Digitalis Tolerance Research Articles

Digoxin cardiotoxicity in aging anesthetized F344 rats

It is generally accepted that the sensitivity to toxic effects of digitalis increases with advancing age; however, the relative contribution of pharmacokinetics and pharmacodynamics to this aging-related change is presently unknown. The current study was designed to determine if senescence affects digitalis tolerance in an animal model and if observed changes are mediated by altered cardiac or autonomic nervous system responsiveness. Male, F344 rats of three age groups (4, 14 and 25 months) were anesthetized and infused intravenously with digoxin at a rate of 880 μ/kg per min. Two separate anesthetic regimens were employed: (a) an age-adjusted dose of urethane in spontaneously breathing animals (AR1); and (b) a non-age-adjusted dose of α-chloralose plus urethane in mechanically ventilated rats (AR2). Heart rate, EKG and arterial blood pressure were monitored continuously; baroreceptor reflex function was estimated before and 10 min following the start of digoxin infusion by examining the response to bilateral carotid occlusion. The infusion time required for digoxin-induced AV-dissociation was significantly reduced by senescence in rats anesthetized by AR1. However, doses of digoxin required to elicit ventricular extrasystoles and death were not significantly different among age groups in this anesthetized model and serum digoxin levels did not differ at the time of cardiac arrest. Similarly, AR2 animals showed a significant aging-related decrease in the time to AV-dissociation. However, in contrast to AR1, animals in AR2 displayed an aging-associated increase in the doses of digoxin required to produce ventricular arrhythmias and cardiac arrest. Thus, result suggest that aging in the F344 rat may,

Mechanisms of increased digitalis tolerance in streptozotocin-induced diabetic rat myocardium

Our earlier studies revealed that the inotropic and cardiotoxic responses to ouabain are depressed significantly in chronically-induced diabetic rats (Navaratnam S and Khatter JC, Arch Int Pharmacodyn 301: 151–164, 1989). In the present study, we examined the Na +-Ca 2+ exchange mechanism in sarcolemmal membrane vesicles (right-side out orientation) isolated from chronically-induced diabetic rat hearts. The apparent initial rates of Na +-dependent 45Ca 2+ uptake were substantially lower in vesicles from 6- and 12-week diabetic rat hearts when compared to non-diabetic controls. These rates were reduced further in vesicles of 24-week diabetic rat hearts. Associated with the progressive reduction in initial rates was also a progressive reduction in the maximum amount of 45Ca 2+ accumulated by the vesicles. A kinetic analysis revealed a significant reduction in the maximum initial rate of 45Ca 2+ uptake ( V max) in vesicles of 24-week diabetic rat hearts. Affinity for 45Ca 2+, however, was the same for both diabetic and control groups. The efflux rate of 45Ca 2+ was also depressed in these vesicles, and they retained significantly more 45Ca 2+ than controls after 2–4 min of initiation of Na +-dependent 45Ca 2+ efflux. These data demonstrate that the trans-sarcolemmal Ca 2+ flux through Na +-Ca 2+ exchange is depressed and may explain the observed increase in digitalis tolerance of the myocardium in diabetic rats.

Mechanisms of reduced digitalis tolerance with advancing age in the guinea pig

In the present study, arrhythmogenic toxicity of cardiac glycoside ouabain was investigated in guinea pigs after intravenous infusion (5 smg/kg/min). Guinea pigs of 18–24 months of age required significantly ( P < 0.05) lower doses of ouabain than 3-month-old animals (72 ± 3 vs 100 ± 3 smg/kg) for the initiation of cardiac arrhythmias. Investigation of Na +-Ca 2+ exchange in the isolated sarcolemmal vesicles revealed a marked reduction in the Na +dependent Ca 2+ uptake. Kinetic analysis of these data has demonstrated a 70% reduction in V max and reduced affinity for Ca 2+ in vesicles from 18-month-old as compared to 3-month-old guinea pigs. The rate of Na +-dependent Ca 2+ efflux was also markedly lower in the vesicles of older animals, and the vesicles retained more Ca 2+ after 3 min of Na +-dependent Ca 2+ extrusion than did those from 3-month-old animals. The results suggest that the sensitivity to cardiac glycocide increases with age and may be associated with altered sarcolemmal Na +-Ca 2+ exchange activity.

The influence of hypoxemia on tritiated digoxin plasma kinetics and tissue distribution in the conscious dog.

The goals of this study were to document the effect of hypoxemia on the distribution of digoxin in conscious dogs. For this purpose, 6 beagles were exposed to air and 6 others to an atmosphere containing 10% O2, to generate a PaO2 equal to 46.3 +/- 0.3 mmHg (mean +/- SEM). The animals received 25 micrograms/kg of digoxin containing 2.17 micrograms/kg of 3H-digoxin, and then blood and urine samples were collected over the next 48 h, at which time they were killed to determine digoxin concentrations in several tissues. Five additional beagles were used to assess the influence of hypoxemia on the blood perfusion to these tissues using radioactive microspheres. The results, expressed as digoxin equivalents, indicated that hypoxemia increased the digoxin apparent volume of distribution (2.85 +/- 0.10 versus 2.01 +/- 0.11 L/kg; p less than 0.001) and the time required to achieve this distribution (9.7 +/- 1.4 versus 2.6 +/- 0.3 h; p less than 0.01). As digoxin clearance was not influenced by hypoxemia, the half-life was increased from 25.2 +/- 1.5 to 33.4 +/- 1.3 h (p less than 0.01). With hypoxemia, digoxin concentrations increased significantly in the brain and diaphragmatic muscle, but only marginally in other organs, including the heart, the latter despite a significant increase in blood flow. It is concluded that hypoxia does change digoxin disposition but does not increase digoxin heart concentrations. Therefore, factors other than changes in digoxin plasma kinetics and heart distribution may be responsible for the decrease in digitalis tolerance during hypoxemia.

Factors affecting tolerance to digitalis

A review of factors altering the safety margin between a therapeutic and a toxic dose of digitalis includes the consideration of: clinical conditions to which digitalis action may be undesirable, allergy and hypersensitivity to digitalis, physiologic factors modifying tolerance to digitalis, factors that change the amount of digitalis in the body, nervous and metabolic factors modifying tolerance to digitalis, modifications of digitalis tolerance produced by the status of the myocardium, and modifications of digitalis tolerance produced by diseases of other organs. The problems related to digitalis toxicity are more common than those of resistance to treatment. The most important factors contributing to decreased tolerance and risk of toxicity are: heart disease, poor renal function, hypokalemia and hypothyroidism. The roles of impaired liver function, chronic lung disease, acid-base disturbances, anesthesia, autonomic imbalance, calcium and magnesium are less important and less well established.

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.

How do digitalis tolerance and toxicity change with age?

Digitalis is perhaps the fourth most frequently prescribed drug in the United States, but it has a low margin of safety. Abnormalities of the heart increase with age. For many cardiovascular conditions that may not respond to any other current treatment, digitalis compounds provide effective therapy. 9 Because the digitalis glycosides and related, compounds greatly increase the force of cardiac contrac9 tion, they are most useful in treating persons with congestive heart failure. The electrophysiological effects of digitalis are beneficial in reversing atrial fibrillation and most ventricular tachyarrhythmias of supraventricular origin. An estimated 5 percent of the population over age 65 are taking some form of digitalis. The most common forms are digoxin (Lanoxin) and digitoxin (Crystodigin, Purodigin). Toxicity to digitalis occurs at about 60 percent of the therapeutic dose. Consequently, it is not surprising that 20 to 30 percent of patients taking digitalis experience some adverse effects.

Increase in myocardial digoxin content associated with circulatory volume overload in the dog.

1. Tritiated (12alpha-3H) digoxin (0-05 mg/kg body weight) was administered intravenously to conscious dogs with circulatory volume overload induced by previous creation of aorto-caval fistulae. Dogs were killed after 5 min, 1, or 4 h, and the myocardium sampled. Digoxin was extracted and counted and results compared to those in normal dogs. 2. At each time, myocardial digoxin concentration of all cardiac chambers in test dogs was greater than normal. Plasma digoxin concentration measured 5 min after administration was greater in dogs with fistulae but the subsequent levels were not different. 3. Anaesthetized and open-chest dogs with fistulae studied 5 min after digoxin administration had greater myocardial concentrations than similarly studied normal dogs. Although myocardial concentrations of digoxin were higher in anaesthetized than in conscious dogs the group with fistulae had higher values than did the normal group, as was the case for unanaesthetized dogs. 4. The basis for the effect of fistula is probably multifactorial. Diminised peripheral blood flow and peripheral digoxin delivery and uptake, resulting initially in higher digoxin levels in plasma perfusing the myocardium, may play a role. Increased myocardial mechanical and metabolic activity almost certainly are important. Cardiac hypertrophy, cardiac failure per se and plasma electrolyte changes are probably not. 5. The results are consistent with previously demonstrated reduced digitalis tolerance in the dog with circulatory volume overload.

Determination of serum-digitalisglycoside concentrations by radioimmunoassay before, during and after operations with extracorporal circulation (author's transl)

In 13 adult patients serum-glycoside concentrations, renal glycoside elimination and endogenic creatinine clearance were determined before, during and in the first 4 days following the operation. A postoperative digitalis cumulation has not been seen. But there was a diminished digitalis tolerance in the immediate postoperative phase. Two patients got ventricular bigeminus. The low potassium values at the same time may possibly affect the sensitivity of digitalis.

The effects of ketamine and of Innovar anesthesia on digitalis tolerance in dogs.

In a comparison of digitalis tolerance in dogs anesthetized with ketamine, Innovar Vet, or pentobarbital, the dosage of ouabain needed to cause ventricular tachycardia was significantly higher, as was the LD50 of ouabain, with ketamine or Innovar than with pentobarbital. Ventricular tachycardia induced by ouabain was generally converted to sinus rhythm following administration of Innovar, ketamine, or droperidol but not after administration of fentayl alone or after pentobarbital.

Action of acetylstrophanthidin on experimental myocardial infarction.

An experimental animal model with acute myocardial infarction of a size insufficient to produce profound heart failure or shock was used to study the effects of acute infarction on digitalis tolerance and the hemodynamic changes produced by moderate and large doses of acetylstrophanthidin. With acute myocardial infarction, digitalis toxic arrhythmias could be precipitated with significantly lower doses of digitalis than in animals without myocardial infarction. There was no precise correlation between the size of infarction and the toxic dose of glycoside. Coronary artery ligation produced a stable but relatively depressed circulatory state, as evidenced by lowered cardiac output and stroke volume and elevated systemic vascular resistance and left atrial mean pressure. When digitalis was infused, the following significant changes were observed at nontoxic doses: (1) elevation of aortic and left ventricular pressures; (2) further decline in cardiac output; and (3) decreased left atrial mean pressure.

The effect of metabolic and respiratory acidosis on cardiac functions.

Experiment was undertaken to evaluate the effects of acidosis upon the susceptibility of the heart by measuring digitalis tolerance, myocardial contractility, and ventricular fibrillation thresh-old. The significant reductions in acetyl stro-phanthidin tolerance, left ventricular contractile force, and ventricular fibrillation threshold value were found during metabolic acidosis induced by lactic acid infusion, whereas they were maintained at almost control values during respiratory acidosis. Moreover, the decreased myocardial contractility after total body perfusion was relative to the decreased arterial blood pH caused by the metabolic factor.

The effect of inorganic phosphate infusion upon digitalis-induced arrhythmias in dogs

Digitalis tolerance was significantly increased and digoxin mortality markedly decreased by infusion of 0.1 M disodium monopotassium phosphate in dogs. The possible mechanism of phosphate protection is discussed.

Digitalis tolerance during septic shock.

DIGITALIS preparations are recommended in treatment of shock because cardiac failure has been shown to occur in the late stages. 1-3 It has been advocated as a general supportive measure since digitalis is known to improve contractility of the normal as well as the failing heart. 4,5 Wiggers 6 states that as many as 80% of patients in shock develop myocardial failure. Though the basis for administration of digitalis appears sound, little is known regarding dosage toxicity relationships during shock. 7 In the present study the tolerance of the heart to acetyl strophanthidin was determined in the normal state and during endotoxin shock. Methods Mongrel dogs (10 to 20 kg) were anesthetized with intravenous pentobarbital (30 mg/kg) and ventilation maintained with a mechanical respirator using room air. Lead II of the electrocardiogram was continuously monitored and periodic segments recorded. An intravenous catheter was placed in a peripheral vein and acetyl

Digitalis tolerance during atrial fibrillation and normal sinus rhythm

In each of 9 normal dogs the toxic dose of acetylstrophanthidin was determined on three separate occasions during normal sinus rhythm and atrial fibrillation. During atrial fibrillation the mean toxic dose was 10 to 30 per cent (average 21%) greater than that recorded in the same animal during normal sinus rhythm. The increased tolerance to acetylstrophanthidin during atrial fibrillation was not a function of the ventricular rate immediately before the occurrence of toxicity. The study provides an indirect explanation for the manifestations of digitalis intoxication that sometimes follow the restoration of normal sinus rhythm in digitalized patients with atrial fibrillation.

The Change in Digitalis Tolerance After Open Heart Surgery

The present investigation was undertaken to evaluate the change in digitalis tolerance immediately after extracorporeal circulation with eleven patients undergoing open heart surgery for the correction of congenital or acquired heart diseases who were ranged in age from 4 to 56 years and experimentally with eleven mongrel dogs by means of acetyl strophanthidin tolerance test. The decrease of digitalis tolerance following total body perfusion has been clinically observed in all cases of the prolonged duration of perfusion of longer than one hour within a period of 4 to 7 hours after perfusion and experimentally in all dogs of one hour perfusion within a period of 2 hours after perfusion. Metabolic acidosis after perfusion may primarily be connected with the decreased digitalis tolerance. Of the electrolyte measurement, no consistent change was observed.

The Effect of Total Body Perfusion on Digitalis Tolerance

SUMMARY 1.The effect of total body perfusion on digitalis tolerance was studied clinically in 84 infants and children undergoing open heart surgery and experimentally in eight mongrel dogs subjected to total body perfusion. 2.The clinical studies consisted of comparison of immediate postperfusion electrocardiograms to preperfusion electrocardiograms. There was no statistically significant difference between the incidence of postperfusion electrocardiographic arrhythmias in patients who had been digitalized prior to perfusion and in patients who had not received digitalis. Additionally there was no correlation between the incidence of postperfusion arrhythmias and the degree of the preperfusion electrocardiographic evidence of digitalis effect. 3.Studies of the effect of perfusion on digitalis tolerance in the dog were performed both for digitalis administered prior to perfusion (tissue fixed) and for digitalis administered following perfusion. Perfusion was associated with no significant change in sensitivity to tissue fixed digitalis; however, all of the animals tested showed a decreased tolerance to digitalis administered one hour following perfusion. Decreased tolerance to digitalis persisted at four hours in 80 per cent of animals and at seven hours in 40 per cent of animals. 4.The application of this information to the administration of digitalis to patients undergoing open heart surgery is discussed.

Effect of Hypercholesterolemia on Digoxin Tolerance

SummaryA significant increase in digitalis tolerance was observed in hypercholesterolemic male rabbits when compared to the normocholesterolemic male rabbit. The explanation, however, is not clear but may be related to the chemical similarity of cholesterol to digitalis.

The treatment of digitalis toxicity

Summary o 1. The ascendency of digitalis intoxication in recent years, due especially to the use of purified glycosides, more effective diuretic procedures, and fluid and electrolyte manipulations, has made the preventive approach an essential part of treatment in every patient receiving the drug. This approach must include (a) the choice of promptly excreted preparations in patients in whom surgical or electrolyte manipulations seem likely; (b) use of minimal effective doses; (c) regular observation of the patient; (d) recognition by the patient as well as by the physician of the evidences of toxicity, and (e) care in the use of parenteral preparations. 2. Recognition of digitalis intoxication is fundamental to active therapy. The subtlety of its development, either through overdosage, or through changes in electrolyte balance of the patient, must be constantly kept in mind. “Less common” manifestations must be sought out. The patient must be aware of such symptoms. A digitalis tolerance test may be necessary for differentiation of the effects of disease and progressive effects due to digitalis. 3. Active therapy must include (a) discontinuance of the drug and may require, depending upon circumstances, (b) withholding of diuretic measures until toxicity clears up, (c) restriction of activity of the patient if necessary, (d) administration of potassium salts, (e) chelation of serum calcium if necessary, and (f) use of procaine amide.

Digitalis tolerance and effect of acetyl-strophanthidin upon serum potassium of dogs with acidosis and uremia

Evidence exists that the cardiac glycosides may initiate important shifts in the concentration of potassium (K) in both cellular and extracellular fluid.l-4 Their administration to normal dogs usually produces slight increases in serum K.1 Two clinical observations have also suggested a peculiarity of action of this drug in the uremic state. First, digitalization of patients with renal insufficiency sometimes apparently causes serum K to rise significantly, and second, some uremic patients have become intoxicated with relatively modest amounts of digitalis. In an attempt to evaluate these clinical impressions the effects of acetyl-strophanthidin (AS) upon the electrocardiogram and the serum electrolyte pattern of normal dogs were compared with those occurring in dogs made acidotic with ammonium chloride or uremic by bilateral ureteral ligation. Changes in tolerance to AS were also studied in each group. The results suggest that digitalis may induce significant hyperkalemia in the presence of uremia or metabolic acidosis. The results may be explained on the basis of previously reported alterations in permeability of the cell membrane.