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PubMed2001

The effects of captopril on serum digoxin levels in patients with severe congestive heart failure.

The effects of captopril on serum digoxin concentrations were studied in 8 patients with severe (NYHA Class IV) congestive heart failure. Serum digoxin concentrations were determined before and after the administration of captopril for 1 week in patients on chronic digoxin therapy. Each patient who was taking 0.25 mg of digoxin PO q.d., was administered 12.5 mg of captopril PO t.i.d. for 7 days. The peak serum concentration of digoxin (Cmax) before and after (on Days 0 and 7) captopril administration was 1.7+/-0.2 ng/ml and 2.7+/-0.2 ng/ml, the time to peak (tmax) was 2.4+/-0.5 h and 1.3+/-0.2 h, and the area under the 24-hour digoxin concentration-time curve (AUC0-24h) was 30.0+/-1.5 ng x h/ml and 41.7+/-3.4 ng x h/ml, respectively. While captopril caused a significant increase in peak serum concentration and the area under the digoxin concentration-time curve, it decreased the time to digoxin peak (p = 0.01, p = 0.04, p = 0.01, respectively). No patient developed evidence of digoxin toxicity. Concomitant administration of captopril with digoxin increases serum digoxin concentration in patients with severe congestive heart failure.

Administration, Oral↗
PubMed1991

Influence of gastric acidity on the bioavailability of digoxin.

OBJECTIVE: To study how changes in gastric acidity induced by omeprazole and pentagastrin affect the absorption of unchanged digoxin and its hydrolytic breakdown products. DESIGN: Double-blind, double-dummy, randomized, crossover study. SETTING: Academic department of clinical pharmacology. SUBJECTS: Six healthy male volunteers. INTERVENTIONS: Subjects received digoxin, 1 mg orally, on three separate occasions: first, after pretreatment with omeprazole; second, after pretreatment with pentagastrin; and third, after "pretreatment" with placebo. MEASUREMENTS: The in-vitro decomposition of digoxin wa studied using a standard dissolution test. The urinary excretion of digoxin over a 120-hour period was measured using selective high-pressure liquid chromatography (HPLC) and a polarization enzyme immunoassay (EIA). Plasma concentrations were measured at 2 hours with the EIA. MAIN RESULTS: Digoxin was rapidly released from the tablets in the in-vitro test. At acid pH, decomposition (as measured with HPLC) was rapid. Pentagastrin reduced the urinary excretion of unchanged digoxin, as measured by HPLC, from 34% to 21.4% of the dose (difference, -12.6%; 95% Cl, -23.5 to -1.8; P less than 0.05), whereas omeprazole increased urinary excretion to 47.4% (difference, 13.4%; 95 Cl, 2.5% to 24.4%; P less than 0.05). However, such differences were not found with the nonselective polarization EIA. CONCLUSIONS: Our data suggest that gastric acidity causes the breakdown of digoxin to products that cross-react in the assay (EIA) that is commonly used clinically. In patients with reduced gastric acidity, increased plasma concentrations of unchanged digoxin may not be detected because of limitations of the EIA, which may invalidate the quantitative use of the plasma digoxin concentration as a predictor of digoxin toxicity. Omeprazole, and presumably other gastric-acid inhibitors, may increase the bioavailability of unchanged digoxin.

Adult↗
PubMed2000

[Solubility and dissolution rate of digoxin from Digitalis lanata drug extracts] .

The influence on solubility and dissolution rate was investigated for digoxin as a model drug with a very low solubility in water. The investigations were carried out with different fractions of extracts from leaves of Digitalis lanata. These fractions differ in the composition of concomitant compounds. The solubility of digoxin from the extract fractions is increased up to 42 times, with considerable differences between the fractions. The solubility depends on the weight of the extract fraction; a limit of solubility exists. Even after separation of the solved extract components the solubility of digoxin in the residues is larger than that of the pure digoxin. The dissolution rate of digoxin of "Vorgereinigter Gesamtglykosidextrakt (VE)" and the glycosid fraction G 1 is influenced significantly, whereas digoxin in the glycosid fraction G 4 has such a degree of purity that the solubility properties are not influenced by the small amount of concomitant compounds. After 10 min already 50.4% of the digoxin in the extract fraction G 1 are dissolved, while only 21.7% of the pure digoxin are dissolved in that interval. The extract fractions exhibit different wettability properties, so that the increased dissolution rate could be attributed to improved wettability of the extract fractions. Physical mixtures of crystal-line digoxin and compounds of the extracts of the almost digoxin free fraction G 2 did not exert an influence on the dissolution behavior. Different batches of the extract fractions showed different solubility in spite of comparable digoxin content.

Cardiotonic Agents↗
PubMed1979

Influence of stimulation of myocardial alpha- as well as beta-adrenoceptors on the effect of digoxin in isolated electrically driven rabbit papillary muscles.

On isolated electrically driven rabbit papillary muscle the cardiac glycoside digoxin was infused at driving rates of 0.5, 1.0 and 2.0 Hz. Two effective concentrations of digoxin were determined: 1. that inducing the maximal inotropic effect (maximal inotropic concentration) and 2, that causing cardiac arrest (toxic concentration). The influence of the alpha-sympathomimetic drug phenylephrine and for comparison that of the beta-sympathomimetic drug isoprenaline on either concentration of digoxin was investigated. 1. Stimulation of alpha-adrenoceptors by phenylephrine at a rate of 0.5 Hz significantly decreased the maximal inotropic as well as the toxic concentration of digoxin by about 36%; this decrease was maximal under the influence of the EC25 of phenylephrine and could be blocked by phentolamine. Phenylephrine did not alter the maximal inotropic effect of digoxin. At a stimulus rate of 1.0 Hz the EC75 of phenylephrine still diminished significantly the effective concentrations of digoxin whereas under these conditions the EC25 was ineffective. At 2.0 Hz stimulation of myocardial alpha-adrenoceptors had no effect anymore on either the maximal inotropic or the toxic concentration of digoxin. 2. In contrast, stimulation of beta-adrenoceptors by isoprenaline at a driving rate of 2.0 Hz resulted in a pronounced decrease of maximal inotropic and toxic concentration of digoxin while the maximal positive inotropic effect exerted by digoxin was found to be not altered by isoprenaline. The decrease of the effective concentration of digoxin caused by isoprenaline was abolished by pindolol. At a driving rate of 1.0 Hz this effect was slightly attenuated but was completely absent at 0.5 Hz. 3. From these results it can be concluded that stimulation of either adrenoceptor, alpha- and beta-, increases the effectiveness of the cardiac glycoside digoxin, i.e. diminishes the maximal inotropic as well as its toxic concentration. While stimulation of alpha-adrenoceptors is effective only at low rates of stimulation that of beta-adrenoceptors is vice versa at higher ones, thus supporting the view of different mechanisms underlying stimulation of alpha- or beta-adrenoceptors.

Animals↗
PubMed1989

The effects of mannitol diuresis on digoxin and phenobarbital handling by the kidney: implications for tubular reabsorption and secretion of the cardiac glycoside.

The effect of mannitol diuresis on the renal clearance of digoxin and phenobarbital was studied in dogs. Mannitol diuresis significantly increased the clearance of digoxin and the ratio digoxin: inulin clearances (from 0.7 +/- 0.2 to 1.1 +/- 0.25). The increase in phenobarbital: inulin clearance ratio was significantly higher than the increase in the digoxin: inulin clearance ratio (4.9 fold vs 1.66 fold) (p less than 0.005). Mannitol diuresis did not significantly affect inulin clearance, nor digoxin protein binding during the experimental period while there was a significant increase in PAH clearance. Significant correlations were found between urine flow rate and digoxin renal clearance or digoxin: inulin clearance ratio. The increase in the ratio drug: inulin clearance with diuresis correlated inversely with the initial ratio; animals with more predominant net reabsorption had a higher increase in ratio. These studies suggest that the mannitol-induced increase in digoxin clearance stems from a combination of increased renal blood flow enhancing digoxin secretion, and increased urine flow rate inhibiting its reabsorption. We conclude that urine flow rate and renal blood flow are important determinants of the renal clearance of digoxin, independent of GFR. Any study assessing the effect of pathophysiological states or drug interactions on digoxin renal clearance must control for these factors.

Animals↗
PubMed1987

Endogenous digoxin-like immunoreactive factors eliminated from serum samples by hydrophobic silica-gel extraction and enzyme immunoassay.

Elimination of endogenous digoxin-like immunoreactive factors (DLIF) that interfere with accurate measurement of digoxin requires use of a highly specific anti-digoxin antibody, or that DLIF be separated from digoxin before immunoassay. Several commercial digoxin-assay kits include a step for separating serum proteins and other substances from digoxin before immunoassay. We tested six different immunoassay methods (some having pretreatment steps) for their ability to detect DLIF in serum from patients in renal failure, pregnant women, and neonates, all of whom were not taking digoxin. Extracting digoxin on a column of derivatized silicagel eliminated detectable DLIF from serum as measured by enzyme immunoassay (EMIT; Syva Co.), but recovery of added digoxin was quantitative. In contrast, protein precipitation with 5-sulfosalicylic acid left significant amounts of DLIF in samples, most probably because the procedure (TDx assay; Abbott Labs.) disrupted protein-DLIF binding. A glass-bead radioimmunoassay (Immophase; Corning Medical) had the most digoxin-specific antisera. By preparative silica-gel-chromatography of serum we could eliminate or significantly minimize inaccurate digoxin measurements attributable to endogenous DLIF.

Blood Proteins↗
PubMed1986

Assessment of bio(in)equivalence of deriphyllin-digoxin in human volunteers. II. Evaluation of rabbits as qualitative animal model.

In rabbits, a three way cross-over test was carried out to assess bioavailability of digoxin from commercially available 'Deriphyllin-Digoxin' tablets. The in vitro dissolution test showed that these tablets had low dissolution even at the end of 4 hr. The in vivo tests in rabbits compared bioavailability of digoxin from Deriphyllin-Digoxin tablets with that from Lanoxin tablets and intravenous digoxin injection. The treatments were given in randomized order with a minimum of 14 days wash-out period between the treatments. After the drug administrations, periodic blood samples were collected and plasma digoxin concentrations were analysed using radioimmunoassay. As indicated by the results of in vitro dissolution tests, Deriphyllin-Digoxin tablets showed poor and delayed absorption of digoxin in vivo. A parallel study on comparative bioavailability for the same batches of digoxin tablets was also carried out in human volunteers. The study in human volunteers involved 14 subjects and had a cross-over dosing. The bioavailability results in rabbits were qualitatively similar to human bioquivalence studies. This is the first report showing digoxin bioavailability in rabbits corresponding to that in humans. The importance of the rabbit as a secondary model for bioequivalence testing of digoxin formulations has been emphasized.

Administration, Oral↗
PubMed1986

[Effect of propafenone on the pharmacokinetics of digoxin administered orally: a study in healthy volunteers].

It is well known that many cardiovascular drugs affect digoxin kinetics, but nothing is defined on propafenone-digoxin interaction. To clarify this problem, we studied digoxin kinetics in 8 healthy men, who received digoxin oral dose (0.50 mg) in the control state and again during maintenance therapy with propafenone (150 mg q.i.d.). Statistically significant changes were observed during propafenone in a number of digoxin kinetic indexes: a rise in peak serum digoxin concentration (4.30 vs 3.07 ng/ml - p less than 0.005), in area under the serum-digoxin concentration curve (4 h: 520.4 vs 368.9; 10 h: 789.6 vs 621.3 ng X min/ml - p less than 0.005; 24 h: 1187.6 vs 954.7 ng X min/ml - p less than 0.05) and urinary excretion of digoxin (277.7 vs 203.5 mcg - p less than 0.005). Renal digoxin clearance was not affected by propafenone. We conclude that propafenone interact kinetically with digoxin in healthy subjects, perhaps increasing digoxin bioavailability.

Administration, Oral↗
PubMed1985

Efficacy of digoxin administration in dogs with idiopathic congestive cardiomyopathy.

Digoxin administration (0.22 mg/m2 of body surface BID) to 10 large-breed dogs with congestive cardiomyopathy increased shortening fraction more than 5.5% in 4 of the dogs. This group of dogs lived longer than the group that did not have a positive inotropic response to digoxin. Heart rate decreased in both groups of dogs. Base-line jugular PVO2 were low in all dogs. Jugular PVO2 decreased significantly in the group that did not respond to digoxin, presumably because of decreased cardiac output. Jugular PVO2 consistently increased in dogs that had a positive inotropic response to digoxin. Base-line shortening fraction, heart rate, and PVO2 did not predict which dogs would respond to digoxin. Serum digoxin concentrations were consistently between 1.5 and 2.5 ng/ml. It was concluded that digoxin administration is not efficacious in all dogs with congestive cardiomyopathy and that the positive inotropic response is not predicted by base-line shortening fraction, heart rate, or jugular PVO2. Dogs that do respond to digoxin usually live longer than those that do not. Jugular PVO2 can be used to separate dogs that do respond from dogs that do not respond to digoxin as long as the base-line PVO2 is low. The negative chronotropic effects of digoxin may be detrimental to dogs that do not have a positive inotropic effect from digoxin.

Animals↗
PubMed1982

Lack of interaction between digoxin and quinidine in cultured heart cells.

Previous investigations have raised the possibility that the digoxin-quinidine interaction is associated with a reduction in the positive inotropic effect of digoxin due to displacement of digoxin from cardiac as well as skeletal muscle. To circumvent some of the complexities presented by intact animal models, this interaction was investigated in cultured chick embryo ventricular cells. Quinidine, even at relatively high concentrations (10(-4)--2 x 10(-3) M), did not significantly affect positive inotropic effects of digoxin and did not protect against cellular contracture induced by toxic digoxin concentrations, despite preincubation of cells with quinidine for 60 min. The effects of digoxin on monovalent cation transport, as judged by active uptake of the K analog 86Rb, were also not altered by 10(-4) M to 2 x 10(-3) M quinidine. These data suggest that quinidine does not displace digoxin from Na, K adenosine triphosphatase binding sites in this preparation. Although these data must be extrapolated to the intact animal with caution, our findings suggest that changes digoxin clearance are more likely of primary importance in the digoxin-quinidine interaction, and indicate that the approximately 2-fold increase in serum digoxin concentration observed after addition of quinidine would be expected to have direct effects on myocardial cells comparable with those seen with increased digoxin concentration in the absence of quinidine.

Animals↗
PubMed1980

Digoxin-quinidine interaction: in vitro studies in rat tissue.

Clinically, the administration of quinidine to digitalized patients results in an elevation of serum digoxin concentration. It has been suggested that quinidine displaces tissue-bound digoxin and that renal digoxin clearance is reduced. We studied the influence of digoxin-quinidine interaction on 125I-digoxin uptake by various rat tissues in vitro, employing the tissue slice method. S/M digoxin ratios were kidney 1.72 +/- 0.24 (mean +/- S.D.), heart 2.36 +/- 0.31, muscle 2.05 +/- 0.21 (n = 23 for each), and fat 0.25 +/- 0.10 (n = 9). Addition of quinidine to the incubation medium resulted in a 17.4% reduction of digoxin uptake by kidney tissue to 1.42 +/- 0.38 (n = 24) (p < 0.01). Quinidine failed to reduce digoxin uptake in both heart and striated muscle. Metabolic blockade resulted in a significant reduction in digoxin uptake in kidney slices from 1.93 +/- 0.23 to 1.34 +/- 0.18 with DNP (n = 10) and to 1.30 +/- 0.15 (n = 10) with sodium azide (p < 0.001). Digoxin uptake in either heart or muscle was uninfluenced by metabolic blockers. We conclude that active energy-dependent transport mechanism for digoxin exists in renal cortical tissue. This mechanism is inhibited by either quinidine or metabolic blockers. In contrast, uptake in heart or muscle represents a different transport mechanism unaffected by quinidine or metabolic blockers.

Animals↗
PubMed1980

Application of individualized digoxin dosage regimens to canine therapeutic digitalization.

Congestive right heart failure was established in three dogs subjected to surgical tricuspid valvectomy and pulmonic stenosis. The eliminative dispositions of digoxin in serum and ascitic fluid were determined after administration of 30 micrograms of digoxin/kg of body weight by IV injection and radioimmunoassay of multiple serum and ascitic fluid samples. Individualized digoxin dosage regimens for the three dogs were calculated from data collected in the present experiment and data from the literature. The regimens were tested on the three dogs after their body weight had been corrected for the volume of ascitic fluid present. An IV maintenance therapy resulted in serum digoxin concentrations slightly lower than anticipated. The administration of digoxin tablets with no food restriction resulted in serum digoxin concentrations mostly in the expected range. The same doses of digoxin in tablet form were given to the three dogs after fasting. Fasting resulted in slight, but significant, increases in serum digoxin concentrations. Serum digoxin concentrations after administration of digoxin elixir were close to anticipated values. These experiments indicate that individualized digoxin dosage regimens may be useful to set serum digoxin concentrations within the therapeutic, nontoxic range.

Administration, Oral↗
PubMed1994

Unexplained increase in serum digoxin: a case report.

We describe a patient with unexpectedly high serum digoxin after cardiac surgery. To control atrial fibrillation in the immediate postoperative period, she was given a brief trial of digoxin (four 0.25-mg doses) over 12 h. Serum digoxin 6 h later was 2.5 micrograms/L. Two days later, the patient developed ventricular fibrillation, which progressed to cardiac arrest. During or immediately after resuscitation, blood was drawn for a digoxin measurement, and the concentration reported was 9.3 micrograms/L; this result was verified by repeated analysis. Digoxin decreased rapidly and progressively to near 4.0 micrograms/L over the next several hours and thereafter decreased slowly to 1.0 microgram/L over the next 11 days, despite no digoxin being administered. The unexpectedly high digoxin raised questions about the accuracy of the digoxin measurement, particularly about the possible influence of the digoxin-like immunoreactive factor. Analytical approaches to distinguishing true digoxin from this factor and other artifacts of digoxin measurement were applied to this patient, with unanticipated results.

Aged↗
PubMed1996

Effect of antibody specificity on results of selected digoxin immunoassays among various clinical groups.

We examined the specificity of three automated digoxin immunoassays (Abbott TDxFLx Digoxin II assay, Baxter-Dade Stratus II Digoxin assay, and Ciba Corning ACS Digoxin assay) applied without modification to (a) sera from 229 digoxin-free patients in 12 cohorts associated with nonspecific or endogenous digoxin-like immunoreactive factor (DLIF) interference, and (b) drug-free serum supplemented with the major metabolites and analogs of digoxin. We observed three patterns of apparent digoxin results among the DLIF samples: one common to kidney and liver failure patients, where TDx and Stratus assays showed significant positive results; one common to newborns and cord blood, where only the TDx assay had significant interference; and one from cardiac surgery patients, where the Stratus assay alone showed interference. Of the three assays, the ACS had the least interference from DLIF. The assays also behaved differently with respect to cross-reactivity with digoxin metabolites, digitoxin, and digitoxin metabolites. The ACS assay again had the least analog or metabolite cross-reactivity. The three methods agreed well on digoxin-positive specimens, with a mean bias of <0.15 microgram/L digoxin for each and discrepancies (defined as >3 SD between the assay pairs compared) of only 3-5%.

Antibody Specificity↗
PubMed1997

The serum digoxin concentration: ten questions to ask.

Although the role of digoxin therapy has been the subject of debate, the drug is generally accepted as effective in the treatment of heart failure due to systolic dysfunction and as therapy for atrial fibrillation and supraventricular tachyarrhythmias. Serum digoxin concentrations are commonly used to gauge patient response to digoxin. Digoxin pharmacokinetics are complex, and many factors can confound the interpretation of digoxin concentrations. The exact therapeutic range of serum digoxin varies in the literature but should be considered to be from 0.8 to 2.0 ng per mL, on the basis of population data regarding therapeutic response and toxicity. Renal function plays a major role in digoxin pharmacokinetics and is an important factor in determining digoxin doses. Many medications, including quinidine, amiodarone and verapamil, alter digoxin pharmacokinetics and can result in two- to three-fold increases in the serum digoxin concentration. Effective interpretation of the digoxin concentration requires consideration of the patient's renal function and clinical status, possible drug interactions, time of the assay and other variables.

Algorithms↗
PubMed1997

The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers.

When propafenone is given with digoxin, digoxin serum concentrations increase. Although the digoxin-propafenone interaction is well known clinically, the mechanism by which propafenone interferes with digoxin elimination is unclear. To test the hypothesis that propafenone or one or both of its two major metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), inhibit the P-glycoprotein-mediated net renal tubular secretion of digoxin, we examined the transport of digoxin and the well-studied P-glycoprotein substrate vinblastine across confluent Madin-Darby canine kidney cell monolayers in the absence and presence of propafenone, 5-OHP and NDPP. Propafenone and its two major metabolites significantly inhibit the secretory flux of digoxin and vinblastine (propafenone > 5-OHP >> NDPP). Despite decreases in net transport, cellular digoxin accumulation did not decrease, suggesting that neither propafenone nor its metabolites prohibited digoxin from entering the cells at the basolateral side. NDPP, but not 5-OHP, was detected after 48 hr of incubation of the cells with propafenone alone. When the cells were incubated with propafenone or 5-OHP, apical accumulation of 5-OHP, but neither propafenone nor NDPP, against a concentration gradient was observed. These findings are consistent with the hypothesis that the digoxin-propafenone interaction results from the inhibition of the renal tubular transport of digoxin by propafenone and its metabolites. Our data suggest that propafenone is an inhibitor of P-glycoprotein, whereas 5-OHP is a possible substrate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

A method of determining the dose of digoxin for heart failure in the modern era.

BACKGROUND: The therapeutic range for digoxin in heart failure has recently changed to become lower and narrower, and the new range is associated with improved mortality. However, dosing methods have not been modified to reflect this change. In this study, we sought to develop a new method to determine the initial dose of digoxin in patients with heart failure. METHODS: Over a 6-month period, medical records were screened and reviewed for hospitalized adult patients who had a steady state digoxin concentration. A multiple linear regression was estimated relating digoxin concentration, digoxin dose, creatinine clearance, and ideal body weight to generate an equation relating the dose of digoxin with these variables and a specific target digoxin concentration of 0.7 ng/mL (0.9 nmol/L). This new method was then compared with 2 existing methods. RESULTS: Included in the study were 54 patients (mean [SD] age, 68 [15] years, with a mean (SD) creatinine clearance of 50 (25) mL/min (0.8 [0.4] mL/s) and mean (SD) ideal body weight of 62 (11) kg. Our proposed method and the Jusko and Koup method were more accurate than the Jelliffe method in predicting digoxin concentration. Root mean square errors were as follows: for the Jelliffe method (using ideal body weight), 0.810; for the Koup and Jusko method (with heart failure), 0.401; our proposed method, 0.375. The proposed method was then used to create a dosing nomogram. CONCLUSIONS: Because the new therapeutic window of digoxin is associated with improved outcomes, more intensive dosage refinement should be considered. To this end, we offer new dosing recommendations and a nomogram for determining the initial dose of digoxin in patients with heart failure.

Aged↗
PubMed1978

Spironolactone-induced changes in digoxin kinetics.

Plasma clearance, volumes of distribution, and renal and extrarenal clearances of digoxin were calculated from plasma digoxin concentrations and urinary excretion of digoxin after intravenous injection of digoxin in 8 subjects. The investigation was repeated in the same subjects during long-term treatment with spironolactone. Increased plasma concentration of digoxin was detected during spironolactone treatment. Calculated plasma and renal clearances of digoxin and the volumes of distribution decreased statistically significant. Near maximal capacity for the tubular secretion of digoxin was found when normal digoxin dosage was used. It is suggested that unless spironolactone decreases the myocardial sensitivity for digoxin, the loading dose as well as the maintenance dose of digoxin should be reduced during treatment with spironolactone.

Adult↗