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PubMed1988

Cellular electrophysiologic effects of vertebrate digitalis-like substances.

Substances structurally and functionally similar to digitalis glycosides are produced by several vertebrate species. There also is evidence for a digitalis-like substance of human origin. Standard microelectrode techniques were used to study the direct effects on the cellular electrophysiology of canine Purkinje fibers of 1) bufalin, an unconjugated cardiotonic steroid molecule that is produced by the toad Bufo marinus, and 2) an extract of human bile that showed digitalis-like immunoreactivity on radioimmunoassay. The goal of this study was to determine whether these substances have arrhythmogenic effects comparable with those seen with toxic doses of digitalis glycosides. Bufalin, 2 x 10(-8) M, significantly (p less than 0.05) reduced maximal diastolic potential, action potential amplitude and duration and maximal rate of rise of phase 0 (Vmax) within 40 min of onset of exposure. All six fibers developed delayed afterdepolarizations and two developed triggered rhythms. Ouabain was less potent, in that a 2 x 10(-7) M concentration was required to comparably reduce maximal diastolic potential, action potential amplitude and duration and Vmax within 30 min. These Purkinje fibers also developed delayed afterdepolarizations and triggered rhythms. A sample of an extract of human bile that showed digitalis-like immunoreactivity with an antibufalin serum also reduced maximal diastolic potential, action potential amplitude and duration and Vmax, and produced delayed afterdepolarizations and triggered activity. In contrast, immunologically unreactive bile extracts had no appreciable effect on the action potential. In summary, the cardiac toxicity of digitalis substances produced by lower vertebrates is comparable with that induced by the glycosides. Moreover, it appears that humans may produce digitalis-like substances that may be cardiotoxic.

Action Potentials↗
PubMed1987

Digitalis toxicity: mechanisms, diagnosis, and management.

Digitalis glycosides have a narrow margin between therapeutic and toxic levels. Although the incidence of digitalis toxicity appears to be decreasing, continuation of digoxin therapy in the face of overt toxicity carries a substantial risk of life-threatening cardiac rhythm disturbances. This review will focus primarily on toxicity produced by digoxin and discuss the mechanisms, clinical manifestations, and current management of digitalis toxicity. The appropriate methodology for measurement and interpretation of serum digoxin levels is emphasized. The varied cardiac dysrhythmias induced by digoxin are detailed and their specific management outlined. Immunological (antibody) treatment has now been established and approved for the therapy of advanced, life-threatening digitalis toxicity and the multicenter trial of digitalis antibodies is described. Proper understanding of the pharmacokinetics of digitalis glycosides and careful followup of digitalis treated patients for early evidence of toxicity should help to decrease further the prevalence of toxic reactions.

Arrhythmias, Cardiac↗
PubMed2006

[Do we use digitalis properly in the management of elderly patients suffering from the signs of chronic heart failure?].

INTRODUCTION: The indications of digoxin therapy has been significantly narrowed and also the effective target therapeutic blood level has been decreased (0.9 micromol/L) compared to the previously desired one. OBJECTIVE: In this retrospective trial the data of 60 consecutive patients over 65 years (25 male, 35 female, mean age 77.3 +/- 5.0 y), hospitalized between 01. 01. 2002 and 31. 12. 2003 with a diagnosis of chronic heart failure and elevated (> 1.2 microg/I) serum level of digoxin, were analyzed. METHODS: Beside the analysis of the age, sex, serum level of digoxin and potassium, creatinine clearance value, symptoms and ECG-signs of digitalis intoxication, presence of atrial fibrillation, concomitant diseases and left ventricular ejection fraction value, the reasonability of digitalis treatment and therapy applied at the time of discharge (considering actual treatment guidelines) were also reviewed. RESULTS: At the admission mean serum level of digoxin was 2.1 +/- 0.9 microg/l. 20 patient's value (33.3%) was found above 2.2 microg/l. Symptoms characteristic for digitalis intoxication were observed in 28 patients. On the ECG performed at admission signs of digitalis effect/overdose were observed in 54 cases ("bigemin" ventricular extrasystoles, bradycardia, characteristic down-sloping ST-depressions). The mean left ventricular ejection fraction of the patients (51.5 +/- 12.7%) did not suggest to a significant left ventricular systolic dysfunction. For the elevated serum level of digoxin the impaired renal function (mean creatinine clearance 42.9 +/- 21.3 mL/min) was responsible in most cases. In patients with the highest serum level of digoxin (n = 20, 3.2 +/- 0.7 microg/L) the creatinine clearance was even lower, 30.4 +/- 13.7 mL/min. During hospital treatment the administration of digitalis was found to be unnecessary and thus terminated in 44 patients. At the discharge only 16 patients were receiving digitalis, 14 of them digoxin and 2 patients digitoxin. CONCLUSIONS: The authors emphasize, that in case of elderly patients the indication and control of digitalis therapy requires greater precaution and tight doctor-patient cooperation.

Aged↗
PubMedDate not supplied

[Digitalis--selected problems and controversies].

Atrial was undertaken of assessment of the usefulness and the place of digitalis glycosides in the treatment of chronic congestive cardiac failure, in myocardial infarction and in mitral stenosis. There is no consensus of opinions of the effectiveness of digitalis treatment in cases of cardiac failure which is due to lack of uniformity of qualification of patients for studies and absence of accepted universally haemodynamic parameters of the effectiveness of the positive inotropic action of these glycosides. The usefulness of these glycosides in patients with cardiac failure and paroxysmal or stable atrial fibrillation and ventricular tachycardia is unquestionable. Digitalis is effective in the treatment of mild cardiac failure, but is ineffective in its IV stage (NYHA). There is still a controversy on the use of digitalis glycosides in acute myocardial infarction with associated myocardial failure. In acute myocardial infarction digitalis glycosided should not be used, with the exception of cases with coexistent supraventricular arrhythmia and ventricular tachycardia. It is still difficult to establish unequivocally the effect of digitalization of patients after acute phase of myocardial infarction and after discharge from hospital on further survival. The future place of digitalis glycosides in the treatment of cardiac failure will depend on the results of studies comparing them with new positive inotropic drugs. The place of digitalis glycosides in the treatment of haemodynamic cousegnences of mitral stenosis, but they are useful in supraventricular arrhythmias during mitral stenosis, and for alleviation of right-ventricular cardiac failure.

Arrhythmias, Cardiac↗
PubMedDate not supplied

[Effects of several anti-arrhythmia agents on excitability and conduction depressed by digitalis agents].

Digitalis intoxication is characterized by the appearance of most of the types of severe arrhythmias described and also by important disturbances of cardiac excitability and impulse propagation. Most of the antiarrhythmic agents that are used in the treatment of these conditions also depress excitability and impulse propagation. These characteristics are frequently responsible of severe complications. The purpose of this paper is to determine the type of interactions that exist between digitalis and some antiarrhythmic agents, and compare them with the effects of magnesium. The experiments were done in several groups, of dogs anesthetized with pentobarbital and with the chest open. Excitability, conduction time and functional refractory period were determined using the classical methods. The protocol used consisted in the comparison of the actions of toxic doses of digitalis on excitability and conduction times of the atrial and ventricular tissues, under control conditions and in the presence of therapeutic doses of procainamide, lidocaine and magnesium. The results showed that procainamide worsened the depression of excitability and conduction produced by digitalis intoxication, while lidocaine does not add to the digitalis effects and in some cases it produces a partial improvement of these parameters. Magnesium completely reverts the effects on excitability and conduction. These results provide us with rational pharmacological bases for the treatment of digitalis intoxication and suggest that magnesium could be very useful in the management of patients with severe digitalis intoxication.

Animals↗
PubMed2004

Digitalis for treatment of congestive heart failure in patients in sinus rhythm.

BACKGROUND: Digitalis glycosides have been in clinical use in the treatment of congestive heart failure (CHF) for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was published in 1990, an update is required to include more current trials. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating CHF in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme inhibitors, and beta-blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with "CHF due to systolic dysfunction" vs. "CHF with preserved systolic function." SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) 2003 Issue 4, MEDLINE (1966 to December 2003) and EMBASE (1990 to December 2003) were searched. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were also searched from 1996-2003. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic CHF who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of CHF such as acute ischemic heart disease or myocarditis was present. DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were evaluated as a joint effort of the coauthors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials. MAIN RESULTS: Thirteen articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show that there is no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. REVIEWERS' CONCLUSIONS: The literature indicates that digitalis has a useful role in the treatment of patients with CHF who are in normal sinus rhythm.

Cardiotonic Agents↗
PubMed1979

One hundred digitalis blood levels. A utilization review.

One hundred consecutive digitalis serum level determination requests and results were analyzed to evaluate the rational of ordering the test and utilizing the results at his hospital. Sixty-six percent of the reasons given for ordering the test were categorized as "acceptable". As many as 25% of physicians requesting the test considered digitalis levels as "routine" diagnostic tests in a patient taking these drugs. There were 12 levels within the potentially toxic range, 19 below the usual therapeutic range. The physicians modified their therapeutic management in 38 patients as a result of their knowledge of the digitalis level in blood. It is concluded that digitalis level determinations at this hospital are reasonably well utilized and that knowledge of the digitalis levels improve the accuracy of digitalis utilization in at least one third of the patients in whom this test is done.

Adult↗
PubMed1989

The use of digitalis for the treatment of congestive heart failure: a tale of its decline and resurrection.

The decline of the use of digitalis for the treatment of congestive heart failure was due to the introduction of oral diuretic therapy, the recognition of the frequency of digitalis induced arrhythmias and the uncontrolled observations that digitalis could frequently be withdrawn from patients with a history of heart failure without recurrence of heart failure. Subsequently, it has been well documented that digitalis has chronic beneficial hemodynamic effects in patients with chronic congestive heart failure. Moreover, digitalis has been shown to improve hemodynamics when added to other drugs including diuretics, ACE inhibitors and vasodilators. It is concluded that digitalis is a mild inotropic agent that is still a primary drug for the treatment of mild to moderate acute or chronic left ventricular failure.

Digitalis Glycosides↗
PubMed1979

Electrophysiologic effect of digitalis on sinoatrial nodal function in children.

Despite the prevalence of digitalis usage in children, the electrophysiologic effects of digitalis on sinoatrial (S-A) nodal function is unknown in this age group. The purpose of this study was to determine the effect of digitalis on sinoatrial conduction time as well as on S-A nodal automatically. Ten subjects (mean age 10.5 years) underwent electrophysiologic assessment of S-A nodal function before and 30 minutes after administration of ouabain (0.01 mg/kg). Total S-A conduction time increased in each subject and the mean value after ouabain (182 msec +/- 13 standard errors of the mean [SEM]) was significantly higher (P less than 0.01) than before (149 msec +/- 11). The sinus cycle length was variable after ouabain (P greater than 0.1). The corrected sinus nodal recovery time also was variable (P greater than 0.1), decreasing substantially in three subjects. Mechanisms of the effect of digitalis on the S-A node and atrium are proposed and discussed. It is concluded that digitalis prolongs the S-A conduction time in children with normal S-A nodal function. By prolonging the S-A conduction time, digitalis may artifactually shorten corrected S-A nodal recovery time in some patients.

Adolescent↗
PubMed1992

Digitalis and neurohormonal abnormalities in heart failure and implications for therapy.

A pathophysiologic hallmark of heart failure is neurohormonal excitation, a prominent feature of which is activation of the sympathetic nervous system. Studies from our laboratories demonstrate that clinical heart failure is characterized by marked increases in efferent sympathetic neural outflow to muscle; the magnitude of this sympatho-excitation parallels the degree of cardiac dysfunction. Impairments of cardiopulmonary and arterial baroreflex sensory mechanisms appear to be responsible to a significant degree for this sympatho-excitation, consistent with findings in animal models of heart failure. Digitalis glycosides exert modest inotropic actions when administered to patients with heart failure. Digitalis also has potent autonomic effects that can potentiate impaired arterial and cardiopulmonary baroreflex mechanisms in experimental models of cardiac dysfunction. Acute digitalis administration to patients with moderate-to-severe heart failure produces profound and sustained sympatho-inhibition, which precedes any observed hemodynamic action of the agent. Further, acute digitalization of such patients rapidly normalizes impaired baroreflex-mediated mechanisms. Data now suggest that the mechanism of action of digitalis in humans is an acute potentiation of baroreceptor-mediated afferent regulation of sympathetic neural mechanisms. Prospective, randomized and controlled studies now are required to test the hypothesis that the acute effects of digitalis on autonomic mechanisms also are observed during chronic administration. In theory, the chronic sympatho-inhibitory action of digitalis, combined with its chronic potentiation of impaired baroreflex mechanisms, may offer beneficial effects independent of its inotropic actions in patients with heart failure.

Digitalis Glycosides↗
PubMed1994

Incidence of hospitalization for digitalis toxicity among elderly Americans.

OBJECTIVE: To document the prevalence of digitalis use and the incidence of hospitalization caused by digitalis toxicity. DESIGN: Observational cohort followed for 6 years. SETTING: Urban community. PARTICIPANTS: Persons were eligible if they were (1) enrolled in the Yale Health and Aging Project and (2) using digitalis when interviewed in 1982 or 1985. The Project comprises a sample of noninstitutionalized persons aged 65 years and over living in New Haven, Connecticut. METHODS: Between 1982 and 1988 when a Project participant was hospitalized in New Haven, a researcher reviewed the medical record and coded up to 16 International Classification of Diseases-Class 9 (ICD-9) diagnoses. To identify hospitalizations caused by digitalis, we reexamined records with ICD-9 codes suggesting toxicity. We confirmed the admission illness was an adverse drug reaction with a decision algorithm. RESULTS: The prevalence of digitalis use was 13% in 1982 and 12% in 1985. The incidence of hospitalization caused by definite or probable toxicity was 4.2% (95% confidence interval = 0.3% to 8.1%) over 6 years. Manifestations of toxicity were malaise or gastrointestinal symptoms (two patients) and heart block plus malaise or gastrointestinal symptoms (six patients). Use of quinidine was associated (P < .05) with toxicity. CONCLUSION: Knowledge about the incidence of severe, morbid toxicity may help clinicians estimate and compare the risks and benefits of digitalis and alternate therapies.

Aged↗
PubMed1979

Ischemic-induced alterations in cardiac sensitivity to digitalis.

Intravenous infusion of acetylstrophanthidin to 6 dogs, after a 60 min left anterior descending coronary artery occlusion, was associated with a 43.0 +/- 10.5% decrease in the dose of digitalis needed to produce ventricular arrhythmias as compared to the pre-ischemic dose (97.5 +/- 8.0 microgram/kg). Reperfusion of the ischemic region for 2 h after a 90 min occlusion resulted in a 54.4 +/- 6.7% decrease in the arrhythmogenic dose. Direct intracoronary infusions of digitalis into the ischemic region, after a 90 min coronary occlusion followed by 2 h of reperfusion, was associated with a 47.7 +/- 6.4% decrease in the dose of digitalis needed to produce arrhythmias. The pre-ischemic (control) arrhythmogenic dose of digitalis via the intracoronary infusion method was 1.5 +/- 0.3 microgram/kg (mean +/- S.E.M. of 7 dogs). Sodium pump activity, estimated from the ouabain-sensitive 86Rb uptake in sodium-loaded ventricular slices, was significantly higher in slices obtained from the ischemic regions (6.84 +/- 0.30 nmoles 86Rb/mg dry wt. (mean +/- S.E.M.), than from the non-ischemic regions (3.43 +/- 0.64 nmoles 86Rb/mg dry wt.). Sensitivity of the sodium pump activity to the inhibitory effect of ouabain also was increased in the ischemic regions as indicated by a shift in the log dose--response curve to the left. Thus, it appears that there is an increase in myocardial sensitivity to the toxic effect of digitalis after temporary ischemia and it appears to be related to an increase in the sensitivity of the Na+,K+-ATPase or sodium pump to the inhibitory effect of digitalis.

Animals↗
PubMed1988

Plasma volume expansion increases lysophosphatidylcholine and digitalis-like activity in rat plasma.

A circulating factor with digitalis-like activity has been proposed to play a role in the regulation of plasma volume. Lysophosphatidylcholine has been found to be active in many assays for digitalis-like activity. To examine the relationship between plasma digitalis-like activity and plasma lysophosphatidylcholine, the effect of plasma volume expansion with saline on the plasma levels of phospholipids and on the ability of delipidated extracts of plasma to displace tritiated ouabain from the digitalis receptor was determined. Lysophosphatidylcholine was elevated after 15, 30, and 120 minutes of volume expansion but was decreased at 60 minutes. Phosphatidylcholine was decreased at 15, 60, and 120 minutes. Plasma sphingomyelin was not altered at any time point. The ability of plasma to displace tritiated ouabain was increased only at the 60 minute time point. These results indicate that the increase in digitalis-like activity in volume expanded states is mediated by a combination of at least two factors, lysophosphatidylcholine and another factor whose digitalis-like activity is not related to the surfactant actions of a lipid.

Animals↗
PubMed1989

Learned fear: a cause of arrhythmia onset in the presence of digitalis.

In earlier studies we have shown that guinea pigs exposed to signal-shock pairs develop digitalis toxicity earlier than control pigs on a test day when shocks are not delivered. Presenting subjects with signal-shock pairs is known to produce learned changes in autonomic tone thought to reflect fear. However, we were unable to find evidence of such changes in that model. A recent report extended our work on psychosomatic digitalis toxicity to the rabbit. Although that animal has been extensively used in studies of visceral learning, that study did not provide sufficient data to rigorously conclude that visceral learning had taken place. In this report, we show that rabbits which have learned that a signal accurately predicts the occurrence of shock develop digitalis-toxic arrhythmias more often during the signal and significantly earlier than other rabbits given prior exposure to equal numbers of signals and shocks, never explicitly paired. The use of this latter control group indicates that rabbits exposed to signal-shock pairs have learned to associate the signal with its consequences; independent evidence of learning exists in the fact that these rabbits showed a signal-locked bradycardia on their training day. However, bradycardia did not appear to be the mechanism for the early elicitation of digitalis toxicity on the test day when ouabain was infused during probes with the signal alone. These data may have clinical significance in their indication that factors in the external milieu can precipitate digitalis-toxic arrhythmias in individuals that would otherwise have no evidence of digitalis toxicity.

Animals↗
PubMed1993

Quinidine enhances digitalis toxicity at therapeutic serum digoxin levels.

OBJECTIVE: To determine the effect of the digoxin-quinidine interaction on rate of in-hospital digitalis toxicity. METHODS: This was a prospective observational study over 9 months, set in two general medical wards. We studied consecutive patients (n = 141) who were receiving digoxin. Measurements included digitalis toxicity, defined by ECG criteria and resolution after stopping digoxin; all additional medications (including antiarrhythmics) continued. The observer was "blinded" to serum digoxin level and to concomitant drugs. RESULTS: Digitalis toxicity rates were as follows: digoxin alone, 4.9% (5 of 101 patients); with amiodarone or verapamil, 5.0% (1 of 20 patients); with quinidine, 50% (10 of 20 patients) (p < 0.01). No toxicity was seen at digoxin levels < 1.0 ng/ml. Toxicity at 1.0 to 2.0 ng/ml was as follows: digoxin alone, 1 of 41 patients; with quinidine, 4 of 15 patients (p = 0.014). Toxicity was similar at levels > 2.0 ng/ml: 4 of 8 patients and 7 of 11 patients, respectively. Independent relative risks and 95% confidence intervals (CI) of digitalis toxicity were as follows: serum digoxin, 9.1 (95% CI, 2.9 to 13.0); concurrent quinidine, 24.3 (95% CI, 3.4 to 124). There was a significant (p < 0.01) interaction between concurrent quinidine, serum digoxin of 1.0 to 2.0 ng/ml, and digitalis toxicity. CONCLUSION: The digoxin-quinidine interaction significantly increases digitalis toxicity, even in the therapeutic range of serum digoxin levels.

Aged↗
PubMed1976

Current management of digitalis intoxication.

Of the commonly used drugs, digitalis has one of the highest therapeutic-toxic ratios. Mortality is significantly increased in the 20% to 30% of patients on digitalis who are in a toxic state when admitted to the hospital. Successful use of digitalis depends on avoidance of its use in situations likely to result in toxicity; recognition of the signs, symptoms, and electrocardiographic findings of digitalis intoxication; and stopping digitalis completely as the initial treatment of digitalis intoxication.

Arrhythmias, Cardiac↗
PubMed1977

Digitalis therapy in a 70-year-old population.

In the population study "70-year-old people in Gothenburg" 14% of the probands were found to be undergoing treatment with digitalis, 6% with digoxin, 6% with digitoxin and 2% with other glycosides. A comparison between results of the interview method and those of S-digoxin analyses indicates that the interview method was acceptable. As far as can be judged from S-digoxin analyses, only about 60% of the treated patients were on a dosage considered to be effective and free from obvious risks of side-effects. Out of the 130 70-year-olds who were on digitalis treatment, 37% had obvious symptoms of heart disease requiring such treatment, 34% lacked symptoms of arrhythmia and/or congestive failure but had heart volumes larger than those used as reference values in younger age groups, and 29% had no symptoms indicating digitalis treatment. At least 13% of the population had indications for digitalis therapy and about 75% of those apparently needing digitalis were on such treatment. Thus both over- and underdiagnosis of heart disease requiring digitalis therapy were common in this age group.

Age Factors↗
PubMed2005

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.

Animals↗