Digoxin- and digitoxin-induced changes in monophasic action potential of the right ventricle of the dog heart.

The effects of digitoxin and digoxin on right ventricular monophasic action potentials were studied in intact dogs during an 8 hour observation period. Pentobarbital anaesthesia was used, and monophasic action potential recordings were obtained with the suction electrode technique. Intravenous injection of 2.0 mg digitoxin to six dogs, 2.0 mg digoxin to two dogs and 1.0 mg digoxin to five dogs caused a rapid increase in the time taken for 90% repolarisation with return to control values after 20 to 30 min. A late increase in 50 and 90% repolarisation times was observed 2 to 4 h after digitoxin, while digoxin had no such effect. The late action potential prolonging effect was inversely correlated to serum concentrations in the early elimination phase (2 to 8 h after the injection) since it reached a maximum towards the end of the observation period. Digitoxin and digoxin thus differed in their late effects on ventricular monophasic action potentials in intact dogs and may possess different antiarrhythmic activity.

Studies on digitalis. VIII. Digitoxin metabolism on a maintenance regimen and after a single dose.

The metabolic pattern of cardioactive and inactive conjugated metabolites of digitoxin on maintenance (9 patients) and after a single 0.6-mg dose (5 patients) was studied in patients with normal renal and hepatic function. Serum samples were obtained 24 hr after the last dose, and urine was collected over 24 hr. The extent of conjugation to glucuronic and sulfuric acid was 35.0% (SD, 17.4) in whole serum and 31.6% (SD, 19.3) in urine samples. Unchanged digitoxin was the main cardioactive substance found both in serum and in urine (89.7% and 87.0%) in the steady-state group. All known cardioactive metabolites were present; digoxin represented less than 1%. All active metabolites were conjugated to glucuronic/sulfuric acid. Serum and urine patterns of metabolites were quite similar, Hydrolysis and conjugation appeared to be more important pathways than hydroxylation. Unchanged digitoxin was the most important cardioactive substance in serum and urine (80.4% and 56.5%) in the single-dose group. Digoxin was the main cardioactive metabolite (12.5% in serum and 25.5% in urine). All active metabolites were conjugated. Hydroxylation, hydrolysis, and conjugation seemed to be equally important. The most important differences between the steady-state and single-dose groups were that in the steady-state group there was significantly more unchanged digitoxin, far less digoxin, and less hydroxylated metabolities than in the single-dose group. Caution is thus necessary when interpreting single-dose data for a drug that is used for maintenance.

Studies on digitalis. VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites.

Serum protein binding of digitoxin was lower (p less than 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimation was 4.8 days and 8.1 days in 5 control subjects (p less than 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p less than 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.

Studies on digitalis. V. The influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin.

The aim of the present investigation is to study digitoxin and digoxin protein binding in patients with normal renal and hepatic function, in patients with uremia, and in patients under treatment with hemodialysis for renal failure. The binding of digitoxin and cardioactive metabolites to serum proteins was studied using equilibrium dialysis (an in vitro chemical assay) alone and in combination with a modified 86Rb method. The following values for protein binding were found: DT-3 (digitoxin), 95.7%; DT-2 (digitoxigenin-bis-digitoxoside), 96.5%; DT-1 (digitoxigenin-mono-digitoxoside), 98.7%; DT-0 (digitoxigenin), 92.7%; DG-3 (digoxin), 21.2%; DG-2 (digoxigenin-bis-digitoxoside), 16.3%; DG-1 (digoxigenin-mono-digitoxoside), 18.5%; and DG-0 (digoxigenin), 13.3%. In vitro addition of procainamide, phenytoin, heparin, and rifampicillin did not influence the in vitro binding of digitoxin. Protein binding of digitoxin showed small individual variations in patients with normal renal and hepatic function. Uremia per se did not influence the in vitro binding of digitoxin. There were marked changes in digitoxin and digoxin protein binding during an 8-hr hemodialysis, digitoxin binding decreasing from 97.1% to 93.7% (p less than 0.0025) and digoxin binding from 23.5% to 15.4% (p less than 0.05). In the uremic patient the metabolic pattern of digitoxin tended toward a decrease in protein-bound metabolites.

Studies on digitalis. XI. Digitoxin metabolism in patients with impaired renal function.

The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG-3) and hydroxylated and hydrolyzed (DG-2, DG-1, and DG-0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia-induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.

Studies on digitalis. X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment.

The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method modified for analysis of myocardial samples. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respectively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).

Studies on digitalis. III. Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites.

Simultaneous serum, urine, and bile measurements of digitoxin and its cardioactive metabolites were preformed in 5 cholecystectomized patients with T tube drainage. A 86Rb method was used for serum and urine analysis. The recovery of digitoxin and cardioactive metabolites in two extractions with dichloromethane was 93%; 7% was left in bile. Peak bile concentrations had a mean value of 41.6 ng/ml and were seen after 15 to 60 min. Bile concentration was higher than serum and urine concentration after 24 hr. Mean T/2 of serum elimination was 4.3 days and 8.1 days in 5 control subjects (p less than 0.01). Mean urine concentration T/2 was 10.4 days and 7.2 days in the control subjects (not significant). Mean bile concentration T/2 was 3.5 days. Urinary excretion of digitoxin and cardioactive metabolites was the same in the two groups. The biliary fistula group excreted 22.5% in urine and bile of a dose after 8 days, whereas it was 15.8% in the control subjects. The ratio between the cumulative excretion in urine and bile varied between 1.6 and 2.2. These findings demonstrate that direct interruption of the enterohepatic circulation leads to a marked reduction in serum half-time of digitoxin and cardioactive metabolites, but T/2 is still longer than for other glycosides, indicating that factors other than the enterohepatic circulation are of importance in the slow elimination of digitoxin.

Studies on digitalis. IX. Some kinetic aspects of digitoxin metabolism.

The metabolic pattern of cardioactive and inactive conjugated metabolites (a maximum of 24 substances) was studied in one female and one male after a single dose of 0.6 mg digitoxin intravenously. Serum samples were obtained after 24 hr, and 24-hr urine was collected after 1, 2, 4, 6, and 8 days. With the methods used, enzymatic cleavage of conjugated bonds, thin-layer chromatography (TLC) separation, and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. The Kendall rank correlation coefficient was used to compare the results from Subjects 1 and 2. Conjugation was the most rapid process, followed by hydrolysis and hydroxylation. Metabolism was progressive, leading to an increase in metabolites resulting from several enzymatic processes with time. Unchanged digitoxin reached minimum values on the fourth and sixth days and increased again on the eighth day. This indicated a continuous release of digitoxin from tissue stores and the enterohepatic circulation.

Studies on digitalis. XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas.

The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty-fourth hour and the 1-, 2-, 4-, 6-, and 8-day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin-layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin but also changed the pattern of digitoxin metabolites in urine.

Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin.

The aim of the present study was to investigate the nature of the previously reported changes in the serum protein binding of digitoxin and digoxin in uremic patients under treatment with hemodialysis. Kinetic studies on protein binding during hemodialysis showed that the free fraction of digitoxin rose from 2.6% to 6.9% after 5 min of hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from 78.3% to 87.1% during the same period. In vitro hemodialysis experiments showed that such changes occurred only in vivo. Injection of heparin (5,000 IU) to control subjects produced similar kinetic changes in the protein binding of digitoxin and digoxin. Free fatty acids changed in the same way. These results indicate that the heparin-induced release of free fatty acids causes displacement of digitoxin and digoxin from their albumin-binding sites. Patients on hemodialysis have lower serum levels of digitoxin and cardioactive metabolites (mean, 8.9 ng/ml) than control patients (mean, 16.7 ng/ml) (p less than 0.005) on similar doses (mean, 0.085 mg/day). They should be maintained on the same digotoxin doses as uremic and control patients, but serum digitoxin levels should be adjusted to 10 to 15 ng/ml in hemodialysis patients compared to 15 to 25 ng/ml in uremic patients and in patients with normal renal function.

Digitoxin kinetics and renal excretion in children.

Digitoxin kinetics were investigated in 11 children, three girls and eight boys, with a mean age of 7.1 yr (5.9 to 9.2). Five children received digitoxin, 17.5 to 20 micrograms/kg IV, and six other children received 20 micrograms/kg as an oral solution. Digitoxin was given as a single dose 24 to 48 hr after cardiac surgery, and patients were monitored in an intensive care unit for 24 hr. Serum and urine digitoxin concentrations were determined by radioimmunoassay. Children had larger apparent volumes of distribution (1 l/kg) than adults (0.57 l/kg). Mean serum elimination t 1/2 was 6.4 days in children (3 to 11.2) and 8.2 days in adults (5.9 to 11.3). Total body clearance was much greater in children (0.085 ml X min-1 X kg-1) than in adults (0.036 ml X min-1 X kg-1). This was because of an increase in metabolic clearance, although there was no difference in renal clearance in children and adults. Absolute oral bioavailability, measured by comparing serum AUCs after intravenous and oral doses, was complete. Peak serum concentrations of 23 to 50 ng/ml developed 90 to 120 min after the oral dose. A single digitalization dose of 20 micrograms/kg was well tolerated and did not induce arrhythmias.

Arrhythmias in heart failure--therapeutic challenges.

Electrophysiologic disorders are common at all stages of heart failure due to myocardial mechanical factors, neuroendocrine disturbances, electrolyte abnormalities, or ischemia, and also because of cardiovascular drugs. The prevalence of various forms of heart block, bradycardias, and arrhythmias in heart failure is largely unknown, as is their relationship to the etiology of the syndrome. Complex and multiform ventricular premature beats and nonsustained ventricular tachycardia are common, and their frequency is broadly related to the severity of heart failure. Supraventricular arrhythmias are also common features of the syndrome. The heart failure syndrome has an ominous prognosis. Approximately half the patients die suddenly, but the causal relationship between preexisting arrhythmias and sudden death is not known. Equally vital is knowledge of the influence of drug therapy on the arrhythmias of heart failure, but at present this is scarce and needs further study.

Protein binding of cardiac glycosides in disease states.

Digitoxin in 97% bound to serum albumin and digoxin only to the extent of 24%. Hypoalbuminaemia significantly changes the protein binding of digoxin in Kwashorkor serum and the binding of digitoxin in patients with chronic active hepatitis and the nephrotic syndrome. Sprue patiens with normal albumin values have normal binding of digitoxin. Preliminary data in patients with thyrotoxicosis and myxoedema show digitoxin binding within the normal range. The effect of uraemia per se on digitoxin binding is controversial as both normal and slightly decreased values have been reported. In uraemic patients on treatment with haemodialysis, heparin administration has been shown to be a powerful serum binding displacing agent for both digitoxin and digoxin, the mechanism probably being a heparin-induced release of free fatty acids. Patients with a significant decrease in serum protein binding of digitoxin or digoxin should be maintained on a total serum concentration lower than usually considered within the therapeutic range.

A double-blind, crossover comparison of flecainide acetate and disopyramide phosphate in the treatment of ventricular premature complexes.

The efficacy and safety of flecainide, 200 mg twice daily, was compared with disopyramide, 150 mg 4 times daily, in a randomized, double-blind, crossover study in 25 patients (19 men and 6 women, aged 20 to 71 years, mean 52.5) with more than 1,000 ventricular premature complexes (VPCs) in a pretrial 24-hour Holter monitoring screen. Each 14-day active treatment period was preceded and followed by a 7-day placebo period. Ambulatory ECGs were recorded at the end of each study week and analyzed blindly. Average VPCs recorded during each of the 2 active periods were compared with average VPCs in the placebo periods. Twenty-two of 25 patients attained therapeutic plasma levels of both drugs. The occurrence of VPCs was significantly less during flecainide than during disopyramide treatment, 92 and 39%, respectively (p less than 0.01). Complex arrhythmic events were significantly more suppressed with flecainide than with disopyramide. No difference was observed between the 2 drugs in the incidence or severity of reported side effects. PQ, QRS and QT intervals increased beyond normal limits on both drugs in some patients, significantly more with flecainide than with disopyramide. The JT interval did not change or decrease; hence, all changes in the QT interval were attributable to a widening of the QRS complex. Neither drug showed any significant effect on blood pressure or heart rate. Flecainide may be a well-tolerated and valuable alternative to currently available antiarrhythmic agents.

Instant and sustained-release verapamil in the treatment of essential hypertension.

In a series of controlled studies for periods of 4 to 6 weeks comprising 103 patients altogether, and in 1 long-term trial for 1 year, various dosages of instant and sustained-release verapamil were administered in the treatment of mild and moderate essential hypertension. One of these trials was a double-blind comparison with nifedipine, in which the 2 calcium antagonists had an equally good effect on blood pressure. A significant blood pressure reduction was achieved with verapamil both at rest and during isometric work in most patients. About 10% of the patients were nonresponders. Pharmacokinetic studies demonstrated great interindividual variations in plasma concentrations of verapamil and its active metabolite norverapamil. Except for 1 study, no significant correlation was found between drug concentration and blood pressure reduction. All formulations of verapamil were well tolerated by the patients, and adverse effects were generally mild and often transient. No negative metabolic effects were observed during long-term treatment; serum lipids, in particular, were unaffected. PQ intervals on the electrocardiogram were significantly but moderately prolonged. QRS and QT intervals were unchanged. No increase in body weight occurred. It is concluded that verapamil is an efficacious, safe drug and a first-line treatment alternative in mild and moderate essential hypertension. The recently developed sustained formulation of the drug renders a simple dosage regimen possible.