digoxin and Nephrotic-Syndrome

This review mainly summarizes selected aspects of the present knowledge of drug elimination kinetics independent of developmental changes, with special attention given to clinical situations. The effects of different disease states, drug interactions, changes in urinary pH, induction of microsomal enzymes, competition for renal excretory mechanisms, possible enterohepatic recirculation, binding of drugs to tissues, effects of a drug on another drug's metabolizing organ, and dose-dependent elimination, on increase or decrease of drug elimination rates in children, have been presented. Based on the available data it seems that one may postulate the following conclusions: (1) that the distribution factors as well as changes in drug elimination capacities seem to play a role, perhaps with differing relative importance, during each of the maturational periods; (2) that the physicochemical properties of a drug and its dosage, as well as changes in the volume of distribution in children, in the course of certain disease states may have a significant effect on kinetics of drug disposition in the body; (3) that systemic clearance, a model independent parameter, rather than elimination half-life, a hybrid pharmacokinetic parameter, more accurately reflects elimination of some drugs from the body; (4) that each drug and every clinical situation may require the evaluation of the direct effect on pharmacokinetic processes, since general principles may not always apply; (5) that drug disposition studies should also be performed, if possible, on patients under actual clinical situations and receiving the usual therapeutic regime, and (6) that the half-life of colistin is independent of postnatal age which should serve as a warning not to generalize about drug excretion in the young infant.

Topics: Adult; Anti-Bacterial Agents; Brain Injuries; Child; Child, Preschool; Colistin; Cystic Fibrosis; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Heart Failure; Humans; Hydrogen-Ion Concentration; Hypothermia, Induced; Infant; Infant, Newborn; Kidney; Kinetics; Liver; Nephrotic Syndrome; Nutrition Disorders; Pharmaceutical Preparations; Phenobarbital; Reye Syndrome; Serum Albumin; Urine

Variability in the response to drugs is due to three principal components-the disease, the responsiveness of tissues, and the concentration of the drug at its site of action (as reflected by its plasma concentration). The relative contributions of these components will differ not only for different drugs but also for different effects of the same drug. Rational drug therapy depends on knowledge of all three factors.

Topics: Acute Disease; Acylation; Chlorthalidone; Chronic Disease; Depression; Diazoxide; Digoxin; Dose-Response Relationship, Drug; Glomerulonephritis; Humans; Hypertension; Nephrotic Syndrome; Norepinephrine; Nortriptyline; Oxidation-Reduction; Phenylthiourea; Serotonin; Spironolactone; Steroids

1. In the nephrotic syndrome the kidneys retain salt and water, which leads to oedema formation. The site of this sodium retention has been localized in the cortical collecting tubule by micropuncture studies. Whether or not this phenomenon is an intrinsic renal problem or is the consequence of changes in hormonal activities is still a matter of discussion. 2. Using the model of puromycin aminonucleoside-induced nephrotic syndrome in the rat, we measured Na+,K(+)-ATPase activity in nephron segments from control and nephrotic rats and investigated the regulatory role of aldosterone and endogenous-ouabain-displacing factor. 3. Nephrotic animals had a twofold increase in Na+,K(+)-ATPase activity in the cortical collecting tubule only (control versus nephrotic: 1065 +/- 68 versus 2081 +/- 274 pmol h-1 mm-1, P = 0.036), which was not modified by adrenalectomy and was independent of the kidney content of endogenous ouabain-displacing factor. Na+,K(+)-ATPase activity in the cortical collecting tubule correlated with the sodium balance in both control and nephrotic rats. 4. The data are consistent with the view that sodium retention in this model of the nephrotic syndrome is a primary event, i.e. an increase in sodium transport throughout the cortical collecting tubule expressed as a twofold increase in Na+,K(+)-ATPase activity which is no longer under hormonal regulation (aldosterone and endogenous ouabain-displacing factor).

Topics: Adrenalectomy; Aldosterone; Animals; Cardenolides; Digoxin; Kidney; Male; Nephrons; Nephrotic Syndrome; Proteins; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

Longitudinal changes of digoxin-like immunoreactive substance (DLIS) in serum and urine from nephrotic children have been studied. The magnitude of DLIS in samples was measured by digoxin RIA kit. The binding activity to the ouabain receptor was measured by radioreceptor assay using crude rat brain synaptosomal fraction. In five cases of nephrosis, the mean value of DLIS in diuresis was significantly higher than during other stages (p less than 0.05). It was also higher than the levels recorded for six patients with nephritis (p less than 0.05). The presence of DLIS in the urine followed a similar pattern. The positive correlation between urine DLIS and ouabain-like substance (OLS) corrected by creatinine was observed for one month after the onset of nephrosis. The present study indicates the presence of DLIS in the serum and urine from patients with nephrosis which have the binding activity to the ouabain receptor. DLIS may be involved in natriuresis and may regulate active sodium transport in nephrotic children.

Topics: Blood Proteins; Cardenolides; Child; Digoxin; Female; Humans; Male; Natriuresis; Nephrotic Syndrome; Ouabain; Radioimmunoassay; Receptors, Drug; Saponins; Sodium-Potassium-Exchanging ATPase; Time Factors

Topics: Adult; Aged; Anti-Glomerular Basement Membrane Disease; Digoxin; Female; Glomerulonephritis; Humans; Hypertension, Malignant; Lupus Vulgaris; Lymphoma; Male; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Plasma Exchange; Plasmapheresis; Purpura, Thrombocytopenic; Vasculitis; Waldenstrom Macroglobulinemia

The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method modified for analysis of myocardial samples. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respectively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).

Topics: Adult; Autopsy; Biopsy; Digitoxigenin; Digitoxin; Digoxin; Female; Humans; Male; Middle Aged; Myocardium; Nephrotic Syndrome; Renal Dialysis

Plasma digoxin was determined by three different radioimmunoassays in blood samples from 12 patients with hypoalbuminemia before and after increasing the concentration of albumin and TBG. With the Clinical-Assays-[125I]-Kit and the Schwarz/Mann-[3H]-Kit reliable digoxin values were obtained even in patients with severe nephrotic syndrome.

Topics: Digoxin; False Negative Reactions; Humans; Nephrotic Syndrome; Serum Albumin; Thyroxine-Binding Proteins

Serum protein binding of digitoxin was lower (p less than 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimation was 4.8 days and 8.1 days in 5 control subjects (p less than 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p less than 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.

Topics: Blood Proteins; Digitoxin; Digoxin; Half-Life; Humans; Kinetics; Nephrotic Syndrome; Protein Binding; Serum Albumin; Time Factors

Topics: Digoxin; Diuretics; Drug Therapy; Ethacrynic Acid; Geriatrics; Heart Failure; Humans; Hydrochlorothiazide; Liver Cirrhosis; Nephrotic Syndrome; Triamterene; Urination Disorders; Urine; Water-Electrolyte Balance

Topics: Angiomatosis; Cholesterol; Chylomicrons; Chylothorax; Chylous Ascites; Digoxin; Diuretics; Drug Therapy; Exudates and Transudates; Geriatrics; Glycerides; Heart Failure; Humans; Lipids; Lung Neoplasms; Nephrotic Syndrome; Prednisone; Tritium