Flora Peters

Role of concentration-dependent plasma protein binding in disopyramide disposition

Plasma disopyramide concentration-time data and plasma protein binding measurements were obtained in 12 patients requiring disopyramide for suppression of their cardiac arrhythmias. The fraction of disopyramide unbound to plasma proteins varies from approximately 0.19 to 0.46 over the therapeutic range of total plasma concentrations (2–8 mg/liter). Data from single and multiple intravenous doses were analyzed using two models based on the hypothesis either that clearance is independent of the total disopyramide plasma concentration (total clearance model) or that clearance is independent of the concentration of disopyramide unbound to plasma proteins (free clearance model). This analysis indicates that only the free clearance model satisfactorily describes the data as a linear system. Using the free clearance model and data obtained from single doses, multiple intravenous infusions were designed for each patient which would rapidly attain and maintain predetermined plasma disopyramide concentrations. The calculated and observed disopyramide concentrations were in close agreement. In the 12 patients studied, at any given total disopyramide plasma concentration, there was an approximately twofold range in the fraction of disopyramide unbound to plasma proteins. Mean plasma protein binding data are therefore of little value in a given patient for predicting free disopyramide concentrations from measurements of total disopyramide concentration. Difficulties in the clinical management of patients receiving disopyramide, resulting from the nonlinear disposition of the usually measured total disopyramide concentrations, are discussed.

Clinical electrophysiologic effects of encainide, a newly developed antiarrhythmic agent

Encainide is a newly developed antiarrhythmic agent. With the use of intracardiac electrophysiologic techniques, its effects on the cardiac conduction system were examined in 10 patients with coronary artery disease. Five patients received 0.6 and five received 0.9 mg/kg body weight of encainide intravenously over 15 minutes. Plasma concentration, heart rate, blood pressure and conduction intervals (A-H, H-V, QRS and Q-T) were measured before, during and after encainide infusion. In addition, sinus nodal recovery time, Wenckebach cycle length, and atrial, atrioventricular (A-V) nodal and right ventricular refractory periods were measured before and after encainide infusion. The average peak plasma concentration was 0.49 +/- 0.35 microgram/ml (mean +/- standard error of the mean). Encainide significantly prologned H-V and QRS intervals in all patients by an average of 31 +/- 7 and 18 +/- 9 percent (standard deviation) (P less than 0.001), respectively. A minimal increase in the Q-T interval was also observed after encainide infusion (2 +/- 9 percent, P less than 0.01), but no significant changes were noted in heart rate, blood pressure, A-H interval, corrected sinus noal recovery time, Wenckebach cycle length or refractory periods of the atrium, A-V node or right ventricle. It is concluded that encainide significantly prolongs conduction in the His-Purkinje system without affecting conduction or refractoriness of other parts of the cardiac conduction system in man.

Possible contribution of encainide metabolites to the long-term antiarrhythmic efficacy of encainide☆

To establish long-term efficacy and the relation between drug plasma concentration and antiarrhythmic response, 12 patients with encainide-responsive frequent complex ventricular ectopic activity underwent 1 year of therapy with encainide. Twenty-four hour ambulatory electrocardiograms were obtained at baseline and every 2 months. Drug withdrawal with concomitant plasma sampling and electrocardiographic monitoring was performed at 6 and 12 months. Average group premature ventricular contraction (PVC) suppression during the year was 97 to 99%, with nearly total suppression of pairs and salvos. The most common adverse effects were transient visual disturbances and dizziness or lightheadedness. During a dose interval (6 to 12 hours) the concentration of encainide metabolites exceeded that of encainide by several-fold. The median time of arrhythmia return after drug withdrawal was 12 to 14 hours. At the time of arrhythmia return encainide was generally no longer detectable but the average concentration of O-demethylencainide and 3 methoxy-O-demethylencainide was 72 +/- 49 and 172 +/- 74 ng/ml, respectively. It is concluded that encainide therapy is extremely effective for continuous long-term suppression of complex ventricular arrhythmias and its metabolites contribute significantly to its antiarrhythmic action during chronic oral therapy.

Randomized double-blind placebo controlled crossover trial documenting oral lorcainide efficacy in suppression of symptomatic ventricular tachyarrhythmias

Lorcainide, a new antiarrhythmic drug, was given to 10 patients with frequent (greater than 1/min) premature ventricular contractions (PVCs) on a baseline 24-hour Holter monitor. Each patient received lorcainide, 100 mg twice daily, and an identical placebo, in a randomized double-blind crossover trial, with 1 week in each treatment period. Before the trial and at the end of each period, routine laboratory, clinical evaluation, 12-lead ECGs, and 24-hour ambulatory ECG recordings were performed. Trough drug plasma concentration measurements were done at the end of each treatment period. All patients had reduction in PVCs, comparing drug to placebo, averaging 82.3 +/- 19.7% (mean +/- SD, p less than 0.01 by Wilcoxin ranked sum), and there was also significant decrease in the number of ventricular pairs and runs. Levels of the major metabolite, norlorcainide, ranged from 34 to 254 ng/ml (mean 160 ng/ml) and exceeded those for lorcainide, range 6 to 169 ng/ml (mean 79 ng/ml). Prolongation of PR, QRS, and QTc intervals was evident during drug therapy, as was decrease in heart rate, but these changes were minimal. The major adverse effect noted was sleep disturbance, which was often initially severe, but improved during the week of therapy.

Clinical pharmacology and antiarrhythmic efficacy of N-acetylprocainamide☆

Eleven patients with chronic ventricular arrhythmias took part in a study of N-acetylprocainamide (NAPA), the major metabolite of procainamide, in order to characterize further NAPAs clinical pharmacology and antiarrhythmic action. The frequency of ventricular arrhythmia on 24 hour ambulatory electrocardiographic recordings was comparable on recordings obtained in a prestudy screening, during treatment with placebo before administration of NAPA and after treatment with NAPA. The initial dosage of NAPA was 500 mg every 8 hours, which was increased by 500 mg increments every few days until 90 percent suppression of arrhythmia or intolerable adverse effects occurred. Only two patients achieved 90 percent suppression of ventricular ectopic complexes. The mean plasma concentration associated with 90 percent suppression of arrhythmia in these two patients ws 12.6 and 32.3 mg/ml, respectively. One of these two patients was unable to continue long-term therapy with NAPA because of a rash. Other adverse effects included gastrointestinal symptoms in seven patients with visual symptoms in four patients at plasma concentratons as low as 6.9 mg/ml. NAPA obeyed linear pharmacokinetics over the range of dosages studied (500 to 2,500 mg every 8 hours) and had a half-life of 10.7 +/- 1.98 hours (mean +/- standard deviation). There was no change in the P-R or QRS intervals and there was a dose-dependent prolongation of the Q-Tc interval. It is concluded that in this patient group, NAPA suppressed chronic ventricular ectopic complexes without adverse effects in only a minority of patients.

Dose-dependent acebutolol disposition after oral administration

The relationship between dose and area under the blood concentration‐time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

Acebutolol disposition after intravenous administration

The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 mllmin/kg and the mean renal clearance, 2.68 mllmin/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two‐compartment model. The mean fast and slow half‐lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady‐state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15‐min infusions were used to predict plateau blood concentrations with good accuracy during an 8‐hr dosage regimen.

Electrophysiologic effects of N-acetylprocainamide in human beings☆

The electrophysiologic properties of N-acetylprocainamide (NAPA) were studied in 10 patients undergoing cardiac catheterization. Each patient received two successive intravenous infusions: one loading infusion over 15 minutes and one maintenance infusion at a slower rate for 30 minutes. Eight patients received 10.5 mg/kg body weight and two received larger doses (16 and 21 mg/kg, respectively). NAPA plasma concentration was measured at 5 minute intervals from 0 to 25 minutes, and then at 15 and 30 minutes of the second infusion. Mean blood pressure and electrophysiologic data obtained by programmed stimulation were recorded before drug administration and at 15 and 30 minutes of the infusion when the concentration of NAPA was nearly constant in each patient (range 12 to 35 microgram/ml). NAPA decreased blood pressure (p less than 0.005), increased corrected Q-T interval (p less than 0.01) and increased the atrial and ventricular effective refractory periods from 267 +/- 40 to 307 +/- 41 ms (p less than 0.01) and from 278 +/- 37 to 301 +/- 32.8 ms (p less than 0.05), respectively. NAPA did not significantly change sinus cycle length or sinus nodal recovery time, conduction intervals (A-H, H-V, P-R, QRS), atrioventricular nodal functional refractory period or nodal Wenckebach cycle length. The patient receiving the largest dose experienced mild nausea when the plasma concentration was above 35 microgram/ml. These data show that the electrophysiology of NAPA in human beings is different from that reported for procainamide. At the plasma concentrations studied NAPA increases atrial and ventricular refractory periods without increasing cardiac conduction times

Characterization of ventricular tachyarrhythmias on ambulatory ECG recordings in post-myocardial infarction patients: Arrhythmia detection and duration of recording, relationship between arrhythmia frequency and complexity, and day-to-day reproducibility*

We performed three consecutive 24-hour ECG recordings in 57 ambulatory patients approximately 8 to 11 days of post-myocardial infarction. There was considerable additional detection of each type of complex ventricular ectopic beat (VEB) with recordings beyond 24 hours. Multiform, R-on-T, pairs, and bigeminy were often first detected from 24 to 48 hours and 5 of 12 patients with ventricular tachycardia had this rhythm detected only after 48 hours of monitoring. Complex forms were deleted with short recording durations primarily in patients who had complex forms present during a large number of hours during the 72-hour recording session. The occurrence of each type of complex ectopic beat was strongly related to PVC frequency and some type of complex form was seen in virtually all 24-hour recordings with greater than a total of 100 VEBs. Sixty-five percent of 24-hour recordings with infrequent VEBs (2 to 10 per 24 hours) also had complex forms present. The day-to-day reproducibility of VEB frequency and complexity was reasonable, but was largely accounted for by the fact that most recordings were free of frequent ectopic beats and a given type of complex PVC. These data suggest that for longer ECG recording period, the frequency of occurrence of complex forms rather than simply their presence or absence may be important for identifying high risk subgroups.

Acute hemodynamic effects of intravenous encainide in patients with heart disease

Encainide, a new antiarrhythmic drug, was given intravenously (0.9 mg/kg) to 18 patients over 15 minutes to evaluate the hemodynamic effects. Hemodynamics and drug plasma concentrations were measured during and 30 minutes postdrug infusions. Encainide infusion was associated with a decrease in cardiac index from 2.6 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than .05), a significant decrease in stroke work index and left ventricular end-diastolic pressure, and with a rise in systemic vascular resistance. There was no change in systemic or pulmonary arterial pressure, left ventricular dp/dt, or pulmonary vascular resistance. The patients were studied 30 to 60 minutes after cardiac angiography. Comparison of hemodynamic values obtained preangiography with those obtained postangiography (before, during, and after drug infusion) strongly suggests that many of the observed effects were due to radiographic contrast media (initial osmotic volume loading and subsequent diuresis). We conclude that if encainide has any significant hemodynamic effects after intravenous use, it is a modest decrease in cardiac output, possibly as a result of decreased left ventricular filling pressure.