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Digoxin therapeutics: straightening out the facts.

This article is essentially a review of the pharmacokinetic rationale behind digoxin therapeutics. It covers the various approaches to digoxin therapeutics including the therapeutic endpoint and the use of plasma concentrations of digoxin, the various problems involved in dosage design (particularly pharmacokinetic variability), prescribing aids (and their total impact on the variability in plasma concentrations achieved), and finally, the alternative use of blood-level data to separate and identify the variation in absorption-disposition from the variation in the relationship of plasma concentration to effect. On the basis of available data, it is concluded that by both turning to prescribing aids that have been formulated from clinical data gathered under more nearly ideal conditions and selecting the dosage to give a target concentration based on single measurements of serum digoxin concentrations, may not result in much improvement over fixed or intuitive dosing as far as achieving a predetermined target level is concerned. The probable causes for this lack of precision are explored, and finally an optimum approach to digoxin therapeutics is defined.

Animals↗

[Chronopharmacokinetics of digoxin in compensated cardiac patients].

The authors provided evidence that the pharmacokinetics of digoxin are influenced by daily rhythms. Using doses of 0.125 mg digoxin by the oral route, after 12 hours they found a statistically higher serum digoxin concentration in the minimum before administration of the morning dose and in the maximum concentration after this dose, as compared with the minimal and maximal concentration before and after administration of the same dose in the evening. The other pharmacokinetic parameters--the area beneath the curve of serum concentrations, the time before the maximum concentration was attained and the total plasma clearance of digoxin did not differ. This chrono-pharmacokinetic relationship in compensated cardiac patients was comparable with data in the literature pertaining to healthy volunteers. To conclude it may be said that on administration of major does in the morning there is a greater risk of serum concentrations beyond the therapeutic range than during the administration of the same amount of digoxin in the evening.

Aged↗

Temperature-dependent immunoreactive assay to screen for digoxin-like immunoreactive factor(s).

Endogenous circulating digoxin-like immunoreactive factors (DLIF) are known to cross-react with antibodies to digoxin and to inhibit Na+/K(+)-transporting ATPase (Na+K+ATPase; EC 3.6.1.37). Moreover, increasing the immunoassay temperature from 4 to 37 degrees C markedly decreases DLIF from human cord serum. We tested several compounds, including hormonal steroids, bile salts, lipids, and methionine-enkephalin, for their ability to cross-react with two commercially available 125I digoxin RIAs, to inhibit porcine Na+K+ATPase, and to see whether they present the same incubation temperature dependence as human cord serum. Except for methionine-enkephalin, all compounds were inhibitors of Na+K+ATPase in the range of 1-10 mmol/L. Progesterone exhibited the highest cross-reactivity in the two RIAs. The apparent digoxin immunoreactivity for the majority of the cross-reacting steroids, bile salts, and linoleic acid was markedly decreased by increasing the incubation temperature from 4 to 37 degrees C, whereas estriol, pregnanediol, and nonspecific compounds (e.g., ethanol, human serum albumin) did not appear to be temperature-sensitive. Both lysophosphatidyl lipids gave an increased apparent digoxin concentration with increasing incubation temperature. Our data suggest that numerous weakly cross-reactive compounds can parallel the response of human cord serum. However, the temperature-dependent effect could be an additional criterion for identifying DLIF.

Antibodies↗

[Treatment with iloprost of critical ischemia of the lower limbs associated with cardiac insufficiency. Study of interaction with the pharmacokinetics of digoxin].

We have treated with intravenous iloprost twelve patients suffering from cardiac insufficiency compensated under oral digoxin (NYHA class II) associated with severe limb ischaemia due to arterial insufficiency. Our aim was to study its possible interaction on digoxin levels and to evaluate the long-term efficacy of iloprost. Although iloprost slowed the digoxin absorption by approximately one hour, we found no clinically significant difference between the digoxin pharmacokinetic data before and during treatment by iloprost. Moreover, 11 out of the 12 patients had a good clinical fate after the treatment, which persisted at 6 months. The pain disappeared in 4 and diminished in 7; and all skin ulcers healed. This improvement has lasted up to two and a half years in two patients. The clinical tolerance of iloprost was acceptable despite frequent headache and flushing associated with hypotension and nausea. We conclude that iloprost seems to be a very promising treatment of severe limb ischaemia when no intervention on the proximal arteries is possible. The patients on digoxin can continue their treatment without dose alteration while starting on iloprost.

Adult↗

Isolation of digoxin-like immunoreactive factors from mammalian adrenal cortex.

Endogenous digoxin-like immunoreactive factors (DLIF) are present in serum and tissues of humans and animals. To date, a tissue source for these factors has not been rigorously defined nor have these factors been isolated to identifiable homogeneity. In this study, we define the distribution of DLIF in mammalian tissues, demonstrate the adrenal cortex to be the principal source of this factor in bovine, and isolate DLIF to chromatographic homogeneity using high performance liquid chromatography (HPLC). DLIF concentrations in tissue extracts from rats measured as follows: adrenal glands, 44.3; serum, 6.3; liver, 5.2; kidney, 1.2; heart, brain, or lungs, less than 1.4 ng of digoxin-equivalent per g of protein. Human tissues showed similar results. In dogs, the ratio of the DLIF concentration in lumbar vein serum to that in infrarenal inferior vena cava serum was 3.3 +/- 0.4 (mean +/- S.E., n = 4). Bovine adrenal cortex contained 7 times more DLIF per g of tissue than the adrenal medulla. 70 +/- 4% (n = 7) of the total bovine cortical DLIF activity (6,159 pg of digoxin-equivalent) applied to a reverse phase HPLC column eluted as one definitive fraction. 60% of the digoxin-like immunoreactivity extracted from bovine serum also co-eluted with DLIF from adrenal. None of the 14 steroid molecules or 7 cardiac glycoside congeners co-eluted with the major DLIF activity. Our data indicate that 947 pmol of DLIF is equivalent to 1 pmol of digoxin-equivalent immunoreactivity. Preliminary mass spectral analysis suggests that purified DLIF has a molecular mass of 780 daltons comprised of one 390-dalton aglycone component plus several sugar moieties. This study establishes a definitive link between DLIF in serum and the adrenal cortex as a source tissue. We also demonstrate a method for purifying DLIF to chromatographic homogeneity with an extraction capacity of 1.2 nmol of DLIF per g of adrenal cortex.

Adrenal Cortex↗

[Enhanced bioavailability of digoxin from silica matrix formulations (author's transl)].

The bioavailability of digoxin from 3 silica matrix formulations was assessed in single-dose crossover studies in 12 healthy human volunteers: digoxin/silica matrix tablets (I, Digacin), digoxin/silica matrix in capsule form (II) and digoxin/silica matrix dragées, protected against gastrict juice by film coating (III). Urinary glycoside excretion for 6 days after 0.5 mg doses were measured by radioimmunoasay. Referring to an intravenous injection the bioavailability of digoxin from Digacin tablets is 82%, from the encapsulated matrix 69%, and from the dragées 54%. In comparison with corresponding results from other investigators Digacin tablets havet the same high bioavailability as digoxin solutions. In vitro liberations of digoxin from the silica matrix formulations (94% in 90 s) is significantly better than from conventional tablets produces from a digoxin-lactose trituration (61% in 90 s).

Adult↗

[Interactions of digoxin with nifedipine and diltiazem].

Biological serum halt-life, relative volume of distribution and digoxin clearance following a single oral dose of digoxin with diltiazem or nifedipine were evaluated. Blood serum digoxin following its administration with diltiazem and nifedipine for 8 days were assayed. It was found that diltiazem and nifedipine did not affect tested pharmacokinetic parameters of digoxin and did not change digoxin serum levels during a 8-day administration in combination with diltiazem and nifedipine.

Adult↗

Inhibition of electrogenic Na(+)-pumping in isolated atrial tissue from patients treated with digoxin.

The effect on the cardiac sarcolemmal Na+,K(+)-pump of therapeutic concentrations of cardiac glycosides administered long-term to humans in a clinical setting is uncertain. We therefore examined Na+,K(+)-pump activity in atrial tissue from two groups of patients undergoing cardiac surgery. Fourteen patients received digoxin long-term until the time of surgery and 12 "controls" never received digoxin. The hyperpolarization produced by the electrogenic Na+,K(+)-pump in response to an increase in intracellular Na+ activity was utilized to evaluate Na+,K+)-pump activity. After excision from the patients, specimens of atrial tissue were Na(+)-loaded by cooling to 2-3 degrees C for 1 hr. They were then warmed to 30 degrees C in Tyrode's solution containing 20 mM K+. After warming the resting membrane potential of the tissues from both groups transiently hyperpolarized to levels more negative than the equilibrium potential for K+ (= approximately -50 mV in 20 mM K+) indicating that the hyperpolarization was the consequence of electrogenic Na(+(-pumping. The maximal hyperpolarization of the resting potential in tissue from patients receiving digoxin long-term (-58.4 +/- 1.9 mV, mean +/- S.D.) was significantly (P less than .01) less negative than that in tissue from patients in the control group (-69.9 +/- 2.2 mV). These data support the hypothesis that digoxin, administered therapeutically in the clinical setting, can inhibit the Na(+)-pump in human heart, and that during long-term administration of digoxin the inhibition can be sustained.

Digoxin↗

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↗

Selection of monoclonal anti-digoxin antibodies with appropriate binding characteristics for immunodiagnostic purposes.

Digoxin is the third most commonly prescribed drug in the United States and is routinely monitored in clinical chemistry laboratories. Polyclonal antisera used up until now in immunoassays for digoxin are not satisfactory and lead to poor precision and problems with standardization. Monoclonal antibodies would certainly be preferable because of high reproducibility and possibility of standardization which they ensure. Twenty-two anti-digoxin monoclonal antibodies (MoAbs) were selected by an ELISA absorption at the earliest stages of hybridoma growth. Dissociation constants of selected MoAbs were determined by ELISA. Detection limit in this system was also assessed. Specificity of twelve antibodies with sufficiently high-affinity constants to detect therapeutic and subtherapeutic levels of digoxin was determined by cross-reactivity experiments with 25 steroid compounds-cardiac glycosides, digoxin metabolites, steroid hormones, spironolactone. On the basis of these data, MoAbs with suitable binding parameters for immunodiagnostic purposes might be selected.

Animals↗

Development of a high-performance liquid chromatographic-post-column fluorogenic assay for digoxin in serum.

A quantitative, sensitive and specific assay for digoxin was developed using a high-performance liquid chromatographic (HPLC) system with post-column (PC) fluorogenic derivatization. Separation of digoxin from its metabolites was accomplished using a 15 cm X 4.6 mm I.D., 3-microns octadecylsilyl HPLC column and an optimum mobile phase of methanol-ethanol-isopropanol-dehydroascorbic acid (52:3:1:45, v/v). Concentrated hydrochloric acid, used as the PC derivatization reagent, was delivered by hexane displacement from a polyvinyl chloride pressure vessel. Construction of the pressure vessel is described. The mixture of HPLC effluent and PC reagent was passed into a 20-m knitted reactor (PTFE tubing) maintained at 79.0 +/- 0.2 degrees C. The resultant fluorophores were monitored by a fluorescence detector equipped with a 360-nm excitation filter and a 425-nm emission filter. Specificity of this HPLC-PC assay for digoxin in the presence of its metabolites was demonstrated. Also, numerous steroids evaluated did not produce fluorescence under these conditions. An extraction procedure for evaluating digoxin in serum without interference from endogenous compounds was also developed. Detector response to digoxin was linear from 0.5 to 3.3 ng extracted from serum.

Chromatography, High Pressure Liquid↗

[Electrophysiologic effects of intravenous digoxin in infants and children with Wolff-Parkinson-White syndrome].

Electrophysiologic properties of the accessory pathway were investigated before and after the intravenous administration of digoxin (0.01-0.02 mg/kg) during electrophysiologic studies in 14 infants and children with the Wolff-Parkinson-White syndrome. Determination of electrophysiologic properties of the accessory pathway was made using transesophageal atrial pacing and/or intracardiac right atrial pacing. Maximal effect on the accessory pathway after intravenous digoxin was observed during one to six hours. Effective refractory period of the accessory pathway increased in 6 of the 14 patients, decreased in 4 and unchanged in 4. Shortest AP 1:1 conduction increased in 5 of the 12 patients, decreased in 3 and unchanged in 4. Tachycardia was not induced after digoxin in only one patient. Tachycardia cycle length, ventriculoatrial conduction time and atrioventricular conduction time were unchanged after digoxin in almost all cases. Thus, digoxin is not the first choice drug for termination and prevention of the preexcitation syndrome.

Adolescent↗

Effect of a Chinese medicine "kyushin" on serum digoxin concentration measurement in dogs.

The effect of the Chinese medicine kyushin administered orally on serum digoxin measurement was studied in an animal model. Administration of 6 pills of kyushin caused a significant increase in the serum concentration of a digoxin-like immunoreactive substance (DLIS). The DLIS concentration increased to a peak value of 1.14 ng/ml at 11/2 hours and declined to 0.5 ng/ml after 24 hours. A one-week administration of 10 pills of kyushin a day produced a steady-state DLIS concentration ranging from 0.91 to 1.07 ng/ml. Among the 7 different kyushin ingredients, toad venom (ch'an-su in Chinese) was the only drug that produced DLIS in the dogs' serum. The similarity in structures of digoxin and toad venom most likely plays an important role in producing a cross-reactivity of DLIS with immunoassay antibody to digoxin. Although these findings require confirmation in human beings, they suggest that this nonprescription drug may seriously compromise the accuracy and interpretation of digoxin concentration measurements.

Animals↗

Formation of [20R]-dihydrodigoxin from digoxin in humans.

The objective of this research was to determine the stereochemical identity of dihydrodigoxin (DHD3), a metabolite of digoxin excreted in urine after digoxin administration in man. Separation of the individual epimers in reference DHD3 was effected by a chemical derivatization-HPLC procedure. Comparison of individual derivatized epimers of DHD3 with the known 20R and 20S epimers of derivatized dihydrodigoxigenin using chromatographic data and NMR spectroscopy permitted identification of the 20R and 20S epimers in reference DHD3. Material corresponding chromatographically to R-DHD3 was isolated from urine of a volunteer taking oral digoxin daily. The NMR spectrum of the chromatographically pure, derivatized urinary isolate was identical to the NMR spectrum of derivatized R-DHD3. Urine samples from 20 patients on chronic digoxin therapy and from two volunteers were surveyed for chromatographic evidence of R- or S-DHD3 using HPLC of a fluorescent derivative as well as HPLC of a UV-absorbing derivative. The more sensitive fluorescence procedure yielded evidence for R-DHD3 in eight patients and both volunteers. There was a sufficient concentration in four patients and both volunteers for independent evidence of R-DHD3 using the UV-absorbing derivative. Chromatographic evidence (fluorescent derivative) for S-DHD3 was found in urine from three patients. However, this evidence for S-DHD3 was demonstrated to be an artifact by the absence of the peak expected for S-DHD3 in the chromatogram of the UV-absorbing derivative as well as by the inability of fecal incubates to convert digoxin to S-DHD3. The results of the investigation indicate that the DHD3 metabolite formed in humans is the 20R epimer.

Adult↗

The effects of central beta-receptor antagonism on digoxin cardiotoxicity.

Pentobarbital-anesthetized dogs were pretreated centrally with either metoprolol, a selective beta1 antagonist, or ICI 118,551, a selective beta2 antagonist, prior to a continuous digoxin infusion (2.5 micrograms/kg/min, i.v.). Both agents produced depressant effects on hemodynamic parameters upon central administration. Metoprolol (1, 3 and 5 mg, i.c.v.) significantly increased the lethal dose of digoxin in a non-dose dependent manner, but these protective effects were not evident upon peripheral administration of the drug (5 mg). This protective effect was not due to local anesthetic properties of metoprolol since pretreatment with lidocaine did not alter the toxicity of digoxin. Central beta2 blockade by ICI 118,551 did not alter the doses of digoxin to ventricular arrhythmias or death. These results suggest that beta receptors are not directly involved in the cardiotoxic actions of digoxin. Metoprolol's effects may be attributed to non-specific central depressant activity.

Adrenergic beta-Antagonists↗

Influence of digoxin and diuretic therapy on sweat fluid composition.

The effect of digitalis and diuretic therapy on sweat fluid composition was investigated. Patients treated for congestive heart failure with a combination of digoxin and diuretics demonstrated a higher concentration of sodium and chloride in their sweat fluid when compared to age-matched controls. The administration of diuretics alone did not affect sweat fluid composition. The digoxin-induced increase in sodium concentration was significantly higher than that observed for chloride. These data suggest that digoxin markedly inhibits sodium reabsorption along the sweat gland tubule, whereas chloride transport is affected to a lesser degree. A significant correlation between sweat fluid sodium and serum digoxin concentrations was observed. We conclude that the increased digoxin-induced sweat sodium and chloride losses may affect sodium homeostasis in patients with congestive heart failure.

Aged↗

Influence of wheat bran and of a bulk-forming ispaghula cathartic on the bioavailability of digoxin in geriatric in-patients.

The present randomized study compared the influence of a gel-forming wheat bran with a nongel-forming bulk cathartic (an ispaghula formulation, Vi-Siblin S) on the steady state concentrations of digoxin in plasma in 30 geriatric in-patients treated with either combination (16 with wheat bran + digoxin, 14 with ispaghula + digoxin) for 4 weeks. After 2 but not after 4 weeks, wheat bran reduced the digoxin levels, although the levels were still within the therapeutic range. Ispaghula had no influence at any time. It is concluded that neither wheat bran nor the ispaghula formulation has any clinically relevant influence on therapeutic digoxin levels in geriatric patients.

Aged↗

Use of cholestyramine in the treatment of digoxin intoxication.

The bile acid-binding resin cholestyramine was administered in a dose of 4 g every six hours to a patient with digoxin intoxication. The serum digoxin concentration declined rapidly, and the digoxin half-life decreased from 75.5 hours to 19.9 hours while cholestyramine was administered. All signs and symptoms of toxic reaction subsided during the period of cholestyramine therapy, which correlated with the decline in digoxin concentrations. Cholestyramine and a related agent, colestipol, presumably interrupt the enterohepatic recycling of digoxin to enhance elimination. These agents represent potentially useful adjunctive measures in the management of non-life-threatening digitalis intoxication.

Aged↗