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PubMed1992

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? II. Digitoxin.

Postmortem digitoxin levels in the choroid-retina and vitreous humor of patients who had undergone digitoxin therapy (therapeutic group) and in one case of suicidal digitoxin poisoning were measured and compared with levels in femoral vein blood, myocardium, kidney and liver. The results were interpreted in light of the medical history of each patient. The digitoxin level in the choroid-retina of the single case of suicidal poisoning was far higher than the choroid-retinal levels in the therapeutic group. In the latter, variation in choroid-retinal levels was comparable to that in the other tissues. In cases where the choroid-retina of the right and left eyes were examined, digitoxin levels in both eyes were essentially equal. There was no indication of significant changes in choroid-retinal levels due to postmortem diffusion of digitoxin into the vitreous body. Based on these results, determination of digitoxin levels in the choroid-retina could contribute to improving postmortem diagnosis of lethal digitoxin poisoning.

Adult↗

PubMed1987

Effect of digitoxin on cardiac arrhythmias in hemodialysis patients.

Digitoxin is considered a risk factor for ventricular arrhythmias in hemodialysis patients. In a randomized, crossover controlled study, 55 hemodialysis outpatients with sinus rhythm were prospectively investigated in two 48-h periods of electrocardiographic monitoring, one on and one off digitoxin or vice versa. The frequency of ventricular ectopic beats (mean +/- SD) which were found in 31 of 55 patients (56%), was slightly higher on hemodialysis (10 +/- 28 beats/h) than in the following 20 h (5.4 +/- 10 beats/h) and the next day off hemodialysis (3.6 +/- 6.6 beats/h); however, no difference was seen in patients on digitoxin during hemodialysis (10 +/- 29 beats/h), in the following 20 h (4.8 +/- 15 beats/h) and on the next day off hemodialysis (1.2 +/- 6.6 beats/h). The frequency of ventricular bigemini, polymorphous ectopies, couplets, more than 30 ectopies/h, salvos and tachycardias (10 vs 9 patients) on and off digitoxin was about the same (n.s., Fisher test). Supraventricular bigemini, salvos, tachycardias, and atrial fibrillation, however, occurred in significantly fewer patients on digitoxin (3 vs 13) than in those off digitoxin (P = 0.01, Fisher test). It is concluded that digitoxin does not increase the risk of ventricular arrhythmias in hemodialysis patients. Digitoxin, however, may have a beneficial effect on the supraventricular arrhythmias frequently observed in these patients.

Adult↗

PubMedDate not supplied

Correlation between pharmacokinetics and intropic and electrophysiologic responses to digitoxin in the intact dog.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

Animals↗

PubMedDate not supplied

Relationship of cardiac muscle tension to Na+,K+-adenosine triphosphatase activity after chronic digitoxin administration in cats.

To obtain a better understanding of the mechanism of action of the cardiac glycosides, we examined inotropic and biochemical effects of digitoxin in myocardium from cats chronically exposed to the drug. The mechanical function of papillary muscles was tested isometrically and left ventricular tissue was analyzed for Na+,K+-dependent adenosine triphosphatase ATPase activity. Muscles from control cat hearts developed tension at 2.5 +/- 0.7 g/mm2; muscles from cats that received subcutaneous digitoxin--100 micrograms/kg on day 1, followed by 40 micrograms/kg/day for 4 days (group A), and 75 micrograms/kg on day 1, followed by 25 micrograms/kg/day for 9 days (group B)--developed significantly greater (p less than 0.05) tension of 4.8 +/- 0.3 and 3.6 +/- 0.6 g/mm2, respectively. Further, in vitro maximal responsiveness to digitoxin was greater in the muscles from digitalized groups than in controls (p less than 0.05): Muscles from control cats had a maximal response to in vitro addition of digitoxin of 3.5 +/- 0.1 g/mm2; muscles from cats in group A reached 4.9 +/- 0.3 g/mm2, and those from group B, 4.5 +/- 0.7 g/mm2. Specific activity of microsomal Na+,K+-ATPase from hearts of digitalized groups A and B was inhibited by 50-70% (p less than 0.01). Developed tension, specific Na+,K+-ATPase activity, and in vitro maximal responsiveness to digitoxin in a third group (C) of cats receiving the least daily digitoxin (75 micrograms/kg on day 1, followed by 15 micrograms/kg/day for 29 days) were not different from controls. Mean plasma digitoxin concentrations were 33, 16, and 3 ng/ml in groups A, B, and C, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Influence of induced cholestasis on pharmacokinetics of digoxin and digitoxin in dogs.

Dogs with ligated common bile ducts were used to determine effects of cholestasis on pharmacokinetics of digoxin and digitoxin. Forty-three dogs were assigned to: group 1--sham-operated controls (n = 13); group 2--dogs with ligated common bile duct (n = 17); group 3--dogs given phenobarbital for 2 weeks before common bile duct was ligated (n = 11); or group 4--dogs with an induced biliary fistula (n = 2). Digoxin (group A) or digitoxin (group B) was given as single IV injections, and digitalis concentration in plasma was measured by radioimmunoassay. In 18 dogs given digoxin, differences in plasma digoxin concentrations among groups 1A to 3A were not significant (P greater than 0.1). Plasma elimination rate of digoxin was delayed in group 2A. Group-3A dogs had a shortened beta phase half-life (t1/2 (beta] and a decreased distribution volume. In 25 dogs given digitoxin, group-2B dogs maintained a significantly higher plasma digitoxin concentration (P less than 0.01) and had a significantly longer t1/2 (beta] than did dogs in groups 1B and 3B (P less than 0.05). In group-3B dogs, plasma digitoxin concentration was decreased and t1/2 (beta] of digitoxin was shortened. In 10 group-B dogs given 3H-digitoxin (groups 1B, 2B, and 4B), the excretion of total radioactivity in urine and bile was 15 to 20 and 7% of the dose, respectively in the first 24 hours. Most radioactivity in urine and bile was a dichloromethane-unextractable fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

Quantitative studies on acid hydrolysis of digitoxin.

Hydrolysis of 3H(G)-digitoxin by hydrochloric acid and human gastric juice is described. Incubation temperatures of 37 degrees C and 22 degrees C were chosen for electrolyte solutions, and 37 degrees C for the experiments with gastric juice. After dichloromethane extraction, the radioactive metabolites were separated by thin-layer chromatography, localized and quantified by a radiochromatogram scanner. The degradation products separated by TLC were digitoxigeninbis-digitoxoside, digitoxigenin-mono-digitoxoside, and digitoxigenin. After 10 min of incubation at pH 1, digitoxin amounted to 38.6% of the total radioactivity in electrolyte solution and 37.6% in gastric juice. After 60 min, the percentage of digitoxin decreased to 5.9% and 0%, respectively. After 120 min at 22 degrees C, amounts of unhydrolyzed digitoxin were: at pH 1 55%; and at pH 2 84%. After 10 min at pH 1, and 60 min at pH 2, digitoxin was hydrolyzed to such an extent that bioavailability should have been significantly reduced. Absorption of digitoxin (liquid) from the stomach was studied during gastroscopy in five patients. Among them, significant differences in absorption kinetics and bioavailability existed, as revealed by radioimmunological measurements of the digitoxin blood levels.

Chemical Phenomena↗

PubMed1979

Use of cholestyramine resin in the treatment of digitoxin toxicity.

Two case reports describing the treatment of digitoxin toxicity with cholestyramine resin are presented. Both female patients were receiving 100 microgram/day of digitoxin when toxicity occurred. In both patients, digitoxin was discontinued and hypokalemia was corrected. In patient 1, lidocaine hydrochloride and phenytoin sodium also were administered. Serum digitoxin levels were decreased from 43 ng/ml to 21.8 ng/ml and from 42 ng/ml to 29 ng/ml in patients 1 and 2, respectively, following administration of three 4-g doses of cholestyramine resin over a one-day period. Previous studies on the treatment of digitoxin intoxication with potassium chloride, phenytoin sodium, lidocaine hydrochloride, digitoxin-specific antibodies, colestipol hydrochloride and cholestyramine resin are discussed. Ion-exchange resins may be valuable adjuncts in the treatment of digitoxin intoxication but further studies of their utility are needed.

Aged↗

PubMed1977

[The biological availability of digitoxin].

The bioavailability of digitoxin after a single dose of 0.5 mg was studied in 6 healthy volunteers by estimation of tmax, cmax, AUC und urinary excretion rate. After tablets, absorption was rapid, after dragées delayed. The mean t1/2 of digitoxin for i.v. administration was 9.5 +/- 0.9 days, for oral administration of tablets 7.4 +/- 0.5 days and for dragées 9.7 +/- 2.0 days. The cumulative recovery of glycosides in urine during the first 48 hours was higher after tablets than after i.v. administration. The shorter t1/2 of digitoxin after tablets compared with the longer t1/2 after gastric juice resistent dragées demonstrated the presence of a substantial extrahepatic "first pass"-effect by degradation of digitoxin before absorption. Such mechanism would partly explain the shorter t1/2 after digitoxin-tablets due to an increased elimination of splitting products. By extrapolation to t-infinite AUC and urinary excretion rates were not significantly different between various formulations. The mean absolute bioavailability of digitoxin-dragées amounted to 82-88 percent and the relative bioavailability of digitoxin-tablets to 84-93 percent.

Administration, Oral↗

PubMed1976

Disposition of digitoxin in renal failure.

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.

Chromatography, Thin Layer↗

PubMed1976

Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin.

The aim of the present study was to investigate the nature of the previously reported changes in the serum protein binding of digitoxin and digoxin in uremic patients under treatment with hemodialysis. Kinetic studies on protein binding during hemodialysis showed that the free fraction of digitoxin rose from 2.6% to 6.9% after 5 min of hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from 78.3% to 87.1% during the same period. In vitro hemodialysis experiments showed that such changes occurred only in vivo. Injection of heparin (5,000 IU) to control subjects produced similar kinetic changes in the protein binding of digitoxin and digoxin. Free fatty acids changed in the same way. These results indicate that the heparin-induced release of free fatty acids causes displacement of digitoxin and digoxin from their albumin-binding sites. Patients on hemodialysis have lower serum levels of digitoxin and cardioactive metabolites (mean, 8.9 ng/ml) than control patients (mean, 16.7 ng/ml) (p less than 0.005) on similar doses (mean, 0.085 mg/day). They should be maintained on the same digotoxin doses as uremic and control patients, but serum digitoxin levels should be adjusted to 10 to 15 ng/ml in hemodialysis patients compared to 15 to 25 ng/ml in uremic patients and in patients with normal renal function.

Blood Proteins↗

PubMed1976

Studies on digitalis. VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites.

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.

Blood Proteins↗

PubMed1975

Species differences in plasma binding and tissue uptake of 3H-digitoxin. A comparative study in rats and mice in vivo and in vitro.

The content of cardiac glycosides in plasma and several organs of rats and mice was investigated 30 min and 12 hrs after i.p. administration of 160 mug/kg b.w. 3H-digitoxin. In rat plasma a glycoside concentration of 124.8 and 44.7 ng/ml resp. was found. The corresponding values in the liver were 834.7 and 579.7 ng/g w.w. An opposite liver/plasma distribution was obtained in mice: while in plasma 772.5 and 571.8 ng/ml were recovered, the glycoside concentration in liver was relatively small (284.8 and 235.6 ng/g w.w.). In order to find out the reason for such species differences observed in vivo, liver slices of rats and mice were incubated with 3H-digitoxin in a medium with and without various plasma proteins. The uptake of 3H-digitoxin into liver slices was drastically reduced by adding mouse plasma or albumin to the medium, while rat plasma lowered the uptake far less. These differences are well reflected by binding studies on agargel electrophoresis: only in mouse plasma a binding of 3H-digitoxin could be demonstrated. The binding rate and binding constant analyzed by equilibrium dialysis were higher in mouse than in rat plasma. It is concluded that the lower tissue accumulation in mice compared to rats must be due to the affinity of 3H-digitoxin to mouse plasma albumin. Moreover digitoxin has a higher affinity to the rat than to the mouse liver in the presence of mouse or rat plasma as well as of bovine serum albumin.

Animals↗

PubMed1977

Studies on digitalis. XIII. A prospective study of 649 patients on maintenance treatment with digitoxin.

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.

Age Factors↗

PubMed1992

[Thrombocytopenia in digitoxin poisoning].

Because she felt unwell, an 80-year-old woman who was receiving treatment with digitoxin (0.07 mg daily) raised the dose on her own initiative to twice or three times the previous level. She then experienced faintness, visual abnormalities and bradyarrhythmia (rate about 40/min). The ECG showed 2 degrees AV block. The digitoxin level was 70.8 ng/ml--far above the upper limit of the therapeutic range (7.5-25 ng/ml). One striking abnormality was thrombocytopenia (33,000/microliters), though the white and red cell counts were normal. Petechiae were not present and there was no evidence of internal bleeding. As the AV block had not produced any critical fall in ventricular rate, there was no need to start treatment with digitalis-binding antibody fragments (Fab fragments). Instead, the patient was given cholestyramine 4 g three times daily with the aim of interrupting the enterohepatic circulation of digitoxin. From then on the rise in platelet count paralleled the fall in digitoxin level. Seven days after discontinuing digitoxin the platelet count reentered the normal range (147,000/microliters). However, the digitoxin level (39.5 mg/ml) was still well above the therapeutic range.

Aged↗

PubMed1991

Digitoxin-associated mortality in acute myocardial infarction.

The use of digitalis in patients who have sustained an acute myocardial infarction has been controversial. A number of reports have suggested that the use of the glucoside actually can increase mortality. In all previous reports, digoxin has been the glucoside in use. In 620 patients admitted to Hamar Hospital from January 1, 1982 to December 31, 1984 with an acute myocardial infarction, 159 were using digitoxin at entry. Their survival until January 1, 1985 was compared with the rest of the population, not using digitoxin. The patients on digitoxin had a significantly higher mortality than those who were not, with a relative risk ratio of 2.33. However, major differences in baseline risk factors existed, and a multivariate Cox regression analysis was employed to adjust for the inequalities in baseline covariates. Only variables available at the entry of the index infarction were used for adjustment. Serum sodium, serum creatinine, age and no smoking were identified in a backward selection procedure as independently influencing mortality. By adjusting for these variables the relative risk ratio was reduced to 1.41, but digitoxin still exerted a significant influence on mortality. It is concluded that the results obtained with the use of digitoxin during a myocardial infarction is similar to previous reports with digoxin. Most of the excess mortality in the digitoxin group can be accounted for by inequalities in baseline characteristics. However, the possibility that a small excess in mortality is due to the digitalis glucoside cannot be excluded.

Aged↗

PubMed1975

Serum digitoxin concentrations in infants and children.

Serum digitoxin levels were measured in 18 infants (under two years) and in 23 children (aged 2-13 years) receiving maintenance therapy. Digitalization was carried out because of heart failure in 17 infants and 13 children and for control of dysrhythmia in one infant and 10 children. Mean maintenance dosage for infants was 0.0042 plus or minus 0.0008 (sd) mg/kg/day and for children was 0.0031 plus or minus 0.0012 mg/kg/day. The mean serum digitoxin level was not significantly different in infants (30 plus or minus 10 ng/ml, range 14-58) from that found for children (34 plus or minus 11 ng/ml, range 19-61). Both values were significantly different (P smaller than 0.001) from those determined in this laboratory for adults (mean 24 plus or minus 7 ng/ml, range 5-39). In four infants with electrocardiographic or other evidence of toxicity, the mean serum level was 71 plus or minus 2 ng/ml (range 68-72), and in four children with electrocardiographic or other evidence of toxicity, the mean serum level for digitoxin was 72 plus or minus 14 ng/ml (range 53-84). The data suggest that infants and children tolerate a higher serum digitoxin concentration without any evidence of toxicity and may require more digitoxin (mg/kg) for therapeutic effect than do adults. Serum digitoxin levels may serve as an important guide in determining the adequacy of digitalization and in the recognition and management of digitalis toxicity.

Adolescent↗

PubMed1976

The effect of colestipol on digitoxin plasma levels.

The effect of colestipol (colestipol hydrochloride; U-26 597 A), a copolymer of tetraethylenepentamine and epichlorhydrine, on plasma digitoxin levels has been investigated. Recently, it has been stated that colestipol decreases the enterohepatic circulation and the plasma half-life of digitoxin. Colestipol was administered to 11 patients having a digitoxin plasma level which is generally accepted to be above the therapeutic range (greater than 40 ng/ml). The elimination rate of digitoxin measured by serial radioimmunoassay in these colestipol treated patients was compared with the elimination rate of digitoxin in 11 patients not treated with colestipol. The results of this study did not demonstrate a significant difference in the mean (+/- S.D.) digitoxin plasma half-life between the colestipol treated (6.3 +/- 1.3 days) and the non-colestipol treated patients (6.8 +/- 1.0 days).

Antidotes↗

PubMed1976

Accidental digitoxin poisoning.

A healthy 141/2-month-old child ingested 1.5 mg of digitoxin by accident. Digitoxin was wrongly identified as digoxin, the initial electrocardiogram was misinterpreted, and the vomiting was underestimated as an important symptom of toxicity. Symptoms persisted and the patient was hospitalized. Serial digitoxin levels were obtained and correlated with ECG and clinical course. It appears that serial digitoxin levels can be a useful adjunct in diagnosis, assessment of severity, and indication of recovery from digitoxin poisoning. In each patient, it is imperative that ECG, pharmacologic, and clinical indicators of digitalis toxicity be accurately identified for proper assessment of severity and appropriate management.

Absorption↗