Pharmacokinetic evaluation of the digoxin-amiodarone interaction.

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.

Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: the PROMISE Study.

OBJECTIVES: The aim of this study was to determine the prognostic significance of alterations in serum magnesium in patients with moderate to severe congestive heart failure. BACKGROUND: Reductions in serum magnesium have been postulated to play a role in promoting arrhythmias and to have an adverse impact on survival in congestive heart failure, although support for this postulate is lacking. METHODS: Serum magnesium levels were measured in 1,068 patients enrolled in a survival study of class III or IV heart failure at the time of double-blind randomization to milrinone, a phosphodiesterase inhibitor, or placebo. All patients received conventional therapy with digoxin, diuretic drugs and a converting enzyme inhibitor throughout the trial. The median follow-up period was 6.1 months (range 1 day to 20 months). RESULTS: Patients with high serum magnesium (defined as > or = 1.9 mEq/liter, n = 242) were less likely to survive than were patients with a normal magnesium level (n = 627) (p < 0.05, risk ratio = 1.41). Patients with a low magnesium level (defined as < or = 1.5 mEq/liter, n = 199) had no difference in survival compared with the group with a normal magnesium level (p = NS, risk ratio = 0.89). At baseline, the patients in the high magnesium group were older and had more severe functional and renal impairment. An analysis after adjustment for these variables demonstrated no difference in survival comparing the low, normal and high magnesium groups. Although the three groups had no difference in frequency of ventricular tachycardia, length of longest run or frequency of ventricular premature beats on baseline Holter monitoring, the group with hypomagnesemia had more frequent ventricular couplets. CONCLUSIONS: Serum magnesium does not appear to be an independent risk factor for either sudden death or death due to all causes in patients with moderate to severe heart failure. Hypomagnesemia is associated with an increase in the frequency of certain forms of ventricular ectopic activity, but this is not associated with an increase in clinical events. The higher mortality rate among the patients with hypermagnesemia is attributable to older age, more advanced heart failure and renal insufficiency.

Mexiletine in refractory ventricular arrhythmias.

The antiarrhythmic efficacy of mexiletine was evaluated in 28 subjects with recurrent ventricular tachycardia or fibrillation (22 subjects) or with symptomatic complex ventricular ectopy (six subjects). In all, either the arrhythmia was refractory to other drugs, or such therapy was not tolerated. Response to mexiletine was assessed by continuous ECGs, and in five cases by programmed electrical stimulation. Mexiletine abolished the arrhythmia in 12 cases, but was not tolerated long-term in four. Mexiletine was ineffective in 10 subjects. Seven subjects had significant adverse reactions during short-term dosing; in six, mexiletine was discontinued because of adverse effects after the first few doses so efficacy was not evaluated. The most common adverse effects were nausea, tremor, and generalized malaise. We conclude that mexiletine is an effective antiarrhythmic in some patients with life-threatening ventricular arrhythmias refractory to conventional drugs. Adverse effects significantly limit its use.

Mexiletine and quinidine in ventricular ectopy.

The antidysrhythmic efficacy and tolerance of mexiletine and quinidine were compared in 26 ambulatory patients with chronic ventricular ectopy. Thirteen patients were treated with mexiletine and 13 with quinidine. The treatment groups were comparable in age and cardiac diagnoses, in frequency of untreated ventricular ectopy, in the presence of complex forms, and in previous drug failures. After two 24-hr ambulatory ECG recordings, the patients were treated according to a double-blind, dose-ranging protocol. Efficacy was defined as reduction in ventricular ectopic frequency by at least 70% in a comparison of two 24-hr ambulatory ECG recordings after drug with the two pretreatment recordings. Suppression of ventricular ectopic frequency by at least 70% was achieved in seven mexiletine-treated patients and eight quinidine-treated patients. Neither drug consistently abolished complex forms of ectopy. The incidence of adverse effects was of the same order in the two groups. We conclude that mexiletine is as effective as quinidine in the suppression of ventricular ectopy. Use of both drugs is limited by adverse effects.

Digoxin-quinidine-spironolactone interaction.

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0-mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t 1/2. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in normal subjects.

The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 ml/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t 1/2 of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t 1/2 of an intermediate length and may have significant therapeutic advantages.

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in renal insufficiency.

The kinetics of digitoxin and two of its major metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six subjects with renal insufficiency and compared to those in six age- and sex-matched normal control subjects. No significant differences between the two groups were found in elimination t 1/2, total body clearance, or volume of distribution. Average renal clearances of all three drugs were reduced in subjects with renal failure, but the differences were significant only in the case of digitoxin. The bis-digitoxoside of digitoxigenin has kinetic properties that offer clinical advantages.

Effect of intravenous metoprolol on reversible obstructive airways disease.

We gave increasing doses of metoprolol intravenously to seven subjects with stable chronic obstructive pulmonary disease (COPD) who were also receiving their usual bronchodilators. Six of the seven tolerated up to 0.2mg/kg metoprolol without adverse effects, although there were declines in forced expiratory volume in 1 sec (FEV1). At 0.15 mg/kg mean FEV1 fell 12% (p less than 0.025), and at 0.2 mg/kg mean decline in FEV1 was 15% (p less than 0.01). These findings suggest that 0.2 mg/kg metoprolol may be given intravenously to most patients with COPD in addition to previously administered bronchodilators without precipitating clinically significant adverse effects. Any side effects that develop can be reversed by beta agonists.

Kinetics of the digoxin-aspirin combination.

Digoxin interacts kinetically with many drugs in man. These interactions may result in digoxin toxicity. Aspirin has been shown to raise serum digoxin levels in the dog. We evaluated the effect of aspirin on digoxin single-dose kinetics in eight healthy adults. Aspirin induced no change in digoxin total body clearance, volume of distribution, elimination half-life, or renal or creatinine clearance. Trough serum salicylate levels ranged from 93 to 163 microgram/ml. We conclude that no alteration is required in digoxin dosing when aspirin is used.

Effect of quinine on digoxin kinetics.

Six subjects were evaluated for the effect of quinine, the l-isomer of quinidine, on digoxin pharmokinetics. A 1.0-mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half-life (t 1/2) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x = 628. 29 micrograms to x = 772.52 micrograms (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quamtitatively different, from quinidine.

Atenolol for ventricular ectopy: a dose-response study.

The antiarrhythmic efficacy, safety, and tolerance of atenolol was evaluated in 32 patients with an average of at least 60 ventricular ectopic depolarizations/hr. Patients received, single-blind, the following treatments for 2 weeks each: placebo and atenolol, 50, 100, and 200 mg daily. A 24-hour ambulatory ECG recording was obtained each week. Reduction in ventricular ectopic frequency by at least 75% occurred in six of 32 patients receiving 50 mg daily, five of 30 patients receiving 100 mg daily, and three of 21 patients receiving 200 mg daily (P = not significant for any paired dose comparison). No patient who failed to respond to a lower dose responded to 200 mg daily. The frequency of ventricular tachycardia was reduced by at least 75% in eight of 17 patients receiving 50 mg daily, seven of 16 patients receiving 100 mg daily, and eight of 11 receiving 200 mg daily (P = not significant for any paired dose comparison). Atenolol was discontinued because of adverse effects in 12 patients. The results indicate that atenolol is more effective in suppressing ventricular tachycardia than in suppressing overall ventricular ectopy.

Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris.

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation.

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Ethmozine for ventricular premature complexes.

Twenty patients with an average of more than 30 ventricular premature complexes (VPCs) per hour were treated with ethmozine. Eighteen had either not responded or had adverse reactions to at least 1 other antiarrhythmic drug. Patients were treated with 200 to 300 mg 3 times daily (8.25 to 11.7 mg/kg) and were followed for up to 6 months. Three patients were withdrawn from ethmozine therapy because of unwanted effects before evaluation of efficacy. One of these patients had sustained ventricular tachycardia (VT) after a loading dose of ethmozine. Eleven of the remaining 17 patients (65%) experienced more than a 75% reduction in ventricular ectopic activity. Six patients had a smaller or no decrease in VPC frequency. Eleven of 16 patients (68%) with paired VPCs had a more than 90% reduction in paired VPC frequency. Eleven of 13 patients (84%) with VT events of 3 beats or more had more than a 90% reduction in VT events. Of the 11 patients in whom a more than 75% reduction in VPC frequency occurred, 1 patient died suddenly after 133 days of effective drug therapy. Three patients discontinued ethmozine therapy for reasons not related to the drug. Of the 6 patients in whom there was less than a 75% reduction in VPC frequency, 2 patients discontinued treatment, 1 patient because of hyperanxiety and 1 because of drug-related left anterior hemiblock. Ethmozine lengthened PR and QRS intervals but not the JT interval. Thus, ethmozine is effective and clinically useful for suppression of frequency VPCs in 50% (10 of 20 patients) of a selected population.

Complete heart block after sublingual nitroglycerin.

A 62-year-old man who was under observation following an episode of severe chest pain developed complete heart block and hypotension after receiving sublingual nitroglycerin. The reaction occurred while the patient was receiving an intravenous maintenance infusion of lidocaine but did not occur in response to either nitroglycerin alone or lidocaine alone. There was no evidence of acute cardiac ischemia nor of clinically significant underlying heart disease. Complete heart block after sublingual nitroglycerin in the absence of significant cardiac disease is an exceedingly rare phenomenon.

Effect of mitral regurgitation on the murmur of pulmonic regurgitation.

We evaluated auscultatory findings in a 67-year-old man with acquired pulmonic and mitral regurgitation. During inspiration, the murmur of pulmonic regurgitation decreased in intensity prior to surgery, but increased in intensity after mitral valve replacement. Inspiration reduces the volume of mitral regurgitation, thereby reducing the volume and murmur of pulmonic regurgitation.

Evaluation of cardiomyoplasty and skeletal muscle ventricle procedures in a clinically realistic animal model.

Cardiomyoplasty and skeletal muscle ventricle procedures have shown increasing promise in the treatment of cardiomyopathy with associated chronic congestive heart failure. More than 100 patients have now received such procedures worldwide. The clinical results to date have been mostly anecdotal with subjective improvement but without firm objective data to collaborate the subjective impression. A clinically realistic animal model would have tremendous advantages to help elucidate the mechanisms by which cardiomyoplasty or skeletal muscle ventricles improve the sense of well-being of patients who have congestive heart failure. Several possible animal models exist, including pharmacologically induced congestive heart failure models and postischemic injury cardiomyopathy models. The most intriguing, however, is a spontaneously occurring cardiomyopathy in large dogs. This idiopathic cardiomyopathy that appears mainly in large-breed dogs (Great Danes, Dobermans, and Saint Bernards) has a rapidly progressive course; it has a 6-month mortality rate of 75% and a 12-month mortality rate of 95% to 100%. The most efficacious use of such an experimental model would include the evaluation of cardiomyoplasty and skeletal muscle ventricle procedures in a multidimensional fashion. Experimental endpoints should include mortality, exercise tolerance, systolic and diastolic ventricular function, and arrhythmia occurrence. Sophisticated techniques now exist for the evaluation of systolic and diastolic ventricular function. Such evaluation may well provide additional insight into how such experimental procedures benefit those with congestive heart failure.

Antiarrhythmic efficacy of desipramine.

The effect of desipramine on chronic ventricular ectopic depolarizations (VEDs) was studied in 10 patients with at least 30 VEDs per hour. A single-blind, placebo-controlled, dose-ranging protocol was followed. Efficacy was defined as a decrease in VED frequency of at least 75%, base on three 24 hour ambulatory ECGs obtained on each dose. Among seven patients with analyzable data, one responded to 75 mg daily, and three others responded to 150 mg daily. Six of the seven patients demonstrated decreases in VED frequency with increases in desipramine serum concentration. Among five patients with episodes of nonsustained ventricular tachycardia, desipramine completely abolished the episodes in two, and reduced the frequency of episodes by at least 90% in two others. Adverse reactions were common, and necessitated drug discontinuation or dose reduction in five patients. Desipramine has an antiarrhythmic effect in patients with chronic ventricular ectopy, but its clinical utility is limited by adverse effects.

Suppression of atrial ectopy with intravenous metoprolol in chronic obstructive pulmonary disease patients.

To determine the efficacy of a cardioselective beta blocker in the treatment of atrial ectopy in patients with chronic obstructive pulmonary disease (COPD), we administered intravenous metoprolol (0.2 mg/kg) to six patients with atrial ectopic depolarizations (AEDs) and chronic partially reversible airflow limitation (FEV1 = 1.24 +/- 0.21 liter, mean +/- S.E.). Metoprolol reduced the mean frequency of AEDs from 713 +/- 237 per hour to 218 +/- 127 per hour. Furthermore, three of six patients experienced an 85 per cent or greater decrease in AEDs. No changes were observed in FEV1, FVC, or FEF25-75 over the course of the study. These data suggest that intravenous metoprolol is effective in reducing the frequency of AEDs and that it can be administered to patients with COPD without causing an increase in airflow limitation.

Effects of oral diltiazem on platelet function: alone and in combination with "low dose" aspirin.

The effects of 3 days of oral diltiazem, "low dose" aspirin (40 mg/day), and their combination on platelet function was studied in 5 normal subjects. Both drugs inhibited platelet aggregation and ATP release induced by collagen, epinephrine and threshold concentrations of ADP. Aspirin and diltiazem decreased thromboxane A2 generation during ADP induced aggregation by 94 percent and 53 percent respectively, however both agents inhibited aggregation similarly, which suggests that diltiazem's anti-platelet effect was due to mechanisms other than inhibition of thromboxane metabolism alone. Combination therapy resulted in a partially additive inhibitory effect on ADP induced aggregation and thromboxane A2 generation. Two subjects had bleeding times over 15 minutes after receiving combination therapy.