans; Hyperthyroidism; Hypothyroidism; Intestinal Absorption; Kidney Failure, Chronic; Molecular Conformation; Obesity

Topics: Anti-Bacterial Agents; Antihypertensive Agents; Cardiac Glycosides; Clofibrate; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Humans; Kidney Failure, Chronic; Phenytoin; Protein Binding; Sulfonamides; Triamterene

The effect of multiple oral doses of activated charcoal on digitalis glycoside kinetics was studied to determine whether an activated charcoal regimen might have utility in treating patients with digitalis toxicity. Normal subjects were given intravenous infusions of digoxin 0.75 mg/70 kg or digitoxin 1 mg/70 kg iv followed by either water alone or water with activated charcoal in divided doses in a randomized crossover design. A subject with chronic renal failure was also given digoxin 0.5 mg/70 kg iv followed by water alone or water with activated charcoal. In six normal subjects, treatment with activated charcoal did not increase digoxin clearance (Cl) significantly (16.79 +/- 1.70 vs. 22.68 +/- 3.51 L/h). However, digitoxin Cl did increase significantly, from 0.24 +/- 0.01 to 0.47 +/- 0.04 L/h. In the renal failure subject, digoxin Cl increased from 3.6 L/h to 10.1 L/h. We conclude that the activated charcoal regimen is probably useful in patients with digitoxin toxicity. Although similar benefit is limited in patients with normal renal function who develop digoxin toxicity, it is possible that activated charcoal will be useful in patients with prolonged digoxin elimination due to renal dysfunction.

Topics: Adult; Charcoal; Digitoxin; Digoxin; Humans; Kidney Failure, Chronic; Kinetics; Male

The indication for digitalis treatment was investigated in a controlled and prospective study lasting 12 months in 110 patients on long-term haemodialysis. In ten patients, digitalis was needed because of tachyarrhythmia due to atrial fibrillation and in five because of recurrent pulmonary edema. In 57 patients receiving digitoxin, therapy was discontinued for 4 to 6 weeks, whereas 13 patients not yet treated with digitalis, received digitoxin for 4 weeks. Without digitoxin, trial fibrillation occurred in 4 patients, while no patient experienced atrial fibrillation with digitoxin (P = 0.002). In 13 patients, radiological findings (heart enlargement, pulmonary congestion) were better with digitoxin than without. Thus digitoxin appeared to be clearly indicated in 29% of the haemodialysed patients. Additionally, digitalis was indicated in 31 patients because of heart enlargement, pulmonary congestion and (or) previous pulmonary edema. Initially, 76% of the patients were receiving digitoxin, whereas, after the investigation, the rate was only 57% (P less than 0.001). The prospective frequency of clinically apparent digitoxin intoxication was low (3%) and so were the overall toxic plasma digitoxin levels (5%). Digitalis should be given deliberately but not restrictively to haemodialysis patients, since atrial fibrillation (13%) and heart failure (50%) are frequent and often concealed.

Topics: Adult; Aged; Atrial Fibrillation; Cardiomegaly; Clinical Trials as Topic; Digitalis; Digitoxin; Digoxin; Female; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plants, Medicinal; Plants, Toxic; Pulmonary Edema; Renal Dialysis; Tachycardia; Time Factors

Topics: Aged, 80 and over; Anticonvulsants; Aspirin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiovascular Diseases; Dementia; Digitoxin; Drug Resistance; Drug Therapy, Combination; Epilepsy, Partial, Motor; Female; Humans; Infarction, Middle Cerebral Artery; Infarction, Posterior Cerebral Artery; Kidney Failure, Chronic; Status Epilepticus; Verapamil

Topics: Digitalis; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis

In 43 ICU patients undergoing continuous volume constant hemofiltration (CVHF), the pharmacokinetics of 12 drugs were investigated to ensure correct dosage adjustments. Under conditions of CVHF, maximum doses were defined for cefotaxime, ceftazidime, digoxin, digitoxin, imipenem, metronidazole++, netilmicin, phenobarbital, phenytoin, theophylline, tobramycin, and vancomycin. For the estimation of sufficient doses without blood level measurements, sieving coefficients (S) were calculated by a new method. In addition, S was integrated as a CVHF-specific factor into a common equation for drug dose adjustment in patients with renal insufficiency. The regression of dosage received from kinetics on blood-level-independent equation adjustment was r = 0.9923. Since the volumes of distribution in ICU patients are variable, it is suggested that further drug monitoring is necessary for toxic drugs.

Topics: Adult; Aged; Cefotaxime; Ceftazidime; Digitoxin; Digoxin; Hemofiltration; Humans; Imipenem; Kidney Failure, Chronic; Metronidazole; Middle Aged; Netilmicin; Pharmaceutical Preparations; Phenobarbital; Phenytoin; Theophylline; Tobramycin; Vancomycin

The protein binding of ethinyloestradiol (EE2) was investigated in the plasma from 14 healthy volunteers, 10 patients with hyperbilirubinemia, 10 patients with liver cirrhosis and 10 patients with renal failure. Binding assay was performed by equilibrium dialysis at 37 degrees C. The unbound fraction (mean +/- SD) of EE2 was 1.17 +/- 0.12 (volunteers), 2.74 +/- 0.77 (hyperbilirubinemics; p less than 0.001) 1.51 +/- 0.31 (cirrhotics; p less than 0.01) and 1.44 +/- 0.11 (renal failure; p less than 0.001). Studies with isolated albumin and alpha-1-acid glycoprotein showed that albumin is the major plasma protein to bind EE2. Warfarin (75 microM) and diazepam (75 microM) increased by 5.0% and 3.0%, respectively, the unbound fraction of EE2 when albumin concentration was 15 microM. Under similar conditions, digitoxin did not modify the binding of EE2. At therapeutic concentrations, warfarin and diazepam did not affect the binding of EE2 in plasma.

Topics: Adult; Aged; Blood Proteins; Diazepam; Digitoxin; Drug Interactions; Ethinyl Estradiol; Female; Humans; Hyperbilirubinemia; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Protein Binding; Warfarin

Digoxin-like immunoreactive substance(s) (DLIS) in the sera of patients with renal insufficiency may confound attempts to monitor serum digoxin levels. We investigated whether DLIS would affect the radioimmunoassay (RIA) for digitoxin. DLIS was detected by RIA in 9 of 38 chronic hemodialysis patients and in none of 25 healthy controls. Digitoxin levels were not elevated in either the control or dialysis group, and false-positive results for digitoxin by RIA were not obtained in any patient with DLIS. It is concluded that DLIS does not interfere with the digitoxin RIA, nor are digitoxin levels spuriously elevated in chronic hemodialysis patients. Digitoxin may be a preferable preparation for digitalis-dependent dialysis patients with DLIS.

Topics: Digitoxin; Digoxin; False Positive Reactions; Humans; Kidney Failure, Chronic; Radioimmunoassay; Renal Dialysis

Topics: Digitoxin; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Protein Binding; Renal Dialysis

Cardiac dysfunction is common in patients with terminal renal failure. However, no consensus has been reached with respect to the indications for digitalis therapy. Depression of myocardial contractility may occur as a result of circulating toxic factors, parathyroid hormone, and altered catecholaminergic responsiveness. On the other hand, paradoxical positive inotropic effects have been observed possibly as a result of a circulating natriuretic factor (an endogenous digitalis analogue) which inhibits Na,K-ATP'ase. Pharmacokinetics and pharmacodynamics of digitalis steroids are altered in uremia. Elimination half-lives of strophanthin and digoxin are prolonged, whereas the elimination half-life of digitoxin is unchanged. Altered protein binding and volume of distribution have been noted. Despite its long elimination half-life, most nephrologists favor administration of digitoxin because of its insensitivity to changes in renal function.

Topics: Animals; Biological Availability; Blood; Blood Proteins; Cardenolides; Cardiomyopathies; Cats; Digitalis; Digitoxin; Digoxin; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Kidney Failure, Chronic; Kinetics; Metabolic Clearance Rate; Myocardial Contraction; Peritoneal Dialysis, Continuous Ambulatory; Plants, Medicinal; Plants, Toxic; Rabbits; Rana temporaria; Rats; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase; Stimulation, Chemical; Ultrafiltration; Uremia

Evidence exists which demonstrates the relationship between a Natriuretic Factor or Na+,K+-ATPase inhibitor and volemic expansion, both in man and animal. Patients having extracellular volume expansion have been studied for the effect of their plasma on erythrocytes 3H-ouabain binding. High levels of ouabain-like activity was found in plasma from acromegalic patients and patients with chronic renal failure. High levels were also observed in some hypertensive patients. A partial purification of such a compound was performed from urine of hypertensives. The partially purified compound inhibited to a greater extent the Na+,K+-ATPase semi-purified from dog kidney than that from sheep brain. The present data are consistent with the possible regulation of the activity or the secretion of plasma ouabain-like activity by extracellular volume.

Topics: Acromegaly; Animals; ATPase Inhibitory Protein; Binding Sites; Brain; Digitalis; Dogs; Dose-Response Relationship, Drug; Erythrocytes; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Kinetics; Ouabain; Plants, Medicinal; Plants, Toxic; Proteins; Swine

The digitalis-like activities of plasma extracts from 108 patients and normal subjects were measured by their ability to compete with ouabain for binding to the digitalis sites of the Na+-pump. High levels were found in 18 of 54 untreated patients with moderate hypertension, 10 of 14 patients with end-stage renal failure and six patients with active acromegaly. These levels returned to control values after dialysis in the patients with renal insufficiency and high levels of the inhibitor, and after successful surgery and cobalt therapy in seven acromegalic patients. An increase in circulating Na+, K+-ATPase inhibitor was also found in rats after chronic sodium loading. These results indicate that levels of the circulating compound with digitalis-like properties do not result from high blood pressure but, rather, are related to blood volume and Na+ balance.

Topics: Acromegaly; Adult; Animals; ATPase Inhibitory Protein; Blood Proteins; Blood Volume; Digitalis; Erythrocytes; Female; Humans; Hypertension; Ion Channels; Kidney Failure, Chronic; Male; Middle Aged; Ouabain; Plants, Medicinal; Plants, Toxic; Proteins; Rats; Receptors, Drug; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Adult; Child; Digitalis; Heart Diseases; Heart Failure; Humans; Kidney Failure, Chronic; Kinetics; Long-Term Care; Plants, Medicinal; Plants, Toxic

Topics: Digitoxin; Digoxin; Female; Humans; Hydroxylation; Kidney Failure, Chronic; Male; Protein Binding; Radioimmunoassay

Topics: Adrenergic beta-Antagonists; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Heart Failure; Humans; Hyperthyroidism; Kidney Failure, Chronic; Liver Diseases; Quinidine

Topics: Digitoxin; Digoxin; Dose-Response Relationship, Drug; Glycosides; Heart Failure; Humans; Kidney Failure, Chronic; Metabolic Clearance Rate; Proscillaridin; Strophanthins; Uremia

Topics: Aged; Digitoxin; Digoxin; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases

In recent years, lactic acidosis has been described in association with metformin therapy in diabetics. We report a fatal case in an elderly diabetic patient with impaired renal function and cardiac insufficiency. The patient presented with an elevated plasma metformin concentration and a concomitant digitoxin intoxication.

Topics: Acidosis; Aged; Diabetes Mellitus; Diabetic Nephropathies; Digitoxin; Female; Humans; Kidney Failure, Chronic; Lactates; Metformin

A gas-chromatographic mass-spectroscopic technique was used to identify dihydrodigitoxin, a metabolite of digitoxin, in the plasma of healthy volunteers and patients with renal failure. Digitoxin and dihydrodigitoxin were extracted from plasma and derivatized with heptafluorbutyric anhydride. In normal subjects, only minimal concentrations of dihydrodigitoxin in plasma could be determined (1 ng/ml) after an intravenous bolus injection of digitoxin. Under a chronic treatment with a daily dose of 0.1 mg digitoxin in three out of seven individuals, detectable dihydrodigitoxin plasma levels were observed (0.7, 1.5, and 1.7 ng/ml) (Table I). On the other hand, in seven patients with renal failure, high dihydrodigitoxin plasma concentrations (8.9 +/- 0.9 ng/ml) were shown which were in a similar range as those of the parent compound (8.7 +/- 2.2 ng/ml) under a maintenance treatment with digitoxin.

Topics: Adult; Biotransformation; Digitoxin; Humans; Hydrogenation; Kidney Failure, Chronic

Digoxin dosage regimens for patients on chronic intermittent hemodialysis (CIH) were calculated from pharmacokinetic data of digoxin in these patients between the during hemodialyses. Especially when a maximal digitalisation is not necessary an administration of 0.125 mg digoxin only on days without hemodialysis will be adequate. The regimens should be considered as a suitable starting-point in therapy as individual differences in bioavailability, apparent volume of distribution. clearance and sensitivity may necessitate an individual correction. The place of hemodialysis in the management of severe intoxications will also be discussed. Besides, it is advised to use digoxin instead of digitoxin in patients on CIH.

Topics: Digitoxin; Digoxin; Humans; Kidney Failure, Chronic; Kinetics; Renal Dialysis

Digitoxin concentration, measured by radio-immunoassay, was significantly lower in 51 patients in chronic renal failure (23.2 +/- 7.8 mug/l) than in 29 patients in heart failure (26.5 +/- 7.3 mug/l), although both groups were on the same maintenance dose of 0.1 mg daily. Despite a normal serum albumin concentration, digitoxin protein binding was less in uraemic patients than in those with normal renal function. Renal failure did not affect intestinal digitoxin absorption. In patients in chronic renal failure elimination half-time was significantly shorter (5.7 +/- 0.9 days) than in healthy controls (7.6 +/- 1.6 days). There was no significant difference in the excretion of water-soluble ("cardioinactive") digitoxin metabolites in urine between patients in chronic renal and those in heart failure. In patients with normal renal function, of dichloromethane-soluble (cardioactive) metabolites only digitoxin could be demonstrated by thin-layer chromatography. The results indicate that patients in chronic renal failure can safely be given the same dose as those with normal renal function, without danger of over- or underdosage.

Topics: Adult; Aged; Digitoxin; Female; Half-Life; Heart Failure; Humans; Intestinal Absorption; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Radioimmunoassay; Serum Albumin

Topics: Digitoxin; Female; Humans; Kidney Failure, Chronic; Male

The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported and, after reaching of a pseudostate-equilibrium at 24 hr, an exponential decline with a mean half-life of 8.0 days. In urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin-layer chromatography in plasma, urine and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24-hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant.

Topics: Chromatography, Thin Layer; Digitoxin; Feces; Female; Humans; Kidney Failure, Chronic; Kinetics; Male; Time Factors

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population. Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dialyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin. When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (plus or minus SE) of 0.84 plus or minus 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 plus or minus 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the parmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.

Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Kinetics; Middle Aged; Renal Dialysis

Topics: Digitalis Glycosides; Digitoxin; Heart Diseases; Humans; Kidney; Kidney Failure, Chronic; Lanatosides; Liver

Plasma digoxin and digitoxin determination has proven to have an important bearing, particularly in patients with renal failure. It permits early detection of digitalis intoxication in the absence of marked clinical and ECG evidence, and adjustment of dosage accordingly. Also, in patent intoxication it makes it possible to select the right moment for resumption of therapy. To illustrate the importance of the method some cases are cited involving plasma digoxin and digitoxin determination.

Topics: Acute Kidney Injury; Bradycardia; Creatinine; Digitalis Glycosides; Digitoxin; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Antigen-Antibody Reactions; Body Weight; Cardiomyopathies; Creatinine; Digitoxin; Humans; Immune Sera; Kidney Failure, Chronic; Methods; Middle Aged; Nephrotic Syndrome; Radioimmunoassay; Serum Albumin

Topics: Administration, Oral; Aged; Arrhythmias, Cardiac; Digitalis Glycosides; Digitoxin; Digoxin; Heart Block; Heart Diseases; Heart Failure; Humans; Hyperthyroidism; Injections, Intravenous; Kidney Failure, Chronic; Middle Aged; Obesity; Ventricular Fibrillation

Topics: Administration, Oral; Adult; Creatinine; Digitalis Glycosides; Digitoxin; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Kidney Failure, Chronic; Middle Aged; Radioisotopes; Rubidium; Time Factors; Uremia

Topics: Aged; Blood Urea Nitrogen; Calcium; Coronary Disease; Creatinine; Digitalis Glycosides; Digitoxin; Digoxin; Electrocardiography; Evaluation Studies as Topic; Heart Failure; Heart Valve Diseases; Humans; Kidney Failure, Chronic; Middle Aged; Myocardial Infarction; Photometry; Potassium; Radioimmunoassay; Saliva; Specimen Handling; Spectrophotometry, Atomic

Topics: Aged; Cerebrovascular Circulation; Coronary Circulation; Digitalis; Diuretics; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Phytotherapy; Plants, Medicinal; Plants, Toxic

Topics: Digitoxin; Digoxin; Drug Tolerance; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis; Strophanthins; Uremia

Topics: Cardanolides; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Kidney; Kidney Failure, Chronic; Ouabain; Pyrans; Strophanthins; Time Factors; Tritium

Topics: Adolescent; Adult; Aged; Blood Urea Nitrogen; Creatinine; Digitoxin; Feces; Female; Humans; Kidney Failure, Chronic; Liver Diseases; Male; Middle Aged; Tritium