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PubMed1985

Pharmacokinetics, bioavailability and serum levels of cardiac glycosides.

Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal range. Since the drug is excreted predominantly by the kidney, the half-life is prolonged progressively with diminishing renal function, reaching about 5 days on average in patients who are essentially anephric. Serum protein binding of digoxin is only about 20%, and differs markedly in this regard from that of digitoxin, which is 97% bound by serum albumin at usual therapeutic levels. Digitoxin is nearly completely absorbed from the normal gastrointestinal tract and has a half-life averaging 5 to 6 days in patients receiving usual doses irrespective of renal function. The bioavailability of digoxin is appreciably less than that of digitoxin, averaging about two-thirds to three-fourths of the equivalent dose given intravenously in the case of currently available tablet formulations. Recent studies have shown that gut flora of about 10% of patients reduce digoxin to a less bioactive dihydro derivative. This process is sensitive to antibiotic administration, creating the potential for important interactions among drugs. Serum or plasma concentrations of digitalis glycosides can be measured by radioimmunoassay methods that are now widely available, but knowledge of serum levels does not substitute for a sound working knowledge of the clinical pharmacology of the preparation used and careful patient follow-up.

Absorption↗
PubMed1985

[Changes of affinity and capacity of cardiac glycoside receptors].

The receptor for cardiac glycosides probably is identical with the (Na+ + K+)-ATPase (approximately 250 000 Daltons). Its affinity for the therapeutically used glycosides is extremely different in different species (KD approximately 10(-9)M (human heart) - approximately 10(-7)M (rat heart]. In the latter, two distinct receptor types have been demonstrated (high- and low-affinity receptors) with different effects. In the human heart, there may be two cardiac glycoside receptors as well, although this has not been proved as yet. The number of cardiac glycoside receptors and their affinity is regulated in certain states and diseases. An increased receptor density is found in hyperthyroid states, in chronic hypokalaemia and in chronic digitalis treatment. A decreased number is measured in ischemic heart disease, in dilated cardiomyopathy and in hypothyroidism. Parallel to the decreased receptor density the maximal cardiac glycoside induced positive inotropy is reduced. Pronounced toxicity occurs, if the digitalis dose is increased in spite of missing effects.

Aging↗
PubMed1996

Enhanced sensitivity of the failing human myocardium to cardiac glycosides and Na(+)-channel activators.

Cardiac glycosides and Na+ -channel activators increase intracellular Na+ and thereby enhance the transport rate of the sarcolemmal Na+/Ca2+ exchanger. We tested the hypothesis of whether increased expression of the Na+/Ca2+ exchanger in failing human myocardium is accompanied by enhanced sensitivity of the failing human myocardium toward cardiac glycosides and Na+ -channel activators. We studied the positive inotropic effects of the new Na+ -channel activator BDF and the cardiac glycoside ouabain in human failing (New York Heart Association [NYHA] functional class IV, heart transplants for dilated cardiomyopathy, n = 11) and nonfailing (donor hearts, n = 5) myocardium on electrically driven left ventricular papillary muscle strips (1 Hz, 37 degrees C). The effectiveness of ouabain and BDF to increase force of contraction was similar in human nonfailing and failing myocardium. BDF was more potent to increase force of contraction in failing than in nonfailing tissue (p < 0.05). The time until maximal inotropic effect developed after ouabain was significantly shorter in NYHA IV (mean 150 +/- 16 min) than in nonfailing myocardium (mean 240 +/- 20 min). These results suggest that human failing myocardium exerts and enhanced sensitivity to cardiac glycosides and Na+ -channel activators, possibly because of enhanced expression of the Na+/Ca2+ exchanger or because of an altered intracellular Na+ -homeostasis.

Adolescent↗
PubMed1982

Specificity of cardiac glycoside binding to membrane filters.

Two cardiac glycosides, with different physiochemical properties, were investigated to assess their binding characteristics to filters. The lipophilic cardiac glycoside, digoxin, demonstrated significant (10%) retention to certain cellulose filters. There were considerable differences in the amount of digoxin retained among the cellulose type filters. The polycarbonate type filter (10 microns thick) demonstrated less than 2% retention. This was similar in magnitude to the cellulose-acetate-nitrate ester filters (100 microns thick) which demonstrated less than 1% retention. Ouabain, the polar cardiac glycoside, appeared to have minimal (2%) retention on all filter types tested. Increasing the size of the pore from .4 microM to .8 microM resulted in a minimal decrease in retention for the Amicon filters, whereas the nucleopore polycarbonate filters demonstrated a significant reduction in retention of the lipophilic cardiac glycoside. A comparison of the 100 micron thick filters with the 10 micron thick filters suggests that there is no correlation with the thickness of the filter and the retention of the drug bound by that filter. These studies suggest that lipophilic drugs are retained on membrane filters depending on the filter's composition and that caution should be utilized with the filtration technique.

Cardiac Glycosides↗
PubMed1975

Membrane currents and tension in cat ventricular muscle treated with cardiac glycosides.

The effect of cardiac glycosides on membrane currents and tension in cat ventricular muscle was studied using the single sucrose gap voltage clamp method. Complete tension-voltage and current-voltage relations were obtained in five preparations before and during treatment with dihydro-ouabain (DHO, 1.7 X 10(-5)M). After 1-2 minutes of DHO, the developed tension was 15% greater than control, but there was no change in either the slow inward (calcium) current (Ica) or the level of the outward current flowing at the end of a 300-msec depolarization (Iout). After 6-8 minutes of DHO, there was a 60% increase in developed tension, a noticeable increase in resting tension, a 20% decrease in Ica, and a smaller increase in Iout. It seems possible that the reduction of Ica was due to a reduced driving force. In preparations treated with ouabain (5 X 10(-7)M, 3-5 minutes), developed tension was 45-150% greater than control with no change in Ica or Iout between -45 and + 15 mv. We conclude that the inotropic action of these cardiac glycosides is not mediated by an increase in Ica.

Animals↗
PubMed2005

The neurotoxic effects of prenatal cardiac glycoside exposure: a hypothesis.

Cardiac glycosides (CGs) are beneficial in treating cardiac conditions; depending on time and dosage, they can also be toxic as they regularly cross the blood brain barrier and the placenta and may affect the unborn baby. This paper therefore focuses on the effects of CGs administered to the mother on normal cellular physiology of the foetus with specific reference to neural tissue. CGs act by binding to the Na+/K+-ATPase and decrease or inhibit Na+-K+ pump activity. In the foetus, CGs may disrupt ion homeostasis. An over-dosage of CGs or when it is taken during pregnancy, can also affect the neuro-energy levels of brain tissue in particular. We conclude and hypothesize that CGs in this case will not only cause severe alterations in neuronal function due to disruption of membrane activity, but also in glutamate clearance, affecting neurotransmission in general. Furthermore, elevated cytosolic Ca2+ will lead to permeabilization of the mitochondrial membranes, resulting ultimately in mitochondrial dysfunction. This will result in neurotoxicity--ensuing in neural cell damage or death, and we propose the mechanism to be due to neuro-necrapoptosis.

Animals↗
PubMed1976

[New aspects on the mode of action of cardiac glycosides].

A dissociation of the therapeutic from the toxic effects of cardiac glycosides has repeatedly been described. Whereas it is generally accepted that the toxic effects of cardiac glycosides are based on an inhibition of the Na+-K+-ATPase, the mechanism of action of therapeutic concentrations of cardiac glycosides still remains uncertain. To test the hypothesis, that cardiac glycosides might be transported into a distinct compartment of the myocardium with the Na+-K-ATPase acting as a carrier, the interaction of some inhibitors of this enzyme (digitoxin, dihydroouabain, cassaine, N-ethylmaleimide, p-hydroxy-mercuribenzoate, ethacrynic acid, spironolactone) with ouabain was studied at different levels of cardiac glycoside actions: Myocardial function, cardiac uptake and subcellular distribution and binding to the Na+-K+-ATPase. The following results were obtained: All cardioactive drugs (ethacrynic acid and spironolactone showed no such effects) reduced dose-dependently the inotropic action of ouabain and in high concentrations increased its toxicity. The same drugs inhibited dose-dependently the cardiac uptake of ouabain without affecting the subcellular distribution pattern of ouabain. The binding of ouabain to the Na+-K+-ATPase was influenced in a similar way by these drugs, showing a competitive type of interaction with digitoxin, dihydroouabain and cassaine and a non-competitive mechanism with N-ethylmaleimide and p-hydroxymercuribenzoate. These results support the concept of a cardiac glycoside-ATPase interaction as a basis for the therapeutic action of these drugs. This may be explained either by a direct influence of cardiac glycosides on the ATPase activity and/or by a carrier mediated cardiac glycoside-transport into a distinct compartment of the myocardial cell.

Action Potentials↗
PubMed1989

Detection of poisoning by plant-origin cardiac glycoside with the Abbott TDx analyzer.

Cardiac glycoside poisoning caused by ingestion of plant material is common in tropical and sub-tropical areas. In evaluating the use of the Abbott TDx Digoxin II assay to detect such cases of poisoning, we found it a rapid and convenient method for confirming the ingestion of glycosides from the plants Nerium oleander, Thevetia peruviana, and Adonis microcarpa, and from the toad Bufo marinus. Here we report some clinical cases illustrating our experience with the use of this assay, and describe results of cross-reactivity studies with compounds structurally similar to digoxin. Because of the competitive nature of the immunoassay as well as the complexity of the mixture of cross-reacting cardiac glycosides present in the plant material, the measured apparent digoxin concentration is not linearly related to the cardiac glycoside concentration.

Adolescent↗
PubMed1985

Cellular mechanism of action of cardiac glycosides.

It has long been known that cardiac glycosides can inhibit the membrane sodium-potassium (Na+-K+) pump, raising intracellular Na+. However, at clinical concentrations of cardiac glycosides, a change in intracellular Na+ that correlates with a change in cardiac contraction has been very difficult to demonstrate. The recent use of Na+-sensitive microelectrodes in the experimental laboratory has made intracellular Na+ measurements possible. A doubling of contraction strength in vitro is associated with a change of only approximately 1 mM intracellular Na+. Another membrane transport system, the Na+-Ca2+ exchange system, exchanges extracellular Na+ for intracellular Ca2+. If this system is responsible for regulating intracellular Ca2+, then it would be very sensitive to the transmembrane Na+ concentration gradient. This influence of intracellular Na+ on Na+-Ca2+ exchange is though to be the cellular basis of the positive inotropic action of digitalis. However, a number of issues remain unresolved, such as the extent of Na+-K+ pump inhibition by the level of cardiac glycoside achieved clinically.

Action Potentials↗
PubMed2005

[Comparative analysis of the cardiac glycosides action on the growth of the cardiac tissue explants].

The method of organotypical cell culture was used. The long-term cell culture of cardiac embryonic tissue of 10-12-days old chicken was investigated. The effects of ouabaine, strophantin K and digoxin on the growth of cardiac tissue explant were measured. The ouabain concentration which stimulates activity of Na+, K+-ATPase as the signal transducer, was determined. It was equal to 10(-10) M. Strophantin K and digoxin stimulate growth of cardiac tissue in concentration equal to 10(-16) M and 10(-18) M, resp. The data obtained show that application of cardiac glycosides led to control of cardiac tissue growth in dose-dependent manner. We hypothesize that alpha3 isoform of Na+, K+-ATPase is a signal transducer that controls the cardiac cell metabolism and growth.

Animals↗
PubMed1977

[Pharmacokinetics of cardiac glycosides and clinical consequences].

The purpose of pharmacokinetics of cardiac glycosides is to study the time courses of glycosides in biological fluids, tissues and excreta. The extent of accumulation of a given dose at uniform time intervals depends only from the overall elimination rate constant. By knowing the elimination rate constant the extent to which a cardiac glycoside would accumulate in the body following a fixed dosing regimen can be calculated. The higher accumulation in the central nervous system requires a much longer time. Therefore it may be assumed that the brain is a deep compartment for cardiac glycosides and this compartment cannot be detected by analysis of plasma glycoside concentrations. Central side effects of cardiac glycosides may occur at therapeutic plasma levels. In renal disease a lower maintenance dose of digoxin and methyldigoxin should be administered or the same dose less frequently. Digitoxin does not accumulate in patients with renal failure or in anuria since the extrarenal elimination of digitoxin is much higher compared to digoxin and methyldigoxin.

Biological Availability↗
PubMed1992

Molecular basis for the insensitivity of the Monarch (Danaus plexippus) to cardiac glycosides.

The Monarch (Danaus plexippus) sequesters cardiac glycosides for its chemical defence against predators. Larvae and adults of this butterfly are insensitive towards dietary cardiac glycosides, whereas other Lepidoptera, such as Manduca sexta and Creatonotos transiens are sensitive and intoxicated by ouabain. Ouabain inhibits the Na+,K(+)-ATPase by binding to its alpha-subunit. We have amplified and cloned the DNA sequence encoding the respective ouabain binding site. Instead of the amino acid asparagine at position 122 in ouabain-sensitive insects, the Monarch has a histidine in the putative ouabain binding site, which consists of about 12 amino acids. This change may explain the ouabain insensitivity.

Amino Acid Sequence↗
PubMed1984

Evidence for two kinetically and functionally different types of cardiac glycoside receptors in the heart.

Cardiac glycosides bind with high affinity to specific receptors in the heart. In cardiac cell membranes of most animal species and man, this glycoside-receptor binding is followed by a subsequent inhibition of the membrane-bound (Na+ + K+)-ATPase, the biochemical equivalent of the active Na+/K+-transport system. Most investigators, however, have been unable to find, as a consequence of the glycoside-(Na+ + K+)-ATPase interaction, an inhibited Na+ or K+ transport in intact cardiac tissue when using low but positive inotropic concentrations of cardiac glycosides. In electrically stimulated contracting rat or guinea pig cardiac muscle we determined two kinetically different 3H-ouabain binding sites. The high affinity/low capacity site is related to positive inotropy, whereas the low affinity/high capacity binding site is connected to an inhibition of the (Na+ + K+)-ATPase. Occupation of the low affinity sites with ouabain molecules was concomitant with an increased intracellular Na+ and loss of K+ as well as onset of arrhythmias. According to our experiments, there are at least two different types of ouabain binding sites, inhibition of the (Na+ + K+)-ATPase was not necessarily related to positive inotropy in rat and guinea pig heart.

Animals↗