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PubMed1985

Digitalis and the autonomic nervous system.

Digitalis produces many of its effects in intact animals and human beings by modifying the properties of the autonomic nervous system. The parasympathetic limb of the autonomic nervous system is most sensitive to these effects of digitalis, and its properties are significantly altered with therapeutic concentrations of the drug. These actions are particularly important in mediating the electrophysiologic effects of digitalis. With toxic concentrations of digitalis, stimulation of sympathetic nerve activity may also occur. This latter action may be involved in the arrhythmogenic effects of digitalis. These effects of digitalis on the autonomic nervous system play a major role in determining the pharmacodynamic actions of the drug in patients. The effects of digitalis on the autonomic nervous system also provide a setting for important interactions with other drugs that modify the properties of the sympathetic and parasympathetic nervous systems.

Acetylcholine↗
PubMed1982

Developmental increase of digitalis receptors in guinea pig heart.

The apparent differences of digitalis tolerance in human newborns or young animals and adults may be due to the difference in either, the sensitivity of Na+,K+ -ATPase to digitalis, the binding characteristics of the Na+,K+ -ATPase receptor sites or the number of receptor sites itself. Sarcolemmal Na+,K+ -ATPase enriched membrane preparations from guinea pig hearts of various age groups were investigated for Na+,K+ -ATPase activity, the ability of ouabain to inhibit the enzyme and the 3H-ouabain binding characteristics of the receptor sites. There was a continuous developmental increase in Na+,K+ -ATPase activity in fetal (45 days fetus, 1.2 mumol Pi . mg-1 protein . h-1) and newborn (2.4 mumol Pi . mg-1 protein . h-1) reaching maturity at the age of 21 to 25 days (9.1 mumol Pi . mg-1 protein . h-1). The ability of digitalis to inhibit the enzyme, however, was same throughout the development with 50% inhibition occurring at 0.1 mumol . litre-1 concentration of ouabain. The sodium stimulated 3H-ouabain binding was saturable and exhibited a single class of receptor sites. The number of digitalis receptor sites increased progressively in fetal (45 days fetus, 2.2 pmol . mg-1 protein) and newborn (9.1 pmol . mg-1 protein) reaching mature levels at the age of 13 to 25 days. The affinity of the Na+,K+ -ATPase receptor sites for digitalis (Kd, 8.68 - 9.33 x 10(-9) mol . litre-1) remain unchanged during development. The data obtained is consistent with the concept that Na+,K+ -ATPase is the receptor site for digitalis and suggests that factors other than the developmental increase in Na+,K+ -ATPase may be relevant to explain the age-related differences in digitalis sensitivity.

Animals↗
PubMed1981

Diuretics, digitalis and arrhythmias.

Arrhythmias induced by digitalis are believed to be secondary to changes in ion concentrations in the myocardial cells or changes in the transcellular ion gradient. Both diuretic induced hypokalemia and digitalis inhibit the membrane-Na+K+ ATPase activity which cause a decrease of the intracellular potassium concentration. This may explain the risk of cardiac arrhythmias during digitalis treatment and during severe hypokalemia, and may further explain the increase for myocardial sensitivity for digitalis when hypokalemia is present. The myocardial uptake of digitalis however is markedly increased at low extracellular potassium concentration and this may be the explanation of the interaction between digitalis and hypokalemia. Not only the myocardial digoxin kinetic is changed during hypokalemia but the renal excretion rate of digoxin is markedly reduced during hypokalemia leading to increased serum digoxin concentration and thereby the risk of digitalis intoxication.

Animals↗
PubMed1986

Digitalis use in a retirement community.

Complex medical problems of older patients demand that particular care be taken with their use of digitalis. Although accounting for more than 5% of the top ten prescribed drugs in the United States, studies have suggested that digitalis use might be discontinued in some patients without harm. To assess the potential impact of these observations, a survey was conducted to evaluate the extent of digitalis use in a retirement community in Florida. The community under study consisted of approximately 5600 persons, mean age 72.6 years; 97% were over age 55. The sample of 463 telephone respondents reflected the local census. Digitalis preparations had been taken by 11.4% of the sample, of whom 60% (or 6.9% of the total sample) were currently taking them. Persons taking digitalis tended to be older (P less than .002) and reported worse overall health status than those not taking the drug (P less than .025). Seventeen percent of those who had stopped use of digitalis claimed adverse symptoms or "complications." Of Florida's 10 million population, 23% are over age 60, a proportion increasing yearly. This survey suggests that digitalis use in the elderly is widespread and a potentially important area for investigating management of cardiac problems in the elderly.

Aged↗
PubMed1987

Role of digitalis in chronic congestive heart failure and sinus rhythm.

Whereas the use of digitalis in atrial fibrillation is universally accepted, its administration in patients in sinus rhythm for its inotropic properties has recently been questioned. The risk of digitalis administration is high and may be unavoidable because of the occurrence of changes in sensitivity to digitalis. Benefits of digitalis are poorly defined. Hemodynamically digitalis is a weak inotropic agent. Clinical improvement is difficult to detect; furthermore, the role of long-term maintenance digitalis therapy appears questionable, inasmuch as several studies failed to show deterioration after digitalis therapy has been discontinued.

Chronic Disease↗
PubMed1985

Digitalis: neurally mediated arrhythmogenic and coronary vasoconstrictor properties.

Studies of digitalis have revealed an appreciable role of the autonomic nervous system in the modulation of the cardiovascular toxicity of digitalis. Neuraxis transection experiments and studies using digitalis compounds that fail to enter the central nervous system suggest that centers located in the floor of the fourth cerebral ventricle play a substantial part in the neural arrhythmogenic effects of the digitalis glycosides. Electrical stimulation of the area postrema in partially digitalized animals, not otherwise manifesting ventricular arrhythmias, elicits ventricular tachycardia. Neuraxis transection experiments and studies with a charged digitalis derivative also suggest localization of the coronary vasoconstrictive properties of digitalis to the area postrema. The results suggest that this region of the brainstem is sensitive to a neurally active substance, digitalis, causing peripheral sympathetic effects of considerable consequence.

Adrenergic alpha-Antagonists↗
PubMed1991

Chemical models for the chemical nature of endogenous digitalis.

The inability or the capacity to promote the phosphorylation of Na+/K(+)-transporting ATPase (Na/K-ATPase) from [32P]Pi is shown to differentiate between mechanistically digitalis-unlike and digitalis-like inhibitors of this enzyme known to be the receptor for all digitalis actions. A negative or positive response in the phosphorylation promotion assay introduced here appears thus to be suitable to diagnose the chemical species in the isolates of animal origin related to the putative endogenous digitalis. Various digitalis-congeneric C/D-cis steroids, progesterone-congeneric C/D-trans steroids and the Erythrophleum alkaloid cassaine promote the enzyme phosphorylation and show a similar pattern of discrimination between three Na/K-ATPase variants. Thus, their cyclopentanoperhydrophenanthrene or perhydrophenanthrene nuclei appear to serve as the minimal pharmacophoric lead structures for bimolecular recognition and to represent chemical models for the chemical nature of endogenous digitalis. Specifically, the hormonal C/D-trans steroids could provide the basic skeleton in endogenous digitalis biosynthesis.

Animals↗
PubMedDate not supplied

Is digitalis a therapy for breast carcinoma?

We have previously reported effects on breast carcinoma by digitalis on patients in vivo with significant effects on cytometric features and recurrence rate. Increased attention is now paid to the anti-proliferative and apoptosis inducing effect on cancer cells in vitro by glycosides from foxglove as well as by some other glycosides. The present study is a long-term follow-up (22.3 years) of 175 patients with breast carcinoma, of which 32 were on digitalis treatment, when they acquired their breast carcinoma. There was a lower death rate (6%) from breast carcinoma among the patients on digitalis, when compared with patients not on digitalis (34%). Also proliferation/aneuploidy was less pronounced of the tumors in patients on digitalis. These observations were statistically significant although the statistical analysis was hampered in the life-table analysis by the fact that only 2/32 patients on digitalis died from breast cancer. Serious consideration should be given to the effects of digitalis derivatives on cancer cells in cancer drug design. This field of research is not sufficiently explored and holds promise to contain drugs superior to present-day adjuvant therapy both with respect to effects and side-effects.

Antineoplastic Agents↗
PubMed1992

Clinical use of digitalis.

Digitalis should be used for slowing a rapid ventricular rate in atrial fibrillation or atrial flutter unassociated with the preexcitation syndrome. Digitalis may be used to convert paroxysmal supraventricular tachycardia to sinus rhythm. Patients with the tachycardia-bradycardia syndrome should receive maintenance doses of digitalis after pacemaker implantation. Digitalis should not be used for treating CHF with normal LV systolic function unless a supraventricular tachyarrhythmia is present. Conflicting studies have been reported as to the efficacy of digoxin in the treatment of patients with CHF in sinus rhythm. Digoxin may be used for treating CHF with abnormal LV systolic function which does not respond to diuretics and ACE inhibitors or in patients unable to tolerate ACE inhibitor or other vasodilator therapy. Digitalis has a low toxic-therapeutic ratio, especially in elderly persons. Digoxin-specific Fab antibody fragments may be used for treating digitalis toxicity refractory to conventional measures with a treatment response in at least 90% of patients with advanced and potentially life-threatening digitalis toxicity.

Clinical Trials as Topic↗
PubMed1990

[Controversies on digitalis].

The introduction of newer drugs with effective cardiovascular action to clinical practice has reduced dependence on digitalis compounds. This tendency has been further justified by statements to the effect that consistently satisfactory results can be obtained with alternative drugs; that the inotropic action of digitalis is not evident in patients with normal sinus rhythm; that digitalis increases myocardial oxygen consumption, and finally that the high incidence of intoxication should limit its use. The present article reviews the use of alternative agents; the inotropic effects of digitalis in the presence of sinus rhythm; the implications of the use of drugs augmenting contractility upon total myocardial performance and oxygen consumption, and the factors pertinent in favoring digitalis toxicity. Digitalis continues to be a useful agent in the treatment of heart failure, either in patients with atrial fibrillation or in sinus rhythm. It may well be administered in addition to diuretics, vasodilators or fosfodiesterase inhibitors. Digitalis toxicity can be minimized by considering factors enhancing such complication or conditions where its use is ineffective.

Cardiac Output, Low↗
PubMed1987

[Endogenous digitalis compounds and adrenal gland activity].

Endogenous inhibitors of the Na+,K+-pump have been postulated to participate in Na+ and water homeostasis. When present in high amounts, they have been proposed to induce a rise in blood pressure. There is no general agreement concerning their chemical structure and their possible tissue origin has not been well defined. In an attempt to identify a tissue source, (i) the digitalis-like contents of various organs (cross reactivity with digoxin antibodies and inhibition of ouabain binding to the Na+ pump) were determined and (ii) the circulating digitalis-like activity was analyzed under various conditions known to alter the activity of the putative source organs. High levels of digitalis-like compounds were present in the adrenal and pituitary glands (4.1 +/- 0.1, n = 15 and 3.7 +/- 0.4, n = 13 ng digoxin equivalents/g) or 328 +/- 66, n = 6 and 460 +/- 76, n = 6 ng ouabain equivalents/g) respectively. Much lower levels were found in heart, kidney, brain and hypothalamus. Plasma digitalis-like activity was measured in 5 groups of rats: control, ACTH treated, hypophysectomised, and in DOCA-salt treated animals with and without bilateral adrenalectomy. Changes in the plasma digitalis-like activity measured by the crossreactivity with anti-digoxin antibodies or by the inhibition of ouabain binding followed the same pattern. When compared to the control values, the plasma digitalis-like activity was partially decreased after hypophysectomy, markedly decreased after adrenalectomy and enhanced in ACTH-treated animals. These results suggest that the pituitary-adrenal axis plays a major role in the control of the circulating "digitalis-like" activity.

Adrenal Glands↗
PubMed1987

Practice and control of digitalis therapy in Finland.

In order to assess the adequacy of digitalis therapy in Finland we studied its practice and control in 747 patients who were receiving it regularly. The patients were derived from a sample (n = 8000) representative of the adult Finnish population. More than 90% of the patients were receiving digoxin, mostly 125 micrograms or 250 micrograms, once daily. Few patients were taking digitalis as the sole drug prescribed. The mean number of prescribed drugs for each patient (including digitalis) was 4.2 for men and 4.6 for women. 85% of the patients generally visited their "own" doctor. About 90% of the patients had seen a doctor at least once during the previous 12 months. In spite of this, the control of the therapy was generally considered poor, since almost half the patients were uncertain when the next visit to the doctor would be. Inadequately low serum digitalis concentrations, suggesting inadequate or questionable use of the drug, were observed in 30% of the patients. In 15% of the patients the therapy was considered especially questionable. Probably due to variable prescribing habits in general practice, the proportions of patients on poorly controlled, inadequate or questionable digitalis therapy varied remarkably between regions within the country. The results suggest that digitalis therapy in Finland is often inappropriate. We conclude that the practice and control of digitalis therapy need careful reappraisal in this country.

Adult↗
PubMed1983

Contemporaneous administration of digitalis and dilazep to subjects with heart failure of ischemic etiology.

The objective of this trial was to determine whether the digitalis-dilazep combination interferes with the inotropic effects of digitalis or produces significant cardiovascular modifications. Twenty patients suffering from heart failure of ischemic or ischemic plus valvular etiologies, undergoing digitalis treatment for at least 3 weeks, were administered dilazep (300 mg/day). Systolic, diastolic blood pressures and heart rate, supine and standing, QS2I, LVETI, PEPI, PEP/LVET, triple product, and percentage diastole were recorded. The controls were undertaken at entry, after the digitalis + dilazep association, and after 1 month of digitalis alone when dilazep was ceased. None of the parameters assessed were modified as a result of dilazep treatment. Since systolic time intervals and the PEP/LVET ratio remained unaltered and equal to the values recorded during digitalis alone, it is concluded that dilazep does not interfere with the inotropic action of digitalis.

Aged↗
PubMedDate not supplied

Digitalis and the Na+,K(+)-ATPase.

Recent clinical, physiological, biochemical, and molecular biology studies strongly suggest that digitalis glycosides function in a complex manner through differential binding to and inactivation of multiple distinct Na+,K(+)-ATPase isoforms that are differentially expressed and regulated throughout the cardiovascular system. The alpha 1 isoform predominates in the ventricular: myocardium, whereas the alpha 2 and alpha 3 isoforms may localize to the conducting system structures. The peripheral vasculature also potentially expresses three digitalis receptors, as do neurons in the central nervous system. It is likely that similar heterogeneity exists in the autonomic nervous system as well as in the cardiopulmonary baroreceptor structures. Therefore, differential regulation of these isoforms, by either genetic predisposition or hormones, could dissociate contractile from conduction function and play a role in determining the degree, if any, of therapeutic response to digitalis glycosides. Similarly, genetic polymorphism of the alpha subunits has been observed in humans and rats and may play an important functional role in the ion transport function in a strain of hypertensive rats. Genetic differences in the regulation or structure and function of each isoform could confer allele-specific functional and pharmacological features such as predisposition to digitalis toxicity. Alterations in the degree and type of Na+,K(+)-ATPase isoforms expressed during cardiac hypertrophy and cardiac development may mediate increases or decreases in cardiac sensitivity to digitalis glycosides. This unexpected complexity of the digitalis receptor raises new questions about the role of digitalis glycosides in the treatment of congestive heart failure.

Animals↗
PubMed1993

Digitalis in patients after myocardial infarction.

For more than two centuries digitalis has been used in the treatment of cardiac disease. Despite this long clinical experience with the drug, controversy still exists as to its clinical effect and impact on survival, especially in patients after myocardial infarction. In the last decade a number of studies have addressed the problem of assessing the clinical effect of digitalis in patients with sinus rhythm and left ventricular dysfunction. An overall conclusion from these studies seems to indicate that a modest clinical beneficial effect can be expected from the drug. Regarding the effect of digitalis on the mortality in patients after a myocardial infarction controversy still prevails. All studies show an increased mortality in patients using digitalis, but opinions differ as to whether this is due solely to baseline imbalances between the populations or that a harmful effect of digitalis itself exists as well. This question cannot be answered with certainty until the results from a large, randomized study are available. In the meantime digitalis can probably be used as a first line therapy in patients with atrial fibrillation and left ventricular dysfunction. In patients with sinus rhythm and heart failure, however, it is probably wise to reserve digitalis to those that are still symptomatic after diuretics, nitrates and ACE inhibitors have been tried.

Digitalis Glycosides↗
PubMed1995

[An unusual case of "catecholamine necrosis" caused by accidental digitalis poisoning].

Toxic manifestations of digitalis are one of the most prevalent adverse drug reactions encountered in clinical practice. The estimated incidence is about 20% in hospitalized patients in the USA. The authors describe a rare case of myocardial "catecholamine necrosis" (anteroseptal myocardial infarction) during accidental digitalis intoxication. A male patient, 75 years old, suffering from cirrhosis and ascites, take on by mistake a tablet of digoxin 0.25 mg. four times at day for eleven days. He hadn't heart disease in the past. At the eleventh day the patient showed a deep tiredness and so he was submitted to a clinical examination and electrocardiogram. The ECG demonstrated an anteroseptal myocardial infarction in the second-third electrical stage. The patient was hospitalized. The successive examination revealed: very high plasma digitalis concentrations; an increase of the serum levels of CPK and LDH; a significant increase of plasmatic and urinary catecholamine levels which return to normal values after fifteen days; apical akinesia at the echocardiographic examination; no signs of residual myocardial ischemia to the echo-dypiridamole stress test; normal coronary artery to the coronary arteriography and absence of coronary artery spasm to the ergonovine test. Furthermore the abdominal echography and the abdominal computerized tomography didn't reveal surrenal disease but showed an important liver disease. The patient was free from other cardiac events in the follow-up. Generally, during the digitalis intoxication we observe various rhythm and conduction disturbances. Instead in this case no serious arrhythmias were registered and the main expression of the drug toxicity was an anteroseptal myocardial infarction with undamaged coronary artery. Also the usual extracardiac symptoms and signs of the digitalis intoxication were absent in this case. All these observations can be explained with the pathological increase of the cathecholamine levels, indirectly induced by digitalis; with the direct toxic effect of the drug at the myocardic level; with the contemporary absence of ionic disturbances; with the concomitant liver disease. The direct toxic effect of the digitalis produced an increase in calcium ions availability for the electromechanical coupling and an increase of the intramyocardial pressure; the increase of the adrenergic activity determined contemporary an increase in the oxygen consumption of the myocardial cells, a rise of vascular tone and coronary artery tone and a reduction of the duration of the diastole. All these factors provoked a "primary and secondary" ischemia which evolved toward a real "cathecholamine necrosis" and produced a myocardial infarction. This hypothesis explains the myocardial infarction in absence of injury at the coronary arteriography and without coronary spasm at the ergonovine test; moreover it explains the transient increase in cathecholamine plasma levels observed in the acute phases an normalized after fifteen days. The "cathecholamine necrosis" is an anatomical definition, nevertheless in our opinion it gives account of the rare clinical situation observed.

Aged↗
PubMed1985

Canine digitalis arrhythmia as a model for detecting Na-channel blocking antiarrhythmic drugs: a comparative study using other canine arrhythmia models and the new antiarrhythmic drugs, propafenone, tocainide, and SUN 1165.

Antiarrhythmic effects of three new drugs, propafenone, tocainide, and SUN 1165, were examined using three canine ventricular arrhythmia models, i.e., digitalis, adrenaline and two-stage coronary ligation arrhythmias. The effects of procainamide, disopyramide, lidocaine, and phenytoin, class 1 antiarrhythmic drugs, on digitalis arrhythmia were also examined. The minimum effective plasma concentrations of all these drugs for each arrhythmia model were determined for a quantitative comparison. Propafenone and tocainide suppressed all the arrhythmias, while SUN 1165 suppressed digitalis and coronary ligation arrhythmias. The minimum effective plasma concentrations of propafenone for digitalis, adrenaline, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 1.8 +/- 0.7, 0.58 +/- 0.20, 3.5 +/- 0.3, and 3.6 +/- 0.9 micrograms/ml, respectively, and those of tocainide were 6.2 +/- 2.1, 23.7 +/- 9.0, 11.4 +/- 0.5, and 8.6 +/- 2.9 micrograms/ml, respectively (mean +/- standard deviation, n = 6-7). The minimum effective concentrations of SUN 1165 for digitalis, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 0.92 +/- 0.19, 2.5 +/- 0.4, and 1.2 +/- 0.4 micrograms/ml. The minimum effective concentrations for digitalis arrhythmias were 1.7 +/- 0.4 micrograms/ml for disopyramide, 10.1 +/- 2.4 micrograms/ml for procainamide, 3.5 +/- 1.6 micrograms/ml for lidocaine, and 11.3 +/- 3.0 micrograms/ml for phenytoin. Digitalis arrhythmia seems to be a useful model for detecting class 1 drugs, as it was suppressed by all the class 1 Na-channel blocking antiarrhythmic drugs, while class 2 beta adrenergic blockers and class 4 Ca-channel blockers had no effect. Also, not all the class 1 drugs suppressed coronary ligation and adrenaline arrhythmias.

Animals↗
PubMed1991

Endogenous digitalis: reality or myth?

Endogenous digitalis is defined as a natural ligand for the digitalis-binding site of the Na+, K(+)-ATPase and is a specific, high-affinity reversible inhibitor of the enzyme activity. Such endogenous digitalis is thought to be involved in sodium homeostasis and blood pressure regulation as a vasoactive and natriuretic substance. The search for endogenous digitalis goes back to the early 1960s. Since then large efforts have been exerted by numerous laboratories worldwide, but little advance has been made until recently except for the identification of nonspecific Na+, K(+)-ATPase inhibitors. Some researchers even doubt the existence of endogenous digitalis. The recognition that assay methodology is associated with many pitfalls and problems has accelerated the rate of recent progress. Chemical identification of endogenous digitalis will be forthcoming in the very near future. In this article, important issues surrounding endogenous digitalis are critically reviewed.

Animals↗