Mg Of Digoxin Research Articles

Effects of Digitalis on the Exercise Electrocardiogram in Normal Adult Subjects

Controversy continues regarding the effects of administration of digitalis upon the exercise electrocardiogram. Thus, maximal treadmill exercise tests were performed before and two weeks after administration of 0.25 mg of digoxin daily in 15 normal subjects (documented by cardiac catheterization and coronary arteriographic studies). Administration of digitalis induced abnormal findings on exercise tests in all 14 subjects with serum levels of digoxin greater than or equal to 0.5 ng/ml; however, at workloads greater than 75 to 90 percent of maximal predicted heart rate, the changes in the ST segment reverted to a normal configuration in all subjects, thereby providing differentiation of digitalis-induced ST-segment alterations from those due to myocardial ischemia at maximal treadmill stress.

Short- and long-term effects of digitalis on resting and posthandgrip hemodynamics in patients with coronary artery disease

The short-term effects at rest of 0.01 mg/kg of ouabain given intravenously and the long-term effects at rest of daily oral administration of 0.25 mg of digoxin on left ventricular ejection fraction, left ventricular end-diastolic volume, cardiac index, blood pressure and heart rate were measured in eight patients with coronary artery disease using a single crystal scintillation probe. Measurements were also made after handgrip exercise (1 minute of 33 percent of maximal) in two of these patients and in two others with coronary artery disease. In all patients the left ventricular ejection fraction was less than 0.50. Ouabain increased resting left ventricular ejection fraction (0.39 ± 0.03 to 0.55 ± 0.03 [mean ± standard error of the mean], P <0.01) and decreased resting left ventricular end-diastolic volume index (86 ± 12 to 64 ± 5 ml/ m 2, P <0.01) and heart rate (75 ± 6 to 69 ± 6 beats/ min, P <0.02). Ouabain did not change resting cardiac index or blood pressure significantly. Handgrip exercise increased heart rate and blood pressure significantly. Left ventricular ejection fraction after handgrip exercise was 0.33 ± 0.02 (difference not significant), but it increased after ouabain administration to 0.55 ± 0.03 from the control value of 0.36 ± 0.01 ( P <0.05). After 2 weeks of daily oral administration of digoxin, associated with a digoxin level of 1.0 ± 0.2 ng/ ml, all resting hemodynamic variables were statistically unchanged from control levels. In the four patients tested daily, the return to control levels took 1 to 5 days. Left ventricular ejection fraction after handgrip exercise remained elevated at 0.50 ± 0.04 ( P <0.05). Thus, with long-term digoxin administration, volumetric variables at rest are initially improved but later return to control values whereas values after exercise continue improved.

Assessment of methodology in single-dose studies of digoxin bioavailability.

Eight healthy males received 0.75 mg of digoxin by ten modes of administration in a single-dose multicrossover bioavilability study. Digoxin concentration in multiple blood samples drawn after each dose and in six consecutive 24-hour urine collections were used to calculate the areas under the 4-, 8-, and 24-hour serum concentration curve (A-4, A-8, A-24), and the excretion of digoxin during 1 day (U-1) and 6 days (U-6) following each dose. All five methods of assessment gave very similar information on bioavailability. Individual values of A-4 and A-8 were highly correlated (r=0.973) and had similar variability. A-24 was more variable than A-4 and A-8, and was not as well correlated with either. U1- and U-6 were highly correlated (r=0.944), and had nearly identical variability which was less than that of any of the area measures. Thus, urinary excreation data provides more reliable and reproducible information about completeness of absorption of digoxin than data based upon serum concentrations. Extending the period of urine collection beyond 1 day or the blood sampling period beyond 4 or 8 h does not enhance the reliability or usefulness of digoxin bioavailability studies.

Variability of hemodynamic responses to acute digitalization in chronic cardiac failure due to cardiomyopathy and coronary artery disease

Eight patients with chronic congestive heart failure (four with cardiomyopathy and four with ischemic heart disease) underwent hemodynamic studies during acute administration of digoxin, given intravenously in two 0.5 mg doses 2 hours apart. Observations were made before administration of digitalis (control period) and serially thereafter for 4 hours after the first dose. Resting mean cardiac index and pulmonary arterial wedge pressure were as follows: 2.0 liters/min per m 2 and 23 mm Hg (control period); 2.1 and 24 (at 1 hour); 2.0 and 23 (at 2 hours); 2.7 and 19 (at 3 hours); and 2.3 and 20 (at 4 hours). Exercise responses of mean cardiac index and pulmonary arterial wedge pressure in five patients were: 3.1 liters/min per m 2 and 36 mm Hg (control period); 3.2 and 33 (at 1 hour); 3.2 and 28 (at 2 hours); 3.1 and 27 (at 3 hours); and 3.4 and 31 (at 4 hours). The pulmonary arterial wedge pressure remained elevated during exercise in all cases. Arrhythmias were seen in five patients after administration of 0.5 mg of digoxin. Hemodynamic improvement at 4 hours involving both reduced filling pressure and increased blood flow was observed in only two patients at rest and in one additional patient during exercise. Acute deterioration of cardiac function (elevated pulmonary arterial wedge pressure or decreased cardiac index) occurred 30 minutes after administration of digoxin in four patients, concomitantly with increased systemic resistance. In six patients, a peak hemodynamic effect appeared 1 to 1 1 2 hours after administration of digoxin, with partial or total loss of initial benefit by 2 and 4 hours. In previously performed studies observations have seldom exceeded 1 hour; the results of this 4 hour study suggest that, in patients with cardiomyopathy or coronary artery disease and chronic congestive heart failure, acute digitalization does not necessarily lead to consistent, marked or lasting hemodynamic improvement. Thus, current concepts of the use of digitalis in such patients may require revision.

Intersubject Variation in Absorption of Digoxin in Normal Volunteers

The absorption of oral digoxin preparations was evaluated following single‐dose administration of 0.5mg of digoxin to 16 normal volunteers in a randomized crossover design. Absorption was estimated using the cumulative excretion of digoxin in urine for 7 days and the area under the 24‐hr serum digoxin concentration curve (AUC). Significant intersubject variability was observed with both parameters, but this variability was greater for the AUC. After intravenous administration, the 7‐day digoxin excretion was 68% of the dose. The elixir and a rapid dissolution tablet were significantly better absorbed (84.5 and 77.8%, respectively) than was a slow dissolution tablet (66.7%), as reflected by the fraction of the amount excreted in the urine following intravenous administration of the same dose. There was a highly significant correlation between the cumulative digoxin excretion in urine during the first 2 days compared to 7 days (r = +0.972, p < 0.001). Bioavailability of oral digoxin preparations can be reliably determined by comparison of the cumulative 2‐day excretion of digoxin following a single dose.

Massive intravenous digoxin overdosage.

ACCIDENTAL or intentional oral digoxin overdosage occurs in persons with and without underlying heart disease. We recently observed a laboratory technician without prior heart disease who self-adminstered 200 mg of digoxin intravenously. Since physicians rarely order more than 100 0.25-mg tablets of digoxin per prescription, oral ingestion of more than 25 mg would be expected to be rare. Reported digoxin ingestions have not exceeded 23 to 24 mg.1 2 In our patient severe hyperkalemia (potassium level of 13.5 mEq per liter) developed. Inexcitability of cardiac tissue occurred despite adequate control of plasma potassium with hemodialysis and magnesium infusion.Case ReportA . . .

Bioavailability and Dissolution Properties of two Commercial Digoxin Tablets

Six healthy male subjects were given 0.5mg of digoxin on three separate occasions in the form of an elixir and two different commercially available brands of compressed tablets. Blood levels were measured by a radioimmunoassay technique at various time intervals up to 48hr following drug administration. A previously unreported variable in the radioimmunoassay method was found. Varying amounts of digoxin-free serum added to aqueous samples such as urine or hydroalcoholic solutions led to significant changes in the apparent digoxin concentration measured in the sample. The elixir form gave much higher blood levels than either tablet during the first two sampling times, but the two tablets showed nearly identical blood levels and relative bioavailabilities. A previously reported dissolution rate test method showed wide differences between the two tablets and thus failed to correlate with the similar bioavailabilities observed in vivo.

Evidence for Variable Digoxin Absorption as Estimated by Pharmacological Response Intensities

A dose-effect curve constructed from ventricular rate slowing and oral maintenance doses for digoxin provided evidence for assuming that occupation theory correctly describes drug-receptor site interaction. From the tenets of occupation theory, response intensities were linearly related to biophasic drug levels and provided the input for bi- and triexponential least-squares fits for an intravenously administered 1.2-mg dose of digoxin to patients hospitalized with auricular fibrillation. A biexponential fit best described biophasic drug levels when the biophase was represented by a peripheral compartment. Intravenous biexponential equation parameters were utilized to perform an absorption analysis following oral dosing of 1.2mg of digoxin to the same patients. From calculations of fractional amounts unabsorbed with time, significant absorption of digoxin was found to be occurring through 24hr at progressively decreasing but noticeably variable rates; absorption was calculated to be 98.7% complete by 120hr. Absorption rates were most rapid over the first 5hr but quite variable thereafter. Oscillations in the intravenous and oral response-time curves, observed between 3 and 12hr following dosing, likewise produced fluctuations in mathematically derived biophasic drug levels, fractional amounts unabsorbed, and absorption rates for the oral dose, suggesting enterohepatic cycling of digoxin to be more significant than previously thought.

A simple enzymatic assay of cardiac glycosides and its application to analysis of glycoside levels in plasma

1. 1. A method of enzymatic assay of cardiac glycosides has been developed. The test principle is based on the inhibition of a preparation of Na +, K +-stimulated ATPase by cardiac glycosides. The smallest amount of digoxin that could be detected was 0.4 pmole (2 S.D.). 2. 2. The inhibiting capacities of six different cardiac glycosides were determined, the amount of glycoside being 4 pmole. After pretreatment of the enzyme with the glycoside for 45 min digoxin was found to be the most potent inhibitor (58% inhibition) and lanatoside C the weakest (47% inhibition) among the glycosides tested. 3. 3. Extractions of the glycosides added to plasma were performed with dichloromethane. Digoxin and digitoxin were extractable to 100%, but the yield of the other glycosides was lower. 4. 4. The method was applied to a study of the plasma digoxin concentration of patients receiving 0.13 or 0.25 mg of digoxin daily. The concentration of digoxin in plasma ranged from 0.5 to 2.1 nM, which is in accordance with results from other laboratories.

Variation in biologic availability of digoxin from four preparations.

The unexplained association of unusually large maintenance doses of digoxin and low serum digoxin concentrations in several patients prompted a study of the biologic availability of various digoxin products recently available for use on the wards of a New York City municipal hospital. In crossover studies in which 0.5 mg of digoxin was administered orally to normal volunteers, marked differences in serum digoxin levels achieved over a five-hour period were demonstrated. With one product peak serum levels were seven times those obtained with another. Significant variation between different lots prepared by a single manufacturer was also observed. Evidence of biologic as well as chemical equivalency of digoxin products for use in man should be required.

Relationship of plasma digitoxin and digoxin to cardiac response following intravenous digitalization in man.

The value of plasma digitalis determinations will depend upon the accuracy with which they mirror the myocardial effects of digitalis. Ten volunteers received 0.8 mg of digitoxin intravenously, and after 2 hours the mean plasma digitoxin level was 45.6 ± 6 mµg/ml but declined over 4 to 6 hours during plasma-tissue equilibration. The cardiac response, as indicated by decreases in the left ventricular ejection time index (LVETI) and Q-S 2 intervals ( P &lt; 0.01), was present at 2 hours and reached maximum at 4 to 6 hours. Subsequently, plasma level, LVETI, and Q-S 2 changed in the same direction during slow excretion. Six subjects received 1.0 mg of digoxin intravenously. Mean plasma digoxin at 30 min was 6.8 ± 0.3 mµg/ml; it fell after 3 to 4 hours to levels usually seen during maintenance digoxin administration (&lt;3 mµg/ml) and then declined more slowly. Correlation of individual digoxin levels with ΔLVETI values during the first 4 hours was significant ( P &lt; 0.01). The half-life (T ½ ) for the dominant slope of the plasma curve was 30.5 hours by plasma determinations and 29 hours by LVETI determination. Plasma levels of digitoxin and digoxin were related to their cardiac effects under the conditions studied. Prior to plasma-tissue equilibration, plasma determinations of digoxin and digitoxin will be higher than levels seen during maintenance administration of these drugs.

Hemodynamic effects of cardiac glycosides on normal human subjects during rest and exercise.

The effect of digitalis on the rest and exercise hemodynamics of eight normal subjects was studied. Cardiac output was determined by the dye dilution technique, using a cuvette densitometer. Arterial and venous pressures were measured on Statham strain gauges. Data were obtained during rest and exercise before and after intravenous administration of 1.0–1.2 mg of digoxin or 1.6–1.8 mg of acetyl strophanthidin. At rest there was a decrease of cardiac output (average 12%), pulse rate (5%) and stroke volume (9%) and an average rise of blood pressure from 129/73 mm Hg (mean 95 mm Hg) to 156/86 mm Hg (mean 109 mm Hg) following digitalization. During exercise there was a decrease of cardiac output (average 18%), pulse rate (6%) and stroke volume (9%), but no change of blood pressure after digitalization. The systemic vascular resistance was increased following digitalization, both during rest and exercise. In three additional subjects, the blood pressure rise accompanying digitalization at rest was verified by demonstrating a prompt increase in blood pressure as acetyl strophanthidin was injected and a fall as the control saline injection was resumed. Since the positive inotropic action of digitalis explained neither the rise of systemic vascular resistance nor the fall of cardiac output following digitalization of normal subjects, a peripheral action of cardiac glycosides was suggested. It is concluded that whatever augmentation of myocardial contractility that may result from digitalization of the resting or exercising normal subject is overshadowed by the peripheral action of the drug. Submitted on May 29, 1958