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PubMed1994

The pharmacokinetics and pharmacodynamics of procainamide in horses after intravenous administration.

Six horses were administered either 15 or 20 mg/kg body weight (b.w.) procainamide (PA) as an intravenous (i.v.) dose over 10 min. The plasma concentrations of PA and N-acetylprocainamide (NAPA) as well as the pharmacodynamic effect (prolongation of the QT interval) were monitored. The PA plasma concentrations could be described by a one-compartment model with a t1/2 of 3.49 +/- 0.61 h. The total body clearance of PA was 0.395 +/- 0.090 l/hr/kg and the volume of distribution was 1.93 +/- 0.27 l/kg. As observed after PA administration, NAPA (an active metabolite) had a t1/2 longer than PA of 6.31 +/- 1.49 h. Peak NAPA concentrations (1.91 +/- 0.51 micrograms/ml) occurred at 5.2 h after the PA i.v. dose. The ratio of area under the curves for NAPA to PA was 0.46 +/- 0.15 which is similar to that expected in humans classified as slow acetylators. Percentage change in the QT interval was examined with respect to PA and PA + NAPA plasma concentrations. For PA, % delta QT = 41.2 log (PA) - 13.26 and correlations (r) ranged from 0.77 to 0.91 among the horses. In the case of PA+ NAPA, % delta QT = 57.3 log (PA + NAPA) - 31.83 and ranged from 0.77 to 0.90. No evidence of toxicity was noted with respect to changes in the PR interval.

Acecainide↗
PubMed1995

Effects of the pacing site, procainamide, and lead configuration on the relationship between the upper limit of vulnerability and the defibrillation threshold.

In six open chest dogs, we determined the upper limit of vulnerability (ULV) and defibrillation threshold (DFT) by an up-down algorithm when the pacing site was at the right atrium, at the left ventricular apex, and at the left ventricular base. Monophasic shocks (6 ms) were given to epicardial patches at 20 and 40 ms before the peak of the T wave to bracket the mid-upslope. In an additional six closed-chest dogs, we determined the ULV and the DFT with transvenous leads with an 8-ms biphasic waveform. The S1 pacing site was at the right ventricular apex and the right atrium, and the shocks were given at 20 ms and 40 ms before the peak of the T wave, and on the peak of T wave. The same test was repeated after intravenous procainamide infusion (20 mg/Kg loading, then 2 mg/min maintenance). In the first six dogs, the ULV determined when pacing was given to the left ventricular apex, the left ventricular base, and the right atrium was 4.2 +/- 1.7 J, 4.4 +/- 2.1 J, and 3.9 +/- 1.5 J, respectively; values that were not significantly different from the DFT of 4.8 +/- 1.9 J, 4.5 +/- 1.9 J, and 4.2 +/- 1.3 J, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1998

Effects of procainamide on the excitable gap composition in common human atrial flutter.

The composition of the excitable gap (EG) in common atrial flutter (AF1) was determined before and during infusion of procainamide (PA) in 9 patients (6 men and 3 women; age 70 +/- 7 years). The EG was determined by introducing a premature stimulus after every 20th AF1 complex detected using a quadripolar electrode catheter placed just above the tricuspid valve. Diastole was scanned in 2- to 4-ms decrements to the atrial effective refractory period (ERP). The relationship between the coupling interval and the return cycle length (CL) determined a reset-response curve (RRC), which described the EG. PA (15 mg/kg) was administered during AF1 over 30 minutes and RRC was repeated at maximum AF1 CL. PA prolonged AF1 CL from 227 +/- 29 to 296 +/- 62 ms (P < 0.01) but did not terminate AF1. ERP during AF1 prolonged from 169 +/- 24 to 219 +/- 41 ms (P < 0.01). Control EG was 57 +/- 16 ms or 25% +/- 6% of AF1 CL and on PA EG was 77 +/- 30 ms (P = 0.01), which was still 26% +/- 7% of the CL. Without drug, RRC was mixed in eight cases demonstrating an EG composed of fully excitable tissue (10 +/- 4 ms or 19% +/- 10% of the EG) and partially refractory tissue (48 +/- 18 ms). PA did not change the duration of the fully excitable region (13 +/- 10 ms or 19% +/- 15% of EG). Peak PA plasma concentration was 47 +/- 20 mumol/L. PA prolonged AF1 CL, ERP, and EG duration but did not change the proportion of AF1 CL occupied by the EG. The persistance of fully excitable tissue at the head of the wavefront in the presence of PA may largely explain its inefficacy in the acute termination of common AF1.

Aged↗
PubMed1984

Procainamide: clinical pharmacology and efficacy against ventricular arrhythmias.

Procainamide (PA) has been a mainstay of treatment against acute and chronic supraventricular and ventricular arrhythmias for more than 30 years. PA's clinical pharmacology has been studied extensively and its bioavailability (75-95%); volume of distribution (1.5-2.5 liters per kg), plasma protein-binding (15-25%), half-time for elimination (3-7 hours), and metabolism are known. PA's efficacy against acute ventricular arrhythmias and chronic stable VPDs is associated with plasma drug concentrations of 4 to 10 micrograms per ml; but much higher plasma concentrations may be required against sustained ventricular arrhythmias. From 30 to 60% of a PA dose is excreted as the metabolite, N-acetylprocainamide (NAPA), and PA's metabolism is determined genetically (fast or slow acetylation phenotype). Studies in patients with VPDs indicate that NAPA is also antiarrhythmic, although the contribution of NAPA to the antiarrhythmic effect after PA is not known. Studies in patients with the systemic lupus-like syndrome from PA show that NAPA is not associated with this. Investigations comparing efficacy and adverse effects of PA with those of new antiarrhythmic agents available for clinical trials are indicated in the future.

Acecainide↗
PubMed1986

Effect of acute renal failure on the disposition and elimination of [3H]N-acetyl procainamide ethobromide in the rat.

The effect of glycerol-induced acute renal failure (ARF) on the disposition and elimination of the organic cation [3H]N-acetyl procainamide ethobromide (APAEB) was investigated in the rat. In rats with ARF the plasma clearance, rate constant for the terminal portion of the plasma concentration-time curve and apparent volume of distribution were all decreased (P less than 0.01). Furthermore, the renal clearance of APAEB and the percentage dose excreted in urine were reduced by 85 and 74%, respectively. Decreased renal excretion probably accounted for the altered kinetics of APAEB in ARF because ligation of the renal pedicles of control rats produced changes in the kinetics of APAEB that were similar to those seen in animals with ARF. No change in either the hepatic content of APAEB or its biliary excretion were detected in rats with ARF. Similarly, the hepatic handling of ouabain and taurocholic acid was previously found to be unaltered in ARF; but by contrast, the hepatic uptake and initial biliary excretion of bromosulphophthalein and indocyanine green were decreased (Bowmer & Yates 1984, Br. J. Pharmacol. 83: 773-782). Together these studies indicate that there is a selective impairment of hepato-biliary transport in ARF.

Acecainide↗
PubMed1977

Wolff-Parkinson-White syndrome. Circus movement tachycardia dependent on procainamide.

A patient with Wolff-Parkinson-White syndrome was disabled by rapid ventricular rates during atrial arrhythmia and by periods of asystole. Circus tachycardia was induced by atrial stimulation only after the administration of procainamide. Nevertheless, treatment with this drug controlled the ventricular rate and spontaneous circus tachycardia did not occur.

Electric Stimulation↗
PubMed1979

Effect of coadministration of procainamide and isoniazid on each other's acetylation pathway.

The effect of isoniazid (INH) and procainamide (PA) on each other's acetylation pathway was studied in 7 normal subjects (3 rapid acetylators, 3 slow acetylators, 1 of indeterminate phenotype). Oral PA (6 mg/kg) was administered every 4 h for a total of seven doses. Following the final dose subjects received a single 300-mg oral dose of INH. Analysis of the parent drugs and their acetylated metabolites in plasma and urine revealed no effect on the acetylation of either drug. In 2 subjects (1 rapid, 1 slow acetylator) increasing doses of PA were given and the effect on INH (300 mg) acetylation measured. High mean circulating levels of PA (7.1 microgram/ml) appeared to inhibit acetylation of INH in the rapid acetylator whereas a mean PA plasma level of 8.6 microgram/ml had no effect on INH acetylation in the slow acetylator. However, the results from this study suggest that alterations of INH acetylation by PA are unlikely to be of clinical significance.

Administration, Oral↗
PubMed1989

Local anesthetics (benzyl alcohol, lidocaine, procainamide) inhibit aminopyrine accumulation in isolated rat parietal cells.

The present studies were designed to examine the effect of local anesthetics (benzyl alcohol, lidocaine, and procainamide) on the secretory response of parietal cells to histamine, dbcAMP, and carbachol. Studies were performed in vitro using isolated cells from rat stomachs, and acid production was determined by 14C-aminopyrine accumulation. In addition, the (H(+)-K+)-ATPase activity of microsomal vesicles isolated from parietal cells was determined. Lower concentrations of the drugs studied increased the basal aminopyrine accumulation and potentiated the secretory response of parietal cells to histamine and dbcAMP. At higher concentrations local anesthetics progressively inhibited both the basal 14C-aminopyrine accumulation and that stimulated by histamine, dbcAMP or carbachol. While a low concentration of local anesthetics increased gastric microsomal (H(+)-K+)-ATPase activity, higher concentrations inhibited enzyme activity to about 80% of those activities found in resting parietal cells. We conclude that increased aminopyrine accumulation may reflect the activation of membrane-bound enzyme(s) involved in the cAMP-dependent signal transduction pathway mediating acid secretion by parietal cells. In turn, it is possible that the inhibition of aminopyrine accumulation by local anesthetics at higher concentrations can relate to two different mechanisms: (1) the nonspecific effect of local anesthetics that causes simple proton neutralization (as weak bases), and (2) to a minor extent their inhibitory effect on proton pump activity.

Adenosine Triphosphatases↗
PubMed1982

Procainamide and retrograde atrioventricular nodal conduction in man.

Recent studies that show a depressant effect of procainamide (PA) on retrograde conduction in patients with atrioventricular (AV) nodal reentrant tachycardia (RT) have suggested possible incorporation of AV nodal bypass tracts. Electrophysiologic effects of i.v. PA, 10 mg/kg, on retrograde AV nodal conduction were examined in 13 patients without RT, demonstrable AV nodal refractory period curves, or accessory pathways. Ventriculoatrial (VA) conduction was recorded before and after PA using intracardiac electrograms, incremental ventricular pacing and extrastimulation. With incremental pacing during the control, VA block occurred at a mean cycle length (CL) of 364.6 +/- 87.9 msec. After PA, VA conduction was abolished in five of 13 patients due to onset of retrograde block in the AV node; in seven of 13, VA block occurred at a longer paced CL after PA (344.2 +/- 51.2 msec vs 477.1 +/- 93.2 msec). In one patient, PA did not affect VA conduction. PA invariably produced prolongation in the VA interval at comparable CL of pacing. With ventricular premature stimulation, the retrograde H2A2 intervals during the control period were short (less than 50 msec) in seven of 13, intermediate (60-100 msec) in three of 13 and long (greater than 100 msec) in three of 13 cases. PA either abolished H2A2 conduction (H2 but no A2) or prolonged the H2A2 intervals by 5-20 msec in most cases in this series. The data suggest that i.v. PA almost uniformly depresses retrograde AV nodal conduction in the intact human heart. This depressant response to PA is not indicative of presence of partial or complete AV nodal bypass tracts.

Aged↗
PubMed1993

Genetic, immunologic and biotransformation studies of patients on procainamide.

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Aged↗
PubMed1993

Effect of procainamide and hydralazine on poly (ADP-ribosylation) in cell lines.

The prescription drugs procainamide (PA) and hydralazine (HYD) are associated with the induction of autoimmunity and a clinical syndrome called drug-induced lupus. Since PA- and HYD-induced autoantibodies are directed primarily against histones and histones are prime acceptors of poly (ADP-ribose) (PADPR), we have investigated the effects of PA and HYD on the activity of poly (ADP-ribose) polymerase (PADPRP). Control substances, with structures similar to PA and HYD but not known to induce lupus, included N-acetylprocainamide (NAPA) and the amino acids phenylalanine, tryptophan and proline, and their amide derivatives. Wil-2 cells were incubated in 0.5-50 microM PA, NAPA and HYD, which included therapeutic concentrations of these drugs. The mean enhancement of incorporation of [3H]-nicotinamide adenine dinucleotide (NAD) into PADPR was 1.84 (P = 0.005) with PA, with HYD 1.48 (P = 0.029), and with NAPA 1.38 (P = 0.036). This increase was suppressed by 3-aminobenzamide, an inhibitor of PADPRP activity. Little or no increase in [3H]-NAD incorporation was observed with equivalent concentrations of phenylalanine, phenylalaninamide or tryptophan. However, a 1.29-fold increase was noted with 0.5 microM tryptophanamide, a 1.26-fold increase with 0.5 microM prolinamide and a 1.4-fold increase with 50 microM proline. PA increased PADPRP activity in B- and T-cell lines but not in promyelocytic leukemia or epithelial cell lines. Since poly (ADP-ribosylation) is important in the cellular response to various agents, the increased ADP-ribosylation of intracellular molecules may be a key event in the induction of autoantibodies.

Acecainide↗
PubMed1983

High-dose procainamide in chronic renal failure.

A patient with chronic renal failure who experienced symptomatic ventricular tachycardia was treated successfully with procainamide (PA) after numerous dosage adjustments to optimize his clinical response and serum PA and NAPA concentrations. Efforts to maintain total combined serum levels at 20-30 micrograms/ml led to sustained ventricular ectopy whenever the serum PA levels decreased to less than 8 micrograms/ml.

Adult↗
PubMedDate not supplied

Procainamide disposition in obesity.

The pharmacokinetics of intravenous procainamide (PA) were studied in seven obese and seven normal subjects. Serum concentrations and urinary excretion rates of PA and its active metabolite, NAPA, were measured by high performance liquid chromatography. Pharmacokinetic parameters were related to ideal body weight (IBW) and total body weight (TBW). The volume of distribution at steady state (Vssd) was similar for both groups when based per unit of IBW. Plasma clearance of PA, corrected for body surface area, was greater in obese subjects when adjusted for IBW, but similar on the basis of TBW. For its components, metabolic and renal clearance, the obese subjects showed similar metabolic clearances, but a significant increase was found in renal clearance per unit of body surface area based on both IBW (normal mean, 11.9 L/h/m2; obese, 19.0 L/h/m2) and TBW (normal mean, 11.7 L/h/m2; obese, 15.7 L/h/m2). This appears to be due to increased tubular secretion of PA in the obese group. In contrast, these subjects had lower renal clearances of NAPA. Variability in disposition of PA may, thus, be affected by patient physiology and method of parameter normalization.

Acecainide↗
PubMed1991

Therapeutic monitoring and pharmacokinetic evaluation of procainamide in neonates.

Past experience with the disposition of procainamide hydrochloride (PA) in neonates is restricted to a single case study involving placental transfer. We studied aspects of PA pharmacokinetics in three neonates who received constant-rate infusion therapy. Results indicated that the total serum clearance of PA is similar to the adult value, but elimination half-lives of both PA and N-acetylprocainamide (NAPA) were slightly prolonged and volume of distribution was variable. Pharmacokinetic evaluations in a renally compromised neonate confirmed that total PA clearance and the renal clearance of both PA and NAPA were reduced, although not to the extent expected for the degree of renal impairment. Peritoneal dialysis was used concurrently and may have contributed to the elimination process. We believe that our experience provides important preliminary guidelines for the management of PA therapy in neonates.

Anti-Arrhythmia Agents↗
PubMed1981

Pharmacokinetic study on saturated hepato-biliary transport of acetyl procainamide ethobromide.

Pharmacokinetic analysis of plasma concentration of acetyl procainamide ethobromide (APAEB) after single injection of 1.5, 8.8 and 20 mumol/300 g rat of APAEB showed that its elimination from plasma followed saturation kinetics. The existence of saturable step in transport of APAEB from blood to bile was also evident from the data of the biliary excretion at three dose levels. The data of the biliary excretion were well fitted to two compartment model with two saturable processes at the hepatic uptake and the biliary excretion. The Michaelis-Menten parameters were calculated according to that model. The model was also applicable to the data of biliary excretion obtained by constant infusion of APAEB Simulation of liver and plasma content gave a good agreement to the experimental data. All these results indicate that the pharmacokinetics of APAEB is satisfactorily represented by the proposed model.

Acecainide↗
PubMed1977

Lupus erythematosus cells in pleural effusion: the initial manifestation of procainamide-induced lupus erythematosus.

A 63-year-old man developed an asymptomatic pleural effusion following the administration of 500 gm of procainamide hydrochloride over a six-month period. The diagnosis was initially suggested by the finding of lupus erythematosus cells in the pleural fluid. Lupus erythematosus cells and antinuclear antibodies appeared in the blood two months later and remained for a period of six months. The diagnosis was corroborated by the presence of antibodies to denatured DNA, but not to native DNA.

Antibodies, Antinuclear↗
PubMed1978

Procainamide-induced left anterior hemiblock of the 2:1 type (pseudoelectrical alternans).

A selective defect in cardiac conduction in the anterior division of the left bundle branch was induced in a patient by therapy with procainamide hydrochloride. The defect in conduction, when intermittent, resulted in 2:1 Wencklebach sequences and produced a pattern similar to classic electrical alternans. The prognosis in drug-induced alternans is good, and it is important to differentiate it from true electrical alternans.

Aged↗