digitoxin and Kidney-Diseases

Plasma protein binding of most acidic drugs is decreased in uraemia, whereas the binding of basic drugs is usually unchanged or decreased. Decreased protein binding in patients with renal disease mainly relates to drugs binding to albumin. Digitoxin binds to a specific site on the albumin molecule. Conflicting reports exist on digitoxin-protein binding in patients with renal disease. In ten patients with end-stage renal disease treated with haemodialysis we found only a slightly increased free fraction of digitoxin. A heparin-induced increase of the free fraction of digitoxin during haemodialysis has been reported. However, this increase was caused by the generation of non-esterified fatty acids in vitro. If this in vitro lipolysis was blocked, no increase of free digitoxin could be detected. Alterations of digitoxin-protein binding in uraemic patients during haemodialysis and during the intervals between haemodialysis treatments are small.

Topics: Blood Proteins; Digitoxin; Humans; Kidney Diseases; Pharmaceutical Preparations; Protein Binding

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

When prescribing cardiac glycosides for patients with renal failure, one should consider the different pharmacokinetics of the two most important glycosides, digoxin and digitoxin. Whereas steady state plasma concentrations of digoxin are altered proportionally to renal clearance of creatinine, those of digitoxin remain the same throughout a wide range of renal impairment. The steady state level of both glycosides is partly determined by several clinical factors such as dose, body weight, height, age and serum potassium. However, it is thought that bioavailability, volume of distribution, biotransformation, and total body clearance have the greatest importance for the variability of the plasma glycoside concentrations in patients with normal and with impaired renal function. The bioavailability and biotransformation of digoxin do not vary between healthy subjects and patients with renal insufficiency. As the volume of distribution is smaller in patients with severe renal failure that in normal subjects, the loading dose has to be altered. With decreasing creatinine clearance the total body clearance as well as the renal clearance of digoxin is reduced. On the basis of this assumption maintenance dosage regiments must be adjusted. For digitoxin, the four above-mentioned pharmacokinetic parameters are not altered in patients with renal failure compared to healthy subjects. Moreover, investigations dealing with this problem have suggested an altered protein binding of digitoxin and its metabolites as a possible factor in avoiding accumulation of the drug. However, it is one of the aims of this article to show that a decreased urinary excretion of digitoxin and metabolites is compensated by an increased excretion via the feces. Loading dose and maintenance dose of digitoxin do not have to be adjusted in patients with renal failure.

Topics: Biological Availability; Biotransformation; Digitalis; Digitoxin; Digoxin; Humans; Kidney Diseases; Kinetics; Metabolic Clearance Rate; Plants, Medicinal; Plants, Toxic

Topics: Biotransformation; Cytochrome P-450 Enzyme System; Diazepam; Digitoxin; Digoxin; Drug Interactions; Drug Therapy; Drug Therapy, Combination; Enzyme Induction; Ethanol; Kidney; Kidney Diseases; Liver; Liver Diseases; Nordazepam; Receptors, Drug

The various cardiac glycosides differ significantly in their retention as a result of renal failure. In the case of digoxin, digitoxin, and strophanthin the retention is directly related to the normal renal clearance of these cardiac glycosides: Strophanthin has the highest clearance and the most marked prolongation of pharmacological action in renal failure, whereas digitoxin shows the lowest renal clearance and even in uremic patients a total elimination comparable to normal subjects as a result of increased hepatic clearance; digoxin takes an intermediate position. The quantity of a cardiac glycoside and its metabolites excreted by the kidneys depends, besides the renal clearance, on the plasma concentration which increases considerably during the first days after onset of treatment. From the daily dose approximately 90% of strophanthin, 70% of digoxin, 50% of digitoxin plus metabolites are excreted by normal kidneys under steady-state conditions. The efficiency of hemodialysis in the elimination of cardiac glycosides is low (3-5%) if estimated in relation to a single dose injected before dialysis and high (30-50%) if estimated in relation to the excretory capacity of normal kidneys during a period corresponding to the duration of a dialysis. During hemodialysis the plasma concentration of digoxin decreases as rapidly as in patients with normal renal function. Beside the efficiency of dialysis this finding may be explained by the decrease in the apparent volume of distribution of cardiac glycosides in patients with advanced renal failure; a reduced tissue protein binding seems likely to be the main reason for these changes in chronic renal insufficiency. A reduced volume of distribution and a reduced myocardial sensitivity are the main reasons for a very low predictability of the necessary individual maintenance dose of cardiac glycosides from the creatinine clearance. In patients with advanced renal insufficiency the tolerance to cardiac glycosides is reduced with respect to the daily dose, but it is rather increased in relation to the plasma concentration required to maintain the positive inotropic effect. The combination of hyperkalemia, hypermagnesemia, bypocalcemia and acidosis which is found almost exclusively with chronic renal failure, may explain the reduced myocardial sensitivity. Dosage regimens based on the measurement of creatinine-clearance are of little help in "effective digitalisation". Serial measurements of steady-state plasma concen

Topics: Cardiac Glycosides; Digitoxin; Digoxin; Drug Tolerance; Glomerular Filtration Rate; Humans; Kidney Diseases; Kinetics; Ouabain; Protein Binding; Renal Dialysis; Strophanthins; Uremia

Topics: Administration, Oral; Aged; Digitalis Glycosides; Digitoxin; Digoxin; Feces; Heart Atria; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Tachycardia; Thyroid Diseases; Tritium; Water-Electrolyte Balance

Topics: Adenosine Triphosphatases; Arrhythmias, Cardiac; Digitalis Glycosides; Digitoxin; Digoxin; Heart; Heart Failure; Heart Rate; Humans; Kidney Diseases; Kinetics; Lanatosides; Lidocaine; Myocardium; Pacemaker, Artificial; Phenytoin; Potassium; Procainamide; Propranolol; Quinidine; Thyroid Diseases

Topics: Adenosine Triphosphatases; Aged; Arrhythmias, Cardiac; Cell Membrane; Chromatography, Gas; Digitalis Glycosides; Digitoxin; Digoxin; Erythrocytes; Evaluation Studies as Topic; Humans; Kidney Diseases; Potassium; Radioimmunoassay; Radioisotope Dilution Technique; Radioisotopes; Rubidium; Sodium; Tritium

To determine whether verapamil, diltiazem, or nifedipine affect digitoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during steady-state dosing in 30 patients with cardiac insufficiency. The mean (+/- SD) digitoxin plasma concentration was 14.27 +/- 3.66 ng/ml before and 18.15 +/- 5.33 ng/ml during verapamil dosing in 10 patients over a period of 4 to 6 weeks. Renal digitoxin clearance was not influenced by verapamil, but total body clearance and extrarenal clearance of digitoxin were reduced by 27% and 29%, respectively. Diltiazem resulted in a 6% to 31% (mean = 21%) increase in plasma digitoxin concentrations in five of 10 patients because of reduced extrarenal clearance of digitoxin. In contrast to verapamil, the concomitant dosing of nifedipine over 4 to 6 weeks did not alter digitoxin plasma levels or daily renal excretion. Based on these observations, the risk of digitalis intoxication after combined dosing with verapamil and digitoxin is much less pronounced than that after digoxin, and thus this glycoside is a valuable alternative.

Topics: Aged; Benzazepines; Clinical Trials as Topic; Digitoxin; Diltiazem; Drug Interactions; Drug Therapy, Combination; Female; Heart Diseases; Humans; Kidney; Kidney Diseases; Kinetics; Liver Diseases; Male; Middle Aged; Nifedipine; Radioimmunoassay; Verapamil

Topics: Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Bradycardia; Cardiac Complexes, Premature; Cardiomegaly; Clinical Trials as Topic; Coronary Disease; Digitalis Glycosides; Digitoxin; Heart Aneurysm; Heart Failure; Heart Valve Diseases; Humans; Hypertension; Kidney Diseases; Lung Diseases; Middle Aged; Spinal Diseases; Tablets; Tachycardia

Endogenous digoxin-like immunoreactive factors (DLIF) can interfere with some digoxin immunoassays. We looked for similar interference, called digitoxin-like immunoreactive factors (DTLIF) in two digitoxin immunoassays: A new chemiluminescent assay (CLIA), processed on the automated random access immunoassay system ACS:180, and a fluorescent polarization assay (FPIA), processed on the semiautomated TDx batch analyzer. One hundred thirty-seven samples of sera were tested from nondigitalized pregnant women, patients with liver or kidney diseases, and cord blood. The CLIA digitoxin assay uses a murine monoclonal antibody and requires no sample pretreatment; the FPIA digitoxin assay uses a polyclonal rabbit antibody and requires sample precipitation. Both assays have a similar dynamic range and sensitivity and give comparable results with commercial controls and external quality control survey samples. Although the CLIA detected no digitoxin in any sample tested, the FPIA showed apparent digitoxin concentrations of more than 2.0 ng/ml for 100% and 44% among cord blood and liver disease specimens, respectively. The highest DTLIF concentration was found in serum from a patient with liver disease (18.1 ng/ml). When spiked with 32 ng/ml digitoxin, six of the samples containing DTLIF generated FPIA digitoxin values of 6% to 27.5% more than the expected digitoxin levels. Two specimens with no detectable DTLIF activity were run as controls, and when spiked with digitoxin, showed target digitoxin concentrations in the FPIA. The CLIA recovered near the target digitoxin values (32 ng/ml) in all spiked samples. It was concluded that the polyclonal FPIA digitoxin assay may give discordant digitoxin concentrations in some patient groups because of interference from digitoxin-like immunoreactive factors. The CLIA digitoxin assay is not affected by DTLIF interference.

Topics: Antibodies, Monoclonal; Cardenolides; Digitoxin; Digoxin; Female; Fetal Blood; Fluorescence Polarization; Fluorescence Polarization Immunoassay; Humans; Immunoassay; Kidney Diseases; Liver Diseases; Luminescent Measurements; Pregnancy; Saponins; Sensitivity and Specificity; Uremia

Topics: Antibody Specificity; Blood Proteins; Cardenolides; Digitoxin; Digoxin; Female; Fetal Blood; Humans; Immune Sera; Kidney Diseases; Liver Diseases; Pregnancy; Saponins

1. Plasma albumin concentration was measured in 118 healthy subjects (aged between 18 and 87 years), in 95 renal patients with creatinine clearances between 15 and 50 ml min-1 (aged between 14 and 79 years) and in 101 uraemic patients maintained on chronic haemodialysis (aged between 27 and 83 years). 2. There was a significant (P less than 0.001) negative correlation between albumin concentration and age in healthy subjects, but no correlation in patients with low creatinine clearance or in uraemic patients. 3. The ex vivo plasma binding of diazepam (1 microM), salicylic acid (2 mM) and digitoxin (37 nM) was studied in groups of age-selected young and aged healthy subjects in patients with low creatinine clearance and in patients with uraemia. The unbound fractions of diazepam and salicylic acid were about double in old compared with young healthy subjects whereas they were similar in young and old patients with lowered creatinine clearance. In uraemic patients, ageing did not affect the binding of salicylic acid whereas the unbound fraction of diazepam was slightly but significantly greater in elderly subjects. The unbound fraction of digitoxin was independent of age in both healthy subjects and in those with renal disease. 4. Decreased plasma binding of diazepam and salicylic acid was partially corrected by extensive dialysis of plasma. The lower plasma binding of diazepam and salicylic acid associated with ageing may be ascribed to the effects of endogenous displacers and to hypoalbuminaemia. The influence of these two factors appears to be drug-dependent.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Blood Proteins; Diazepam; Digitoxin; Humans; Kidney Diseases; Middle Aged; Salicylates; Salicylic Acid; Serum Albumin

The molecular structure is one of the keypoints that govern both the extent of extracardiac action of cardiac glycosides and their different kinetics. The apolar, fat soluble digitoxin is very well absorbed from the intestine, its onset of action is slow, binds to a high degree to albumin and undergoes enterohepatic recirculation which accounts for a long elimination half time and stability of plasmatic levels. Digitoxin is largely excreted via gastrointestinal tract. The absorption of digoxin is less reliable, onset of action occurs earlier and the binding to albumin is considerably less than that of digitoxin. The drawback, however small, of digoxin lies in a lower stability of plasma levels and prevailing renal excretion. The molecule of strophatin is highly polar, its absorption from the intestine negligible and can be administered only intravenously. The onset of action is prompt, elimination half time short and about half the injected amount is excreted extrarenally.

Topics: Cardiac Glycosides; Digitoxin; Digoxin; Gastrointestinal Diseases; Humans; Kidney Diseases; Strophanthins; Thyroid Diseases

Topics: Administration, Oral; Arrhythmias, Cardiac; Biological Availability; Digitoxin; Dosage Forms; Humans; Immunoenzyme Techniques; Kidney Diseases; Liver Diseases; Radioimmunoassay; Specimen Handling

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.

Topics: Administration, Oral; Adult; Aged; Digitoxin; Female; Hepatorenal Syndrome; Humans; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged

Following administration of digitoxin, 1 mg intravenously, the pharmacokinetics of this glycoside were studied in eight healthy volunteers and in eight patients with hepatorenal insufficiency (mean creatinine clearance 19.6 +/- 2.9 ml/min; antipyrine clearance 25.6 +/- 3.2 ml/min; means +/- SEM). Liver cirrhosis of the patients was confirmed by liver biopsy. Plasma protein binding of digitoxin (means +/- SEM) was 95.1 +/- 0.7% in the patients and 95.6 +/- 1.2% in the volunteers (NS). Total body clearance of digitoxin was 0.0530 +/- 0.0040 ml/min/kg of body weight in the patients and 0.0547 +/- 0.0043 ml/min/kg of body weight in the healthy subjects (NS). When elimination half-lives of the patients and the volunteers were compared, there was also no significant difference (7.0 +/- 0.77 days in the patient group and 7.8 +/- 0.8 days in the volunteers). Our data concerning digitoxin kinetics in patients with hepatorenal insufficiency do not indicate an accumulation of the drug in these patients.

Topics: Adult; Aged; Biological Availability; Body Weight; Digitoxin; Female; Half-Life; Humans; Kidney Diseases; Kinetics; Liver Diseases; Male; Middle Aged

Serum digitoxin levels were measured during maintenance treatment with digitoxin, 0.1 mg daily i.v., in 12 patients under intensive postoperative care who had hepatorenal failure resulting from multiple organ failure. Thirteen patients in intensive care with comparable basic diseases served as controls; they had developed predominantly renal failure. Serum digitoxin levels in the two groups were no different and remained within therapeutic range during the total period of observation of 8-40 days. During this time toxic serum digitoxin levels were measured in 2.9% of patients in renal failure and 2.7% of patients with hepatorenal failure. The pathogenesis of the liver failure and the severity of the underlying disease did not influence serum digitoxin levels. Digitoxin was tolerated similarly in the two patient groups.

Topics: Adult; Aged; Digitoxin; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Shock; Shock, Septic

Topics: Anti-Inflammatory Agents; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Humans; Kidney Diseases; Liver Diseases

Topics: Chemical Phenomena; Chemistry; Digitalis; Digitoxin; Digoxin; Drug Interactions; Humans; Kidney Diseases; Kinetics; Liver Diseases; Plants, Medicinal; Plants, Toxic

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

Topics: Adult; Aged; Angina Pectoris; Digitoxin; Echocardiography; Electrocardiography; Female; Heart; Heart Auscultation; Heart Diseases; Heart Failure; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Risk

Topics: Digitoxin; Digoxin; Dose-Response Relationship, Drug; Half-Life; Heart Failure; Humans; Intestinal Absorption; Kidney Diseases; Protein Binding

Topics: Absorption; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Kidney; Kidney Diseases; Liver; Proscillaridin; Strophanthins

In a prospective study of digitalis intoxication in 649 patients on maintenance treatment with digitoxin a low incidence of digitalis toxicity was found, namely, 5.8 per cent. This is mainly due to a more careful use to digitalis glycosides. It is especially important to reduce the dose of digitoxin in the liver and partly excreted metabolized in the liver and partly excreted through the kidneys as metabolities. Serum half-time of digitoxin is shortened in patients with impaired renal function. Patients with reduced renal function may be treated with digitoxin in the same doses as individuals with normal renal function. This is in contrast to patients treated with digoxin. Digitoxin should therefore be the cardiac glycoside of choice in treatment of patients with renal failure. Digitoxin is further rapidly eliminated in patients with reduced liver function in spite of its extensive hepatic metabolism. In this study extracardia symptoms were found equally often as cardiac signs of toxicity. Patients intoxicated usually had several symptoms and signs of toxicity at the same time. The specificity of commonly used symptoms and signs a digitalis intoxication is very low. In this study atrial tachycardia with block, which has been considered to be an important cardiotoxic arrhythmia, very seldom was found in digitalis intoxication. There is an overlap in digitalis serum concentration between toxic and nontoxic patients. The diagnosis of toxicity was made on clinical grounds. Most of the intoxicated patients had high serum concentrations, but some had concentrations in the normal or low range. Apart from being a guide to the diagnosis of digitalis intoxication, serum digitalis levels may further be a guide to underdigitalization of cardiac patients, especially patients in sinus rhythm.

Topics: Age Factors; Aged; Arrhythmias, Cardiac; Body Weight; Digitoxin; Female; Humans; Kidney Diseases; Liver; Male; Middle Aged; Prospective Studies

Topics: Biological Availability; Cardiac Glycosides; Creatinine; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Humans; Hypokalemia; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Ouabain; Thyroid Diseases

Topics: Digitoxin; Humans; Kidney Diseases; Radioimmunoassay

In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 (+/- 1.86, range 0.6-8.2) ng/ml, significantly higher (P less than 0.001) than the "eudigitalized" concentration (1.3 +/- 0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ng/ml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 +/- 2.66 v. 1 +/- 0.26 mg/dl for non-toxic subjects, P less than 0.001), partly due to a higher mean daily digoxin dose (0.40 v 0.31 mg/day, P less than 0.05) and frequently associated with potent diuretic therapy (73 v 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (14%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 (+/- 63.3, range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration (r=0.8107, P less than 0.01) or serum creatinine concentration (r=0.4637, P less than 0.001).

Topics: Adult; Aged; Blood Urea Nitrogen; Coronary Disease; Creatinine; Digitoxin; Diuretics; Female; Heart Arrest; Humans; Kidney Diseases; Male; Middle Aged; Myocardium; Time Factors

Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Dialysis

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: Digitoxin; Digoxin; Humans; Kidney Diseases

Topics: Adenosine Triphosphatases; Adolescent; Adult; Age Factors; Animals; Calcium; Cell Membrane; Child; Child, Preschool; Digitalis; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Kidney Diseases; Myocardium; Ouabain; Plants, Medicinal; Plants, Toxic; Sodium; Tritium

Topics: Acidosis; Angina Pectoris; Digitalis; Digitalis Glycosides; Drug Therapy; Electrocardiography; Humans; Hyperkalemia; Kidney Diseases; Potassium; Toxicology; Uremia; Water-Electrolyte Balance

Topics: Digitalis; Digitoxin; Humans; Hypokalemia; Kidney Diseases