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PubMed1982

N-Acetylprocainamide kinetics after single and repeated oral doses.

The kinetic behavior of N-acetylprocainamide (NAPA) was studied after single and repeated oral doses in six healthy subjects and five patients with cardiomyopathy. Renal clearance (CLR) of NAPA was lower in patients than in normal subjects after an initial 1-gm dose (1.3 +/- 0.4 [x +1- SD] and 2.7 +/- 0.4 ml . min-1 . kg-1, P less than or equal to 0.001) and a final 2 gm dose (1.6 +/- 0.4 and 2.6 +/- 0.5 ml . min-1 . kg-1, P less than or equal to 0.01) even though there was no difference between measured creatinine clearance (ClCR) 80.8 +/- 23.6 and 93.2 +/- 19.3 ml . min-1 [1.73 M2]-1). The decrease in the ratio of NAPA ClR to ClCR (R) could not be accounted for by age alone. A published regression formula overestimated the R ratio for patients (1.65 +/- 0.09 and 1.25 +/- 0.17, P less then 0.025), but accurately predicted the R ratio for healthy subjects (2.10 +/- 0.04 and 1.99 +/- 0.54). Mean steady-state concentration (normalized for daily dose per unit of body mass) after 2 gm every 8 hr for at least 3 days was higher for patients (P less than or equal to 0.05). Comparing the parameters for all subjects after the initial 1-gm dose to those after the last 2-gm dose with paired data, oral clearance was somewhat lower after the last dose (3.7 +/- 1.0 and 3.1 +/- 1.0 ml . min-1 . kg-1, P less than or equal to 0.01). In spite of this, before and 2 hr after dose steady-state NAPA serum concentration were generally proportional to dose over the concentration range studied. Net deacetylation of NAPA to procainamide in both groups was minimal.

Acecainide↗
PubMed1982

Hemodynamic effects of N-acetylprocainamide in heart disease.

In six normal subjects and 6 patients with primary cardiomyopathy, left ventricular performance was evaluated at rest and during isometric handgrip exercise after 4 days of oral N-acetylprocainamide (NAPA) at each of the three dosage levels (3, 4, 5, and 6 gm/day). Changes in heart rate, blood pressure, and echocardiographic performance indices were noted during isometric exercise, but no effect of NAPA could be demonstrated. In five additional patients with ventricular dysrhythmias due to cardiac diseases, NAPA was given by vein until dysrhythmias were controlled and then a maintenance infusion was continued for 48 hr. Continuous ECG recordings showed excellent dysrhythmia control in four of the five patients, but no effect of NAPA on heart rate, blood pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, or cardiac output was demonstrated, either at the peak of initial infusion (serm NAPA 27 +/- 6.7 microgramsm/ml) or at steady state during the maintenance infusion (16 +/- 4.5 microgramm/ml). We conclude that NAPA by vein and mouth in clinically appropriate doses should be safe in patients with the reduced left ventricular performance due to cardiac disease.

Acecainide↗
PubMed1983

Efficacy and safety of N-acetylprocainamide in long-term treatment of ventricular arrhythmias.

Four patients with chronic ventricular arrhythmias, shown to respond over the short term to N-acetylprocainamide (NAPA), were treated for between 3 and 4 yr with NAPA, and 24-hr ambulatory ECGs were obtained monthly to monitor their responses. When the patients were ambulatory and receiving NAPA, the mean frequency of premature ventricular complexes averaged 70% (range 60% to 82%) below that recorded at 6-mo intervals when the patients were hospitalized and receiving placebo. Analysis of variance showed that NAPA exerted an antiarrhythmic effect in these patients and that tolerance to this effect did not develop with long-term therapy. Plasma NAPA concentrations required to achieve this level of response averaged 21 micrograms/ml (12 to 35 micrograms/ml) and were roughly twice as high as those which appeared to be maximally effective when the patients were hospitalized for their initial evaluation. NAPA therapy was associated with positive antibody titers in only one patient and seems less prone to cause drug-induced lupus erythematosus than procainamide, but NAPA shares the gastrointestinal and other side effects of procainamide.

Acecainide↗
PubMed1984

Cimetidine inhibits renal procainamide clearance.

Procainamide and cimetidine are eliminated in large part by the kidneys. Both are secreted by an active transport mechanism in the proximal tubule and each inhibits secretion of the other in the isolated, perfused rabbit tubule. In this study in man, cimetidine inhibited renal clearance of oral procainamide by 36%. This was associated with a 28% decrease in the ratio of systemic clearance of procainamide to bioavailability, an 18% decrease in the elimination rate constant, and a 24% prolongation of elimination t1/2. These results suggest that cimetidine increases plasma t1/2 and decreases systemic clearance of procainamide in part by inhibiting its active secretion by the kidneys.

Acecainide↗
PubMed1987

Food-induced gastric retention and absorption of sustained-release procainamide.

The relationship between variations in the gastric residence time and the absorption of procainamide from a waxed matrix, sustained-release tablet was evaluated in a repeated-measures study conducted in eight healthy men. Subjects received sustained-release procainamide together with a Heidelberg capsule, alone and with food. Blood and urine samples were collected for up to 24 hours before and after gastric emptying of the Heidelberg capsule for procainamide and N-acetylprocainamide concentration determinations. The gastric residence time of the Heidelberg capsule was prolonged by food (median 3.5 [range 1.5 to 10.0] vs. 1.0 [range 0.5 to 2.5] hours; P less than 0.02). No significant differences (median [range]; fasting vs. fed) in procainamide lag time (0.5 [0.5 to 1.0] vs. 0.5 [0.5 to 1.5] hours) or time at which peak procainamide plasma concentrations occurred (2.9 [1.0 to 4.3] vs. 2.8 [2.0 to 6.0] hours) were evident with feeding. Slight increases in procainamide AUC and peak concentrations occurred with feeding. No alteration in the extent of urinary excretion of procainamide or N-acetylprocainamide occurred with feeding. Thus food did not influence the absorption of sustained-release procainamide despite apparent prolonged gastric retention.

Acecainide↗
PubMed1987

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation.

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.

Acecainide↗
PubMed1988

Trimethoprim alters the disposition of procainamide and N-acetylprocainamide.

The steady-state pharmacokinetics and pharmacodynamics of procainamide and its active N-acetyl metabolite (NAPA) were assessed alone and in combination with trimethoprim. Eight healthy men received oral sustained-release procainamide, 500 mg every 6 hours for 3 days, alone and with oral trimethoprim, 200 mg daily for 4 days. Concomitant trimethoprim significantly increased the plasma AUC(0-12) of both procainamide and NAPA (63% and 52%, respectively), with concurrent decreases in their renal clearances (47% and 13%, respectively) and a 39% increase in the mean urinary recovery of NAPA (as percentage of procainamide and NAPA recovery). After trimethoprim coadministration, there was also a trend toward a decrease in the apparent acetylation clearance of procainamide (19%, p = 0.057). The change in procainamide and NAPA renal clearances after trimethoprim coadministration strongly correlated with their baseline renal clearances (r = 0.84 and r = 0.74, respectively, p less than 0.0001). There was small but significant increase in the corrected QT interval with procainamide administration, which increased further with trimethoprim coadministration. We conclude that trimethoprim increases the plasma concentrations of procainamide and NAPA by decreasing their renal clearances and allowing more conversion of procainamide to NAPA.

Acecainide↗
PubMed1989

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

Absorption↗
PubMed1988

Metabolites of procainamide and practolol inhibit complement components C3 and C4.

Drug-induced systemic lupus erythematosus arises from toxic side-effects of administration of hydralazine, isoniazid, procainamide and practolol. Hydralazine and isoniazid are nucleophilic drugs and inhibit the covalent binding reaction of complement components, C3 and C4, an effect likely to lead to deposition of immune complexes (a feature of systemic lupus erythematosus). Procainamide and practolol do not themselves inhibit C3 and C4. A range of metabolites and putative metabolites of procainamide and practolol were synthesized, and tested for their ability to inhibit the covalent binding reactions of C3 and C4. The highly nucleophilic hydroxylamine metabolite of procainamide was strongly inhibitory in both tests, as was a putative hydroxylamine metabolite of practolol. These studies indicate a potential role for the hydroxylamine metabolites in mediating the toxic side-effects of procainamide and practolol, and emphasize the need for adequate measurements of hydroxylamine metabolites in human tissue.

Acecainide↗
PubMed1998

Cardiac anticholinergic effects of procainamide and its N-acetylated metabolite: experimental pharmacological and radioligand binding studies.

1. The cardiac anticholinergic effects of procainamide (1 mg kg(-1) min(-1)) and its N-acetylated metabolite (NAPA) at equimolar dose (1.16 mg kg(-1) min(-1)) were studied using in vivo experimental pharmacological and in vitro radioligand binding studies. 2. Procainamide and NAPA progressively reduced vagal stimulation-induced bradycardia in chloralose-anaesthetized dogs. As indicated by the ED50, the vagolytic activity of NAPA is 1.5-2.0 times weaker than that of procainamide. Both drugs increased heart rate, with lowering of mean blood pressure during the second part of procainamide infusion, but not during NAPA infusion. 3. Binding studies on rat heart membranes yielded Ki values that were 1.5 times higher for NAPA than for procainamide. 4. These results show that NAPA exerts a weaker cardiac vagolytic action than procainamide, which is probably linked to a lower ability to bind to cardiac muscarinic receptors.

Acecainide↗
PubMed1982

Development of Fluoroimmunoassays for the determination of individual or combined levels of procainamide and N-acetylprocainamide in serum.

A fluoroimmunoassay has been developed for the simultaneous determination of serum levels of procainamide and its active metabolite N-acetylprocainamide. It employs procainamide linked through its aromatic amino group to fluorescein isothiocyanate as tracer and an antiserum raised against procainamide conjugated to human thyroglobulin through the same position. Separation is rapidly and simply achieved by covalently linking the antiserum to magnetisable microparticles and use of a magnet. Specific magnetisable particle fluorimmunoassays were also developed for procainamide and for N-acetylprocainamide by the use of suitable immunogens and fluorescein-labelled tracers. That for procainamide uses an antiserum raised to a procainamide-enzyme conjugate and fluorescein-labelled p-aminobenzoic acid while the fluoroimmunoassay for N-acetylprocainamide employs an antiserum against a N-acetylprocainamide-enzyme conjugate and fluorescein-labelled p-acetamidobenzoic acid.

Acecainide↗
PubMed1998

Improved high-performance liquid chromatographic assay for the determination of procainamide and its N-acetylated metabolite in plasma: application to a single-dose pharmacokinetic study.

An improved high-performance liquid chromatographic assay for the determination of procainamide and N-acetylprocainamide (NAPA) at concentrations observed up to 32 h after a single oral dose administration of procainamide to human subjects is reported. Following liquid-liquid extraction of plasma samples, procainamide, NAPA, and the internal standard (N-propionylprocainamide) are separated on a reversed-phase C8 column with retention times of 4.0, 6.7, and 13.2 min, respectively. The ultraviolet detection limit (wavelength, 280 nm) of procainamide and NAPA is 2 ng/mL (signal-to-noise ratio, 3:1), and the quantitation limit is 4 ng/mL (signal-to-noise ratio, 5:1). Intra- and interday coefficients of variation are less than 8% in the range of 20-500 ng/mL.

Acecainide↗
PubMed1981

N-acetylprocainamide induced changes in refractoriness and monophasic action potentials of the dog heart in situ.

The major metabolite of procainamide (PA) is N-acetylprocainamide (NAPA). The effect of this drug on the electrophysiology of the right ventricle was studied in the dog heart in situ by means of programmed electrical stimulation and monophasic action potential (MAP) recordings. A decrease in the beat interval caused a progressive decrease in refractoriness and MAP duration. Intravenous injection of NAPA 50 mg.kg-1 body weight increased refractoriness to a greater extent than MAP duration at shorter, while the opposite was observed at longer beat intervals. These observations are compatible with delayed recovery of excitability. On the basis of these findings, it is concluded that NAPA belongs to antiarrhythmic drugs of type I according to Vaughan Williams' classification, and NAPA may be an alternative drug for treatment of cardiac arrhythmias.

Acecainide↗
PubMedDate not supplied

Propylene glycol as a vehicle for percutaneous absorption of therapeutic agents.

Propylene glycol (PG) was evaluated as a vehicle for the in vivo percutaneous absorption of the hydrochloride salts of desipramine, nortriptyline, procainamide, and N-acetyl-procainamide. Each drug was administered topically to hairless (hr-1/hr-1) mice in water and in aqueous 10% and 50% PG. Mean drug concentrations in blood, brain, heart, liver, and lung were measured by high-pressure liquid chromatography after either two or three hours of topical absorption. The presence of PG generally enhanced the absorption of each drug, and the degree of enhancement appeared to be related to the percentage of PG in the dosing solution.

Acecainide↗