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PubMed1986

Analysis of digoxin at therapeutic concentrations using high-performance liquid chromatography with post-column derivatization.

A high-performance liquid chromatographic (HPLC) procedure has been developed for the analysis of digoxin in plasma at therapeutic concentrations. The assay method provides resolution of digoxin from its metabolites using a 15 cm X 4.6 mm HPLC column containing 3-micron octadecylsilane-bonded stationary phase. The effluent of the column is passed through a post-column reactor in which a fluorescent derivative is formed by the co-addition of hydrochloric acid and dehydroascorbic acid. Detection of the derivative is accomplished in a fluorometer with excitation at 336 nm and emission at 425 nm. The extraction efficiency for recovery of digoxin from plasma samples was 70% using chloroform-isopropanol (9:1) following a pre-wash with isooctane to remove endogenous substances. The calibration curve was linear (r = 0.9999) over the range 0.5-4 ng/ml digoxin in plasma using digitoxigenin as internal standard. The minimum detectable quantity of digoxin in plasma was 0.5 ng/ml at a signal-to-noise ratio of 4:1. Split-samples of digoxin control sera were assayed by the HPLC procedure and by the prescribed radioimmunoassay procedure. Excellent correlation was observed between the two methods (r = 0.999). No interference was noted when a selection of commonly co-prescribed drugs were evaluated for chromatographic co-elution or interference in detection with that of digoxin or the internal standard.

Chromatography, High Pressure Liquid↗
PubMed2003

Digoxin in heart failure.

Digoxin is an agent with a long history of use in the management of heart failure; its benefits have just been quantified in recent years. It has long been known that digoxin provides a small amount of inotropic augmentation; however, it is now realized that digoxin also modulates the neurohormonal activation that occurs in heart failure. Although long-term therapy with digoxin does not decrease mortality, it does provide clinical benefit in terms of improved exercise tolerance and decreased hospitalizations across all severities of heart failure. Serum concentrations of digoxin associated with clinical benefits are lower than previously recognized (0.8-1.0 ng/mL). Digoxin toxicity can be easily avoided by maintaining these relatively low serum concentrations, avoiding and aggressively treating hypokalemia, and being mindful of poor renal function and drug interactions that may result in digoxin accumulation.

Cardiotonic Agents↗
PubMed1997

Digoxin therapy in chronic heart failure.

Digitalis has been used for more than 250 years, but its role in the treatment of chronic heart failure has been intensively investigated only during the past two decades. Digoxin increases cardiac output both at rest and during exercise, alone or in combination with ACE inhibitors, and these hemodynamic effects are sustained during chronic therapy. A daily dose of digoxin that achieves a serum concentration of approximately 1.2 ng/ml is associated with a significant improvement in central hemodynamics, particularly in patients with impaired cardiac function despite pretreatment with diuretics and ACE inhibitors. Acute administration of digoxin in patients with chronic heart failure has an immediate sympathoinhibitory effect, and chronic therapy is associated with a sustained decrease in serum norepinephrine concentration. Discontinuation of digoxin in patients with chronic heart failure resulted in hemodynamic deterioration, which was reversed when the drug was readministered. Randomized withdrawal of digoxin in patients receiving only diuretics (PROVED study), or its withdrawal in patients receiving diuretics and ACE inhibitors (RADIANCE study), was associated with worsening of the clinical evidence of heart failure and a decrease in left ventricular systolic function in both studies. In the only large-scale, placebo-controlled mortality study reported thus for (DIG Trial), 7788 patients received standard drug treatment for chronic heart failure in addition to either digoxin or placebo. Digoxin had no impact on survival over the 37 months of follow-up, but the incidence of hospitalizations due to worsening heart failure was significantly reduced in patients receiving the drug compared with those receiving placebo.

Cardiac Output, Low↗
PubMed1981

Digoxin-verapamil interaction.

To explore a possible interaction between digoxin and verapamil, a single-dose kinetic study of digoxin was performed and then repeated after 10 days of verapamil treatment in eight healthy subjects. Verapamil diminished the apparent central distribution volume of digoxin from 0.83 +/- 0.25 to 0.64 +2- 0.17 l/kg (P less than 0.05) and reduced total body clearance of digoxin from 3.28 +/- 0.58 to 2.15 +/- 0.66 ml/min/kg (P less than 0.001) by impairing both renal and extrarenal clearance. Biological digoxin half-life rose from 38.6 +/- 8.5 to 50.5 +/- 8.3 hr (P less than 0.005). Reduction of renal clearance of digoxin may be due to inhibition of tubular secretion. The underlying mechanisms of extrarenal interaction are not known, but impaired hepatic degradation of digoxin induced by verapamil should be considered.

Adult↗
PubMed1981

Influence of gastric pH on digoxin biotransformation. II. Extractable urinary metabolites.

High-performance liquid chromatography (HPLC) analysis was performed on methylene chloride extracts of urine from six subjects after administration of 3H-digoxin-12 alpha and unlabeled digoxin by nasogastric tube under four conditions: pentagastrin and control saline infusions, each in the supine and ambulatory states. There were no differences with change in position. With pentagastrin stimulation of acid secretion, there was extensive intragastric hydrolysis, mainly to digoxigenin; there was further extensive biotransformation leading to an increase in both extractable and unextractable metabolites in urine, particularly the latter. In the first 5 hr mean digoxin was only 17% and unextractable metabolites were 54% of total urine radioactivity. Extractable radioactivity was found under HPLC peaks with retention times of digoxin, digoxigenin, and its mono- and bis-digitoxosides. There were also three other peaks that were not identified; two correlated with gastric H+ activity and with the peak for digoxigenin, which is probably their precursor since similar peaks were found after ingestion of digoxigenin. The third unidentified peak eluted immediately after the digoxin, with which it correlated; it may have a close structural relationship to digoxin. Gastric acid stimulation induced a major increase in the production of urinary metabolites and may prove a useful model for the study of digoxin biotransformation, which is not yet well defined.

Biotransformation↗
PubMed1983

On the interaction between digoxin and disopyramide.

Combined oral therapy with digoxin (0.375 mg/dl) and disopyramide (300 and 600 mg/dl) in nine subjects did not alter steady-state digoxin serum concentrations just before the daily single digoxin dose. Digoxin and creatinine clearances were not changed. After a bolus IV dose of 0.8 mg digoxin, volume of distribution (from 672 +/- 176 l to 407 +/- 153 l) and elimination t1/2 beta of digoxin were reduced significantly in five subjects after 600 mg oral disopyramide daily (from 40.2 +/- 11.7 hr to 22 +/- 7.3 hr). Total clearance and digoxin distribution t1/2 alpha did not change significantly. The clinical significance of this interaction is not clear.

Adult↗
PubMed1983

Determination of myocardial and serum digoxin concentrations in children by specific and nonspecific assay methods.

After obtaining samples at open heart surgery, serum and right atrial digoxin concentrations were measured in 25 children by a nonspecific, direct radioimmunoassay method (NS) and by a specific method in which digoxin was separated from its metabolites by HPLC before radioimmunoassay was applied to the digoxin fraction (S). Digoxin was detectable by S assay (sensitivity 0.1 ng/g) in 16 heart specimens and 22 serum samples. The mean and range of the S/NS ratio was 0.74 (0.23 to 2.63) for serum and 0.81 (0.068 to 1.38) for atrial tissue. By NS assay the mean and range of the atrial/serum ratio was 78.1 (2.4 to 340, n = 21) and by S assay the corresponding values were 100 (10.7 to 318, n = 15). A multiple linear regression indicated that 72.5% of the variance of the heart digoxin concentrations measured by S assay were accounted for by the variables height, body weight, daily digoxin dose before operation, plasma digoxin concentration by S assay, and BUN.

Adolescent↗
PubMed1984

Significance of the endogenous digoxin-like substance in infants and mothers.

Digoxin serum concentrations were measured by a routine radioimmunoassay in 30 neonates not receiving digoxin; nonetheless, digoxin levels were between 0.17 nM and 1.64nM (means = 0.64nM +/- 0.27 nM). There was a negative correlation between gestational age and concentration of an endogenous digoxin-like substance (EDLS). Neonates less than or equal to 32 wk gestational age had higher levels of EDLS than neonates greater than 32 wk old. EDLS concentrations were compared in 22 mothers and their 24 offspring and were higher in all newborn infants (0.34nM +/- 0.09nM and 0.15nM +/- 0.08nM). EDLS was shown to inhibit Na+-K+-adenosinetriphosphatase activity by measurement of 86Rb uptake in erythrocytes exposed to sera samples from 30 infants in the study. EDLS levels greater than 0.6 ng/ml were associated with lesser 86Rb uptake. Simulation kinetics suggest that the presence of 0.6nM EDLS would lengthen the digoxin t1/2 by 64%, reduce the volume of distribution by 23%, and lower clearance by 53% if the peak "true" digoxin level were 2 ng/ml. EDLS concentrations of 1.5 ng/ml would increase the t1/2 by 207% while reducing the volume of distribution by 43% and clearance by 81%. These considerations cast serious doubts on the validity of currently accepted digoxin kinetics and dosing in preterm infants.

Birth Weight↗
PubMed1985

Acceleration of digoxin clearance by activated charcoal.

The effect of repeated oral doses of activated charcoal on intravenous digoxin kinetics was evaluated in a randomized, crossover study. Ten healthy subjects received infusions of 10 micrograms/kg digoxin alone and with 225 gm activated charcoal over 40 hours. Multiple serum digoxin concentration determinations were made after each dose by radioimmunoassay. Noncompartmental kinetic analysis was used. Digoxin clearance increased an average of 47% (range -2% to 119%) during charcoal treatment, from 12.2 +/- 2.0 to 18.0 +/- 2.9 L/hr. The volume of distribution at steady state decreased from 495 +/- 196 to 375 +/- 162 L, and the terminal t1/2 was shortened from 36.5 +/- 11.8 to 21.5 +/- 6.5 hr during charcoal treatment. Likewise, mean residence time decreased, from 41.1 +/- 20 to 19.9 +/- 7.8 hr. Kinetic predictions would suggest greater proportional increases in digoxin clearance in patients with renal impairment. We conclude that repeated doses of charcoal enhance the clearance of digoxin and should be considered for use in digoxin toxicity.

Administration, Oral↗
PubMed1986

Digoxin and bepridil: pharmacokinetic and pharmacodynamic interactions.

The influence of bepridil on steady-state serum digoxin concentrations (SDCs) and the pharmacodynamic actions of both drugs were tested in 48 healthy subjects in a randomized, double-blind study. Subjects were assigned to one of two groups of 24 subjects each: One group received placebo 1, while the other received digoxin, 0.375 mg/day, loaded with doubled doses on days 1 and 2, for 14 days. After 7 days the groups were subdivided into four groups of 12 subjects each and received concurrent dosing of digoxin with either placebo 2 or bepridil, 300 mg/day, loaded with 900 mg on day 8. Mean (+/- SD) SDCs rose during concurrent bepridil dosing from 0.93 +/- 0.22 to 1.25 +/- 0.25 ng/ml (P less than 0.001). Noninvasive cardiovascular parameters from ECG, systolic time intervals, and electrical impedance cardiography were not influenced by the placebos. Digoxin and bepridil reduced heart rate and prolonged the PQ interval because of negative chronotropic and dromotropic properties. Positive inotropism from digoxin shortened the corrected electromechanical systole (QS2c) and the preejection period and increased impedance cardiography [(dZ/dt)/RZ index]; the opposite effects occurred after bepridil, indicating negative inotropism. The QT interval corrected for heart rate (QTc) showed a similar pattern of changes, as did QS2c for each drug. Concurrent dosing of both drugs resulted in an addition of their chronotropic effects, whereas the dromotropic effects of each drug alone was not intensified. The strengthened digoxin effect from the increased SDC diminished the negative inotropic effect of bepridil. Overall, drug coadministration resulted in a nearly unchanged digoxin-induced positive inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Variability of steady-state digoxin kinetics during administration of tablets or capsules.

An encapsulated solution of digoxin has been repeatedly shown to have greater bioavailability than tablet forms of the drug. It is predicted that such a preparation would show reduced within- and between-patient variability in absorption, as most studies in normal subjects have shown reduced intersubject variation with the capsule. We tested inter- and intrapatient variability during 4-week periods of dosing with digoxin capsules and tablets in 28 subjects with cardiac disease. In the overall group there were no significant differences between the formulations at steady state in between-patient variability in trough serum digoxin concentrations or 24-hour urinary digoxin excretion. Within-patient variability in urinary digoxin excretion was somewhat lower for the capsules. In a subgroup of six patients who excreted significant amounts of cardioinactive bacterial metabolites (digoxin reduction products [DRP]), the mean (+/- SD) percent urinary DRP excretion was less (p less than 0.05) during capsule (20.5% +/- 15.1%) than tablet (34.4% +/- 10.9%) dosing. Within-patient variability in urinary DRP excretion was much greater after tablets than capsules. Certain subgroups of patients should benefit from the enhanced bioavailability of digoxin capsule preparations.

Absorption↗
PubMed2000

Effect of digoxin on circadian blood pressure values in patients with congestive heart failure.

BACKGROUND: The aim of the study was to investigate the effect of chronic digoxin treatment on circadian blood pressure profile in normotensive patients with mild congestive heart failure. METHODS: In a randomized double-blind, placebo-controlled cross-over protocol, 12 normotensive patients with mild congestive heart failure took digoxin or placebo for a total of 7 days. Automatic 24-h ambulatory blood pressure measurements were carried out at day 7, of either digoxin or placebo. RESULTS: Diastolic blood pressure significantly decreased and systolic blood pressure significantly increased during overnight sleep in the digoxin phase compared to placebo. Digoxin had no effect on either systolic or diastolic blood pressure during daytime. Heart rate decreased in the overnight sleeping phase but did not differ significantly between placebo and digoxin phase. CONCLUSIONS: Digoxin significantly decreases diastolic blood pressure during overnight sleep in patients with congestive heart failure. This effect is likely to be caused by reduction of sympathetic activity or increase of parasympathetic activity. Increase of systolic blood pressure during sleep is probably caused by the positive inotropic effect of the drug.

Aged↗
PubMed2002

Effects of the concomitant administration of tamsulosin (0.8 mg) on the pharmacokinetic and safety profile of intravenous digoxin (Lanoxin) in normal healthy subjects: a placebo-controlled evaluation.

A 20-day, nonrandomized, open-label, placebo-controlled study was performed to investigate whether concomitant administration of tamsulosin (0.8 mg) affects the pharmacokinetic and safety profile of intravenous digoxin (0.5 mg) in healthy subjects. Ten healthy subjects aged 21-39 years received a single oral dose of placebo on study days 1-8 and tamsulosin on days 9-18. Tamsulosin was initiated at 0.4 mg/day and the dose was increased to 0.8 mg/day from day 11. On days 2 and 15, subjects received a single intravenous dose of digoxin (0.5 mg). Safety monitoring was carried out throughout the study. Following digoxin administration, blood was drawn and urine collected over a 96-h period for pharmacokinetic determinations. Plasma tamsulosin concentrations were measured at regular intervals after dosing on day 15. The digoxin pharmacokinetic parameters with and without concomitant tamsulosin were compared. No significant difference was observed, and no irregularity was found in the plasma tamsulosin concentration data. Six subjects experienced adverse events while receiving placebo and seven while on tamsulosin. The most frequent adverse event was mild dizziness reported by four subjects. Moderate chest pain was reported in two subjects, but this was not considered to be related to the administration of the study medications. Some significant changes in vital signs were observed; however, none was accompanied by symptoms of medical concern. These changes were not temporally related to the administration of study drugs. Thus, concurrent administration of digoxin with tamsulosin did not produce any change in the pharmacokinetics of digoxin and the safety profile was acceptable. As reflected in the prescribing information for tamsulosin, no adjustment in tamsulosin dosing is required when it is administered concomitantly with digoxin.

Administration, Oral↗
PubMed2001

Coadministration of digoxin with itraconazole in renal transplant recipients.

Digoxin toxicity is a major public health issue in the United States. Often this is due to drug interactions, and renal transplant recipients are at particularly high risk for drug-drug interactions. We present cases of 2 renal transplant recipients who received itraconazole and digoxin concomitantly and experienced digoxin toxicity. We have also reviewed the relevant literature to elicit the mechanisms, signs, and symptoms of digoxin toxicity in the presence of itraconazole. When clinicians know the potential drug-drug interactions that may lead to digoxin toxicity, the mechanisms of interaction, the signs and symptoms of digoxin toxicity, and appropriate monitoring, digoxin toxicity is largely preventable.

Anti-Arrhythmia Agents↗
PubMed1979

[Biological availability of digoxin and beta-acetyldigoxin after single-dose administration (author's transl)].

The biological availability of digoxin tablets (Lanicor) and beta-acetyldigoxin tablets (Novodigal) was tested after single-dose administration. Plasma levels over 48 hours, the area under the blood-level curves and the cumulative urinary excretion over seven days served as a measure of biological availability. The area under the blood-level curve after 1.0 mg digoxin by mouth was 40.7 +/- 1.7 ng . ml-1 . h and after 1.0 mg beta-acetyldigoxin by mouth 39.1 +/- 1.4 ng . ml-1 h, compared with 56.1 +/- 1.4 after 1.0 mg digoxin intravenously. Seven days later 0.67 +/- 0.12 mg digoxin of the orally administered digoxin, 0.68 +/- 0.12 mg digoxin of the orally administered beta-acetyldigoxin and 0.81 +/- 0.08 mg of the intravenously administered digoxin were excreted in the urine. There was no significant difference in the biological availability of the two drugs (P greater than 0.05).

Acetyldigoxins↗
PubMed1979

Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications.

Administration of quinidine with digoxin increased serum digoxin concentrations in 79 patients and five volunteers. In 38 patients on a constant glycoside maintenance dose, the addition of quinidine to digoxin therapy resulted in a mean 2.5-fold increase (from 0.98 +/- 0.37 to 2.47 +/- 0.71 ng per milliliter, mean +/- 1 S.D.) (P less than 0.001). The addition of quinidine decreased renal glycoside clearance (from 91.6 +/- 27.8 to 40.6 +/- 15.8 ml per minute) (P less than 0.001). Unlike other investigations, our studies provided no evidence that quinidine displaced digoxin at specific cardiac binding sites. The elevated digoxin levels found during quinidine administration suggest a 30 to 50 per cent reduction of the digoxin dose. Adverse reactions to combined quinidine-digoxin therapy may be partly due to digitalis intoxication.

Adult↗
PubMed1989

A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.

We randomly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin, milrinone, both, or placebo. The effects of each were compared during a 12-week, double-blind trial. Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo (by 82 and 64 seconds respectively; 95 percent confidence limits, 44 and 123, and 30 and 100). Both treatments reduced the frequency of decompensation from heart failure, from 47 percent with placebo to 34 percent with milrinone (P less than 0.05; 95 percent confidence limits, 22 and 46) and 15 percent with digoxin (P less than 0.01; 95 percent confidence limits, 7 and 26). However, the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun, as compared with only 3 percent of those taking digoxin (P less than 0.05). The left ventricular ejection fraction at rest was not significantly changed by milrinone (+0.2 percent; 95 percent confidence limits, -1.5 and 1.9), but it was increased by digoxin (+1.7 percent; P less than 0.01; 95 percent confidence limits, -0.03 and 3.4) and decreased by placebo (-2.0 percent; 95 percent confidence limits, -3.8 and -0.1). Three-month survival was related inversely to the base-line ejection fraction. Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone (P = 0.064). After adjustment for an excess of patients with lower ejection fractions randomly assigned to receive milrinone, this trend was not significant (P = 0.26). Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not (18 vs. 4 percent; P less than 0.03). We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure. However, in the population of patients studied, milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone. Furthermore, our data suggest that milrinone may aggravate ventricular arrhythmias.

Administration, Oral↗
PubMed2003

Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin.

BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate. METHODS: Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16. RESULTS: After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2). CONCLUSION: Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.

Adult↗