Digitalis Promotes Ventricular Arrhythmias in Flecainide- and Ranolazine-Pretreated Hearts.

A post hoc analysis of the PALLAS trial suggested life-threatening interactions of digitalis and dronedarone. Thus, there is concern about an interplay between digitalis and other drugs that influence cardiac electrophysiology. We therefore investigated the interaction between digitalis and flecainide or ranolazine. Twenty-five rabbit hearts were Langendorff-perfused and treated with flecainide (2 µM, 12 hearts) or ranolazine (10 µM, 13 hearts). Infusion of flecainide prolonged mean action potential duration [APD90, from 153 ms (interquartile range (IQR): 29.7 ms) to 159 ms (IQR: 24.9 ms, p = 0.04)] and effective refractory period [ERP, 170 ms (IQR: 40 ms) vs. 200 ms (IQR: 32.5 ms, p < 0.01)]. Administration of ranolazine prolonged APD90 [144 ms (IQR: 34.3 ms)) vs. 157 ms (IQR: 31.2 ms, p < 0.01)] and ERP [180 ms (IQR: 40 ms) vs. 200 ms (IQR: 30 ms, p < 0.01)]. Additional infusion of the digitalis glycoside ouabain (0.2 µM) abbreviated APD90 and ERP in both groups (flecainide: APD90: to 128 ms (IQR: 19 ms), ERP: to 170 ms (IQR: 20 ms), p < 0.01 each; ranolazine: APD90: to 141 ms (IQR: 40 ms), ERP: to 160 ms (IQR: 30 ms), p < 0.01 each). Ventricular vulnerability was assessed by a pacing protocol employing premature extra stimuli and burst stimulation. No proarrhythmic effect was observed with flecainide (1 vs. 3 episodes at baseline) or ranolazine (3 vs. 11 episodes at baseline). However, further infusion of ouabain had a proarrhythmic effect for both drugs (flecainide: 15 episodes, p = 0.04; ranolazine: 21 episodes, p = 0.09). Concomitant treatment of the sodium channel blockers flecainide or ranolazine with digitalis seems to be proarrhythmic. Abbreviation of repolarization and refractoriness that can facilitate re-entry was found as underlying mechanism.

Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias.

The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 µM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD90 ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 µM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD90 (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 µM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 µM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine.

[Considerations about study on mechanisms of acupuncture underlying efficacy-enhancement and toxicity-attenuation of digitalis drugs for heart failure].

Digitalis glycosides, a group of cardiotonic agents for heart failure, have been used for a long time, but may often trigger arrhythmias as a result of digitalis intoxication. It is of great significance in finding a method to reduce their toxicity and improve clinical curative effects simultaneously in the application of digitalis glycosides. It has been well documented that acupuncture has good therapeutic effects in improving cardiac function and inhibiting arrhythmia induced by myocardial ischemia. Acupuncture combined with chemotherapeutics can reduce the adverse effects of chemotherapeutics. Accordingly, acupuncture combined with digitalis is likely to reduce the side effects of digitalis by regulating intracellular Ca2+, improving the function of Ca(2+)-ATPase in the sarcoplasmic reticulum, increasing calcium sensitivity of cardiac troponin, etc. These considerations may provide a novel clue for treatment of heart failure by joint administration of acupuncture and drugs.

Intoxicaciones digitálicas agudas en pacientes de edad avanzada y propuesta de un nomograma de digitalización / No disponible

No disponible

[Analysis of hospital admissions associated with digitalis glycosides]. / Fingerhut--ein alter Hut?: Eine Analyse stationärer Aufnahmen durch digitalisassoziierte unerwünschte Arzneimittelwirkungen.

BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.

Is digitalis compound-induced cardiotoxicity, mediated through guinea-pig cardiomyocytes apoptosis?

Our aim in performing this study was to analyze in vivo the cell death mechanism induced by toxic doses of digitalis compounds on guinea-pig cardiomyocytes. We analyzed three study groups of five male guinea pigs each. Guinea pigs were intoxicated under anesthesia with ouabain or digoxin (at a 50-60% lethal dose); the control group did not receive digitalis. A 5-hours period elapsed before guinea pig hearts were extracted to obtain left ventricle tissue. We carried out isolation of mitochondria and cytosol, cytochrome c and caspase-3 and -9 determination, and electrophoretic analysis of nuclear DNA. TdT-mediated DUTP-X nick end labeling (TUNEL) reaction was performed in histologic preparations to identify in situ apoptotic cell death. Ultrastructural analysis was performed by electron microscopy. Electrophoretic analysis of DNA showed degradation into fragments of 200-400 base pairs in digitalis-treated groups. TUNEL reaction demonstrated the following: in the control group, <10 positive nuclei per field; in the digoxin-treated group, 2-14 positive nuclei per field, while in the ouabain-treated group counts ranged from 9-30 positive nuclei per field. Extracts from ouabain-treated hearts had an elevation of cytochrome c in cytosol and a corresponding decrease in mitochondria; this release of cytochrome c provoked activation of caspase-9 and -3. Electron microscopy revealed presence of autophagic vesicles in cytoplasm of treated hearts. Toxic dosages of digitalis at 50-60% of the lethal dose are capable of inducing cytochrome c release from mitochondria, processing of procaspase-9 and -3, and DNA fragmentation; these observations are mainly indicative of apoptosis, although a mixed mechanism of cell death cannot be ruled out.

Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels.

1 Cardiac glycosides have been used for centuries as therapeutic agents for the treatment of heart diseases. In patients with heart failure, digoxin and the other glycosides exert their positive inotropic effect by inhibiting Na(+)-K(+)-ATPase, thereby increasing intracellular sodium, which, in turn, inhibits the Na(+)/Ca(2+) exchanger and increases intracellular calcium levels. As the therapeutic index of digitalis is narrow, arrhythmias are common problems in clinical practice. The mechanisms and mediators of these arrhythmias, however, are not completely understood. 2 The involvement of the sympathetic and parasympathetic nervous system in digitalis cardiac toxicity is reviewed. 3 Receptors, channels, exchange systems or other cellular components involved in digitalis-induced cardiotoxicity are also reviewed. 4 Possible mediators of digitalis-induced cardiac toxicity are discussed. 5 Management of digitalis toxicity in patients is summarized. 6 The determination of the possible mediators of digitalis-induced cardiac toxicity will enhance our knowledge and lead to the development of new therapeutic strategies to treat these lethal arrhythmias.

La digital: planta con relevancia en la medicina / Digital: plant with relevance in medicine

Se presentan aspectos históricos, fitoquímicos, farmacológicos, toxicológicos y referentes a la utilidad medicinal de Digitalis spp., género con gran valor ornamental y comercial, sobre todo para elaborar purpureaglucósidos, digitoxina y gitoxina, compuestos utilizado en el tratamiento de enfermedades cardiacas. Digitalis purpurea fue utilizada desde el siglo XI y experimentada científicamente por W. Whitering en 1785, Inglaterra. Se le cultiva en Europa y en Estados Unidos de América del Norte, al igual que otras especies como Digitalis lanata Ehrh. y Digitalis lutea L.; actualmente son objeto de numerosos estudios y cultivos in vitro

Ouabain-sensitive Na+,K(+)-ATPase activity in toad brain.

Toads of the genus Bufo are highly resistant to the toxic effects of digitalis glycosides, and the Na+,K(+)-ATPase of all toad tissues studied to date has been relatively insensitive to inhibition by digitalis and related compounds. In studies of brain microsomal preparations from two toad species, Bufo marinus and Bufo viridis, inhibition of ATPase activity and displacement of [3H]ouabain from Na+,K(+)-ATPase occurred over broad ranges of ouabain or bufalin concentrations, consistent with the possibility that more than one Na+,K(+)-ATPase isoform may be present in toad brain. The data could be fitted to one- or two-site models, both of which were consistent with the presence of Na+,K(+)-ATPase activity with high sensitivity to ouabain and bufalin. Ki (concentration capable of producing 50% inhibition of activity) values for ouabain in the one-site model were in the 0.2 to 3.7 microM range, whereas Ki1 values in the two-site model ranged from 0.085 to 0.85 microM, indicating that brain ATPase was at least three orders of magnitude more sensitive to ouabain than B. marinus bladder ATPase (Ki = 5940 microM). Ouabain was also an effective inhibitor of 86Rb+ uptake in B. marinus brain tissue slices (Ki = 3.1 microM in the one-site model; Ki1 = 0.03 microM in the two-site model). However, the relative contribution of the high ouabain-sensitivity site to the total activity was 17% in the transport assay as compared with 63% in the Na+,K(+)-ATPase enzymatic assay. We conclude that a highly ouabain-sensitive Na+,K(+)-ATPase activity is present and functional in toad brain but that its function may be partially inhibited in vivo.

Structure-activity relationships of synthetic digitoxigenyl glycosides.

Antiviral, cytotoxic and anti-ATPase activities of 14 synthetic digitoxigenyl glycosides were compared with each other. The activities of those containing gentiobioside and melibioside were much weaker than the others. On the other hand, the three activities were highly correlated with each other.

Effect of halothane on in vivo and in vitro cardiotoxicity of an aminocardenolide.

Halothane opposes cardiotoxicity of neutral-sugar digitalis compounds in intact animals, presumably by depressing a sympathetic component of arrhythmogenesis. However, halothane also produces a dose-related reduction in arrhythmogenicity of ouabain in isolated canine Purkinje fibers, suggesting that the anesthetic may oppose direct mechanisms of cardiotoxicity as well. The present study examined in vivo and in vitro the effect of halothane on the arrhythmogenicity of ASI-222 (3-beta-O[4-amino-4-6-dideoxy-beta-D-galactopyranosyl] digitoxigen in HCl), a highly polar aminocardenolide with no sympathetic component to cardiotoxicity. For in vivo studies, ASI-222 was infused at a rate of 1 microgram/kg/min until appearance of third-degree atrioventricular (AV) block or sustained ventricular arrhythmias in 5 conscious (control) and 6 halothane-anesthetized (1.4% end-tidal) dogs. For in vitro studies, standard microelectrode techniques were used to measure action potentials (AP) in seven excised canine Purkinje fibers superfused with oxygenated Krebs-Henseleit buffer. AP were recorded during control superfusion, after induction of toxicity with 10(-7) M ASI-222, and during exposure to 0.5, 1.0, and 2.0% halothane. Purkinje fibers were paced at 500-ms cycle lengths (CL) for 20 beats, and the amplitude of delayed afterdepolarizations (DAD) were recorded. Pacing at 250 ms CL was used to trigger ectopy. In vivo studies showed no difference in the cardiotoxic dose of ASI-222 between control dogs and those anesthetized with 1.4% halothane. However, in 4 of 6 anesthetized dogs, acutely increasing the inspired halothane concentration suppressed arrhythmias once end-tidal concentration were >2.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of oscillatory potential and pacemaker shifts in digitalis intoxication of the sinoatrial node.

BACKGROUND: Digitalis intoxication causes tachycardia, pacemaker shifts, and conduction disturbances in the sinoatrial (SA) node, but the mechanisms underlying these changes have not been clarified. We studied the role played by oscillatory potentials, electrical inhomogeneity, and calcium overload in cardiac steroid intoxication of the SA node. METHODS AND RESULTS: Guinea pig SA nodes (isolated from atrial tissue) were perfused in vitro. Transmembrane potentials and force were recorded. Strophanthidin (1 mumol/L) induced minor changes, although it was perfused for more than 30 minutes. In contrast, ouabain (0.5 mumol/L) and digoxin (1 mumol/L) intoxicated the SA node in 10-20 minutes. Ouabain and digoxin increased spontaneous rate and slope of diastolic depolarization, shifted the plateau to more negative values, and decreased the maximum diastolic potential. These cardiac steroids increased and then decreased contractile force and eventually caused the action potential and twitch to become irregular in amplitude and rhythm. In the presence of acetylcholine (ACh, 0.01-1 mumol/L), cardiac steroids decreased the resting potential, caused spontaneous activity, and increased force and, eventually, oscillatory potentials (Vos) and aftercontractions as well as overdrive excitation. To make the SA node electrically homogeneous (only slow responses), the SA node was perfused with high extracellular potassium concentration (with and without norepinephrine), tetrodotoxin (2.61 mumol/L), or lidocaine (50 mumol/L). Adding ouabain or digoxin to these solutions increased the rate but far less than in Tyrode's solution. Recovery in Tyrode's solution initially caused fast and irregular rhythms, which then subsided. Low extracellular calcium concentration ([Ca]o) (0.54 mmol/L) decreased force; adding ouabain markedly increased force and induced Vos. High [Ca]o (8.1 mmol/L) increased force; adding ouabain decreased force and made action potentials as well as contractions quite irregular. CONCLUSIONS: Ouabain and digoxin quickly intoxicate the SA node by inducing calcium overload and its manifestations (Vos, decrease in contractile force and aftercontractions), whereas strophanthidin does not, possibly because of the lack of a sugar moiety. The intoxication is less pronounced when sodium influx is decreased (slow responses), and this accounts for the shifts from dominant to subsidiary pacemakers. Marked conduction disturbances result from calcium overload, leading to the fractionation of SA node activity.

The bronchodilator terbutaline enhances digitalis-induced arrhythmia.

The hypothesis that beta 2-sympathomimetics augment digitalis-induced arrhythmias and antagonize its positive inotropic action was tested in isolated, electrically driven guinea-pig left atria. Alone, 0.3 mM terbutaline enhanced myocardial force generation but did not induce dysrhythmia. Terbutaline shortened the time to the onset of 3 microM ouabain-induced arrhythmia by approximately 75% from 19.7 +/- 3.2 minutes to 5.7 +/- 1.2 minutes (p less than 0.005). The enhancement of arrhythmias appeared to be the result of triggering ouabain-induced delayed afterdepolarizations (DAD) into overt arrhythmia. The effect of terbutaline was antagonized by blocking cardiac beta-adrenoceptors with propranolol. Terbutaline did not affect the ability of ouabain to increase myocardial contractility.

Na(+)-activated K+ current in cardiac cells: rectification, open probability, block and role in digitalis toxicity.

The Na(+)-activated K+ current was studied in inside-out patches and in whole cells isolated from the guinea-pig cardiac ventricle. The single channel conductance showed inward rectification for K+i less than K+e, but outward rectification for K+i greater than K+e. The open probability was dependent on Na+i and Na+,K(+)-pump activity. In the presence of pump blockade the channel remained active at low Na+i. Similar results were obtained in whole cells. These results suggest the existence of Na+ gradients depending on Na+,K(+)-pump activity and passive inward leak of Na+. The channel and whole cell current were blocked by R56865. The drug did not change the single channel conductance but markedly reduced open probability by shortening burst duration. The current may play an important role in action potential shortening during pump blockade.

Digitalis cardiotoxicity: cellular calcium overload a possible mechanism.

Isolated perfused guinea pig (Langendorff) heart was employed to determine if the myocardial mechanical dysfunction (mechanical toxicity) produced by toxic concentration of ouabain (1 microM) was accompanied by alterations in mitochondrial function. Ouabain (1 microM) produces a transient increase in the myocardial contractile force and then a continuous decline in the left ventricular mechanical function. Mitochondria isolated from ouabain perfused hearts showed a significantly higher rate of 45Ca2+ uptake and reduction in oxidative phosphorylation. The rate of ATP generation was reduced by almost 50% at the time of contracture development. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, delayed or abolished the mechanical toxicity in a dose dependent manner. The mitochondria isolated from these hearts demonstrated normal rate of Ca2+ uptake and ATP generation capacity. The data indicate that the cardiac mechanical dysfunction induced by toxic doses of ouabain may be associated with mitochondrial Ca2+ overload and dysfunction and that the Ca2+ channel blockers may have a protective effect.

How effective is digitalis in the treatment of congestive heart failure?

The evidence suggests that digitalis glycosides do indeed improve ventricular performance through a sustained but moderate positive inotropic effect. This effect is more marked in failing than in nonfailing myocardium. The clinical studies suggest a moderate salutary effect in patients with chronic CHF who are in sinus rhythm. The drug can be given safely to patients with CAD and in combination with other medications when the physician is aware of those factors leading to increased sensitivity to digitalis.

Differential inactivation of inotropic and toxic digitalis receptors in ischemic dog heart. Molecular basis of the deleterious effects of digitalis.

When applied to ischemic hearts digitalis exhibits depressed inotropic effect and increased toxicity. The molecular basis of these effects was investigated at the level of the digitalis receptors characterized by Na,K-ATPase assays and [3H]ouabain-binding measurements. In sarcolemma obtained from dog hearts rendered ischemic for 15, 30, and 60 min (left anterior descending), two populations (high and low affinity) of digitalis receptors were detected. The apparent affinity (KD, 300 nM) and the binding capacity of the low-affinity sites (responsible for toxicity) remained constant and similar to those found in normal hearts. The KD value of the high-affinity sites, "responsible for inotropy," remained unchanged (2 nM), but the site number sharply decreased (up to 90%). These inotropic sites that account for 66% of the total binding in normals are gradually inactivated, as the duration of ischemia increases. This inactivation would occur in situ since it was detectable in homogenates and was not depressed by the isolation procedure per se. The loss of function of the inotropic sites and the increased contribution of the low-affinity toxic sites represent the setting of a new distribution of the digitalis receptors in the ischemic heart before reperfusion is instituted. This constitutes the molecular basis of the deleterious pharmacological effects observed with digitalis.