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PubMed1984

Therapeutic range of cardiac glycosides.

The narrow therapeutic range of cardiac glycosides continually challenges chemists to synthetize new derivatives with improved therapeutic properties. One of the best investigated semi-synthetic glycosides is 16 alpha-gitoxin. Compared to ouabain and gitoxin, it produces positive inotropic effects on the isolated guinea-pig heart in a wider range of concentrations and causes less pronounced rhythmic disturbances. These results were confirmed by electrophysiological investigations in isolated fibres of the canine myocardium and of the Purkinje system, by investigations in the anaesthetized cat and dog and in healthy volunteers. The effects of various semi-synthetic compounds (e.g. actodigin, ASI-222) are described and possibilities to trigger these effects are discussed. Of some significance seem to be differences in the structure of the (Na+ + K+)-ATPase system of different tissues, e.g. the working muscle and the Purkinje system of the heart, as well as differences due to the formation and dissociation of the glycoside-enzyme complex. The significance of K+, Ca2+ and of several pharmacokinetic parameters (e.g. the volume of distribution) for these reactions are briefly discussed.

Animals↗
PubMedDate not supplied

Current status of cardiac glycoside drug interactions.

The effects of concomitant drug therapy on the absorption, distribution, and elimination of digoxin and digitoxin are reviewed. A number of agents can increase or decrease the absorption of digoxin and digitoxin from the gastrointestinal tract by altering GI motility, binding the drugs through physical adsorption, altering the properties of the intestinal wall, or altering the bacterial flora of the intestine. The steady-state serum concentrations of digoxin and digitoxin can be affected if the changes in absorption are of sufficient magnitude, and adjustments in digoxin or digitoxin dosage may be required. A reduction in digoxin and digitoxin protein binding has occurred during concomitant administration of heparin and cardiac glycosides. Since digitoxin is more highly protein bound than digoxin, interactions that involve changes in protein binding are of much greater clinical importance with digitoxin. A number of drugs increase or decrease the elimination of digoxin and digitoxin, and subtherapeutic or toxic concentrations of the cardiac glycosides often result. Drugs that induce hepatic microsomal enzymes can increase the elimination of digitoxin, which is eliminated mainly by hepatic biotransformation. Digoxin is eliminated mainly by renal excretion; renal clearance of digoxin may be increased by vasodilators and thyroid hormones and decreased by quinidine, verapamil, amiodarone, and potassium-sparing diuretics. The clinical importance of changes in serum concentrations of the cardiac glycosides that result from alterations in glycoside elimination requires further study, as does the importance of preliminary reports of interactions between cardiac glycosides and diazepam, captopril, and combination therapy with quinidine-pentobarbital or quinidine-rifampin. Because the cardiac glycosides have a narrow therapeutic range, patients receiving concomitant therapy with agents that might affect the absorption, distribution, or elimination of the cardiac glycosides should be monitored carefully for symptoms of digitalis toxicity or undertreatment.

Anti-Arrhythmia Agents↗
PubMed1981

[The problem of the cellular receptor for cardiac glycosides (author's transl)].

This review concerns the Na+, K+ -ATPase as well as the Na+, K+ -pump in the intact membrane and the highly specific inhibition of this transport system by cardiac glycosides. The interaction between glycoside and enzyme and the regulation of the kinetics of glycoside binding by ATP, K+, Na+, Mg2+ and Ca2+ are described. Emphasis is placed on the significance of the Na+, K+ -pump as the pharmacological receptor for cardiac glycosides. The problem encountered and progress made in attempting to correlate the inotropic action of cardiac glycosides with the binding of these drugs to the heart muscle and with the inhibition of the Na+, K+ -pump are reported. Recent results concerning increases of the intracellular Na+ concentration which are obtained by a partial inhibition of the Na+, K+ -pump and which are followed by an elevation of the intracellular Ca2+ -activity are reviewed. The discovery of a digitalis-like endogenous activity corresponds to the high specificity of the receptor for cardiac glycosides.

Cardiac Glycosides↗
PubMed1975

[Use of cardiac glycosides in chronic circulatory insufficiency].

Features specific for the action produced by the most widely employed cardiac glycosides (strophanthin, corglycon, proscillardin A, methyl- and acetyldigoxine, isolanide, digoxine and digitoxin) on the hemodynamics, peripheral resistance, electrolyte composition, acid-base equilibrium, the blood adenyl system, etc were studied in 375 patients with different stages of chronic circulatory insufficiency. The data thus made available allowed some suggestions to be made as to the choice of cardiac glycosides, the duration of their application, possible combinations thereof, and also to propose a number of measures aimed at preventing the development of poisoning with cardiac glycosides.

Adolescent↗
PubMed2000

Cardiac glycosides from Erysimum cheiranthoides.

Two new cardiac glycosides called cheiranthosides VI (2) and VII (3) were isolated together with a known one, glucoerysimoside (1) from the seeds of Erysimum cheiranthoides. Based on spectroscopic data, the structures of 2 and 3 were characterized as periplogenin 3-O-beta-D-glucopyranosyl(1-->4)-beta-D-fucopyranoside and periplogenin 3-O-beta-D-glucopyranosyl(1-->4)-beta-D-antiaropyranoside, respectively.

Carbohydrate Sequence↗
PubMed1992

Receptor kinetics and concentration-effect relation of cardiac glycosides.

Therapeutic and toxic actions of cardiac glycosides are attributed to an inhibition of Na, K-ATPase. The therapeutically relevant range is between 25% and 50% inhibition. There is a good correlation between the average steady state serum concentration of glycosides and their therapeutic action. However, therapeutic and toxic effects set in with a latency and therefore do not follow the daily variations in glycoside concentration. Although the effect follows the average serum concentrations, only the minimal concentration is measured. In principle this is only adequate if the ratio of average/minimal concentration is constant. A model calculation showed that with a constant average steady state concentration an increase in the distribution volume or a decrease in total body clearance with corresponding reduction of the daily dose lead to an increase of the minimal concentrations of 5-7%. This means a corresponding underestimation of the average concentration from the minimum concentration. However, the deviations are too small to be of clinical relevance.

Cardiac Glycosides↗
PubMed2002

Cardiac glycosides from Erysimum cheiranthoides.

Three new cardiac glycosides named cheiranthoside VIII (1), cheiranthoside IX (2) and cheiranthoside X (3) were isolated from the seeds of Erysimum cheiranthoides. Based on spectroscopic data, the structures of 1-3 were characterized as strophanthidin 3-O-beta-D-glucopyranosyl-(1-->4)-beta-D-antiaropyranoside, cheiranthidin 3-O-beta-D-glucopyranosyl-(1-->4)-beta-D-boiviopyranoside and cheiranthidin 3-O-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-digitoxopyranoside, respectively. The aglycone moiety possessing a carboxyl group at C-10 of 2 and 3 was regarded to be determined for the first time.

Brassicaceae↗
PubMed1980

[Smooth muscle and cardiac glycosides (author's transl)].

Actions of cardiac glycosides (C.G.) on smooth muscles are reviewed. 1. C.G. inhibit the Na-K ATPase of smooth muscle membrane, though the degree and mode of the inhibition vary among the types of smooth muscles. 2. The uptake of C.G. by smooth muscles has been reported to be influenced by K+, Na, ATP, and temperature. The difference between the uptake and its effect can be observed. 3. Intracellular K concentration decreased and intracellular Na concentration increased by the treatment with C.G. 4. They depolarized the membrane; the action being affected by extracellular ion concentration. An increase in spike discharges is observed. 5. C.G. potentiate or inhibit the concentrations of smooth muscles, depending on the types of smooth muscles and the causes of the contraction. C.G. can also cause transient contraction of smooth muscle. 6. C.G. influence the Ca content and Ca movements of smooth muscles. 7. C.G. cause the release of noradrenaline, acetylcholine, or prostaglandins. These substances can affect the contractile responses of smooth muscles.

Animals↗
PubMed1988

Preparation and evaluation of technetium-99m labeled cardiac glycoside derivatives as potential myocardial imaging agent.

Three cardiac glycosides, two natural, cymarin and convallotoxin and one synthetic, strophanthidin-beta-D-glucoside were converted to their thiosemicarbazone and subsequently radiolabeled with 99mTc by chelation. The resulting radioactive chelate complexes were evaluated in animals to determine the suitability of this class of compounds for myocardial imaging. It was observed from the animal biodistribution data of the three radioactive compounds, there was a considerable variation in the heart to non-target organ uptake ratio. A possible explanation of this variation was offered in the light of their lipophilic character, protein binding ability and affinity towards non-target receptors. It is anticipated that this study may help to develop a 99mTc-cardiac glycoside complex with better distribution characteristics, and such a compound may offer a suitable alternative to 201Tl, which is at present used for myocardial imaging.

Animals↗
PubMed1997

Influence of extracellular K+ concentration on the time-course of Na+/K+-ATPase inhibition by cardiac glycosides with fast and low binding kinetics.

The magnitude of the K+ antagonism of cardiac glycoside binding to Na+/K+-ATPase prepared from porcine heart, was estimated from the enzyme activities determined in the presence of different concentrations of K+ ([K+]), ouabain, and alpha-methyl-digitoxigenin-glucoside, the latter showing a 30 fold greater dissociation rate than ouabain. An increase of [K+] (3-20 mmol/l) prolonged the half-lives of Na+/K+-ATPase inhibition and caused a rightward shift of the cardiac glycoside's dose-response curves by the same factor, almost maximal (4 fold) at 14 mmol/l K+. These data could be verified from the cardiac glycoside-elevated intravesicular Na+ concentrations of rat brain vesicles. These concentrations declined rapidly in brain vesicles treated with alpha-methyl-digitoxigenin-glucoside but not with ouabain after K+ was increased from 3.5 to 14 mM. The results suggest that the magnitude of the K+ antagonism under physiological conditions is only limited by the lifespan of the cardiac glycoside-binding E2P enzyme conformation reduced by K+.

Animals↗
PubMed2003

Effect of cardiac glycosides on action potential characteristics and contractility in cat ventricular myocytes: role of calcium overload.

There is increasing evidence that cardiac glycosides act through mechanisms distinct from inhibition of the sodium pump but which may contribute to their cardiac actions. To more fully define differences between agents indicative of multiple sites of action, we studied changes in contractility and action potential (AP) configuration in cat ventricular myocytes produced by six cardiac glycosides (ouabain, ouabagenin, dihydroouabain, actodigin, digoxin, and resibufogenin). AP shortening was observed only with ouabain and actodigin. There was extensive inotropic variability between agents, with some giving full inotropic effects before automaticity occurred whereas others produced minimal inotropy before toxicity. AP shortening was not a result of alterations in calcium current or the inward rectifier potassium current, but correlated with an increase in steady-state outward current (Iss), which was sensitive to KB-R7943, a Na+-Ca2+ exchange (NCX) inhibitor. Interestingly, Iss was observed following exposure to ouabain and dihydroouabain, suggesting that an additional mechanism is operative with dihydroouabain that prevents AP shortening. Further investigation into differences in inotropy between ouabagenin, dihydroouabain and ouabain revealed almost identical responses under AP voltage clamp. Thus all agents appear to act on the sodium pump and thereby secondarily increase the outward reverse mode NCX current, but the extent of AP duration shortening and positive inotropy elicited by each agent is limited by development of their toxic actions. The quantitative differences between cardiac glycosides suggest that mechanisms independent of sodium pump inhibition may result from an altered threshold for calcium overload possibly involving direct or indirect effects on calcium release from the sarcoplasmic reticulum.

Action Potentials↗
PubMed2001

All human Na(+)-K(+)-ATPase alpha-subunit isoforms have a similar affinity for cardiac glycosides.

Three alpha-subunit isoforms of the sodium pump, which is the receptor for cardiac glycosides, are expressed in human heart. The aim of this study was to determine whether these isoforms have distinct affinities for the cardiac glycoside ouabain. Equilibrium ouabain binding to membranes from a panel of different human tissues and cell lines derived from human tissues was compared by an F statistic to determine whether a single population of binding sites or two populations of sites with different affinities would better fit the data. For all tissues, the single-site model fit the data as well as the two-site model. The mean equilibrium dissociation constant (K(d)) for all samples calculated using the single-site model was 18 +/- 6 nM (mean +/- SD). No difference in K(d) was found between nonfailing and failing human heart samples, although the maximum number of binding sites in failing heart was only approximately 50% of the number of sites in nonfailing heart. Measurement of association rate constants and dissociation rate constants confirmed that the binding affinities of the different human alpha-isoforms are similar to each other, although calculated K(d) values were lower than those determined by equilibrium binding. These results indicate both that the affinity of all human alpha-subunit isoforms for ouabain is similar and that the increased sensitivity of failing human heart to cardiac glycosides is probably due to a reduction in the number of pumps in the heart rather than to a selective inhibition of a subset of pumps with different affinities for the drugs.

Cardiotonic Agents↗
PubMed1989

[The past and present of cardiac glycosides. II. Structure, physical and chemical properties. Pharmacodynamics].

An outline is presented on the physical and chemical properties and structure of the most important cardiac glycosides, i.e. digoxin, digitoxin and g-strophanthin. The overall effects of cardiac glycosides on the cardiovascular system not only are a composite of changes in the force of ventricular contraction and heart rate but also result from effects on the autonomic nervous system and on vascular smooth muscle. Furthermore reflex adjustments to the initial hemodynamic changes caused by the drug are also important. In the normal heart and circulation cardiac glycosides increase inotropy and decrease the chronotropy and dromotropy of the heart. They increase the peripheral vascular resistance and venous tone. Cardiac output remains unchanged or decreases slightly owing to increased peripheral vascular resistance and slowed heart rate. In patients with compromised cardiac inotropy the effects of the glycosides on the heart is essentially the same as in normal subjects, however by suppressing the enhanced sympathetic activity the negative chronotropic and dromotropic effects are more prominent. Peripheral vascular resistance is lowered, cardiac output and venous capacity are increased.

Cardiac Glycosides↗
PubMed2001

Na+,K(+)-ATPase inhibiting activity of cardiac glycosides from Erysimum cheiranthoides.

We previously reported the isolation of eleven new cardiac glycosides called cheiranthosides I-XI together with two known ones (olitoriside and erysimoside) from the seeds of Erysimum cheiranthoides L. The glycosides were evaluated for their inhibitory activity against Na+,K(+)-ATPase by comparing with typical cardiac glycosides. Two of them, cheiranthoside III and VIII, showed high inhibiting activity which was equivalent to that of digitoxin. Cheiranthoside XI containing a rhamnopyranosyl digitoxopyranosyl moiety and a carboxyl group showed the lowest activity which was similar to that of the inactive aglycone, strophanthidin. Some characteristics in the structure-activity relationship are also discussed.

Animals↗
PubMed1990

Cardiac glycosides and pregnanes from Adenium obesum (studies on the constituents of Adenium. I).

Cardiac glycosides and pregnanes from the roots and the stems of Adenium obesum Roem. et Schult. were investigated. Among 30 cardiac glycosides including 15 known glycosides and 15 new combinations of the known aglycones and sugars, the structures of 11 glycosides were elucidated. Oleandrigenin beta-gentiobiosyl-beta-D-thevetoside was the main glycoside. Neridienone A and 16,17-dihydroneridienone A, common pregnanes in Apocynaceae, were also isolated.

Cardiac Glycosides↗
PubMed1990

Chromatography of cardiac glycosides.

Most of the recently reported methods for the quantitation of cardiac glycosides have been for digoxin and its metabolites. Recent procedures using high-performance liquid chromatography-radioimmunoassay (HPLC-RIA) and HPLC following derivatization show appreciable improvements in accuracy and specificity for quantitating digoxin in the low nanogram range. Gas chromatographic procedures have been explored to a very limited extent and further advances in the quantitation of cardiac glycosides are anticipated to arise from the use of laser desorption-Fourier transform mass spectrometry. However, currently, HPLC with derivatization and HPLC-RIA techniques remain the techniques of choice for quantitation of digoxin and/or its metabolites based on considerations of ease of use, sensitivity, specificity, accuracy and reproducibility.

Cardiac Glycosides↗