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PubMedDate not supplied

Improved semi-automated analysis of procainamide and N-acetyl procainamide utilizing a totally volatile mobile phase.

A semi-automated technique has been devised for the analysis of the antirhythmic drugs, procainamide (PA) and N-acetyl procainamide (NAPA) from human serum. Reverse-phase high-performance liquid chromatographic (HPLC) separations were performed by means of an autoinjector system in combination with microBondapak C18 column. A mobile phase containing only volatile buffers (e.g., triethylamine-acetic acid or N-ethyl morpholine-acetic acid) at apparent pH 5.3 was necessitated to prevent the buildup of salt residues on the valves and fittings within the autoinjector and high pressure pump. For HPLC analysis of these drugs, the within-run precision, as estimated by coefficient of variation analysis, was less than 9%. Comparable precision was shown for day-to-day variation in analysis. No interference was noted from 20 other substances, metabolites or drugs that might be present in the sera extracts. This semi automated procedure has been utilized successfully to quantitate over 200 patient sera on a bach or emergency basis.

Acecainide↗
PubMedDate not supplied

Enzyme immunoassay, liquid chromatography, and spectrofluorometry compared for the determination of procainamide and N-acetylprocainamide in serum.

Procainamide, an antiarrhythmic drug, and its biologically active metabolite, N-acetylprocainamide, were quantitated in serum by a commercially supplied enzyme immunoassay procedure. Replicate analyses of controls resulted in within-assay and between-assay coefficient of variation (CV) of less than 10%. Regression analyses of serum samples analyzed by immunochemical (y) and chromatographic or spectrofluorometric methods (x) gave equations with a slope of 0.99 to 1.11, y-intercept of -0.52 to -0.02, and correlation coefficient greater than 0.92. Clinical evaluation of the results indicates the respective enzyme immunoassay to be specific and sensitive for procainamide and N-acetylprocainamide. Immunochemical selectivity of the respective assay was quantitated by challenging the assay with other drugs. When the antibody reagent was crossreactive toward the other drugs, selectivity was determined to be inversely related to the concentration of the other drug.

Acecainide↗
PubMedDate not supplied

An HPLC method for the simultaneous quantitation of quinidine, procainamide, N-acetylprocainamide, and disopyramide.

A high performance liquid chromatographic method is reported, which incorporates three internal standards (I-cinchonidine, N-propylprocainamide, and para-chlorodisopyramide) for the simultaneous quantitation of four commonly prescribed antiarrhythmic drugs: quinidine, procainamide, N-acetylprocainamide, and disopyramide. Compounds were separated using combined ion-pairing and adsorption chromatography on a silica column. Inter-run variation was 5.9 CV% for all drugs.

Acecainide↗
PubMedDate not supplied

Kinetic analysis of the vasodilator and ganglionic blocking actions of N-acetylprocainamide.

The hypotensive effects of N-acetylprocainamide (NAPA) were studied in anesthetized dogs and in a normal subject. In dogs, intravenous NAPA infusions reduced mean arterial pressure and the pressor response of the isolated, perfused gracilis muscle vascular bed to preganglionic, but not postganglionic, sympathetic stimulation. The kinetics of these effects were correlated with NAPA pharmacokinetics. The time course of NAPA concentrations in a hypothetical biophase was characterized, and the relationship between NAPA biophase concentrations and the intensity of the effects was determined. From these results, it was estimated that peak effects would occur in dogs 6.6 min after intravenous bolus injection of NAPA, and that biophase NAPA concentration would lower mean arterial pressure 0.39 mm Hg/microgram/ml and would attenuate by 0.224 mm Hg/microgram/ml the gracilis muscle vascular bed pressor response to preganglionic stimulation. In the normal subject, a similar analysis indicated that maximal hypotension would occur 8.0 min after intravenous NAPA injection, and that blood pressure would fall 0.40 mm Hg/microgram/ml relative to biophase NAPA concentrations. These results suggest that blood pressure should be monitored for at least 10 min after patients receive and intravenous NAPA injection, and that repeated NAPA doses probably should not be administered more frequently.

Acecainide↗
PubMedDate not supplied

Comparative vagolytic effects of procainamide and N-acetylprocainamide in the dog.

Procainamide exerts vagolytic effects which are deleterious in clinical therapy for supraventricular arrhythmias. The purpose of the present study was to determine if N-acetylprocainamide (NAPA), an active metabolite of procainamide which has been proposed as an effective and less toxic alternative, would exert an equivalent degree of vagal blockade. In anesthetized dogs, the right cervical vagus nerve was electrically stimulated at supramaximal voltage using frequencies from 0.5 to 20 Hz to slow the sinus rate. The ability of NAPA and procainamide to block this response was tested with infusion of equimolar doses (1.0 and 0.87 mg/kg/min i.v., respectively) continuously over a period of 40-78 min. Both drugs exerted statistically significant vagolytic effects at the higher frequencies of stimulation. Although the vagolytic effect appeared to be more pronounced with procainamide, this could not be demonstrated by statistical analysis of the data.

Acecainide↗
PubMedDate not supplied

Effects of pharmacologic agents on induced atrial flutter in dogs with right atrial enlargement.

The effects of selected drugs on the sustained atrial flutter induced in conscious dogs with surgically produced right atrial enlargement (TI dogs) were evaluated. This was done to better understand the electrophysiologic mechanism of the tachyarrhythmias. Agents known to cause a slowing of atrioventricular (AV) nodal conduction--verapamil, methacholine, and phenylephrine--did not significantly decrease the rate of the induced flutter, whereas beta-adrenergic stimulation with an infusion of isoproterenol increased the rate of the flutter in all trials. Propranolol and atropine had little effect on the atrial flutter rate. Agents known to increase atrial refractoriness, such as procainamide, n-acetylprocainamide, bretylium, and clofilium, all increased the cycle length of the induced flutter and, in some cases, terminated the arrhythmia. These results suggest then that the perpetuation of the sustained atrial flutter in the conscious TI dog is not due to a delayed afterdepolarization mechanism but is more likely due to reentrant excitation. Furthermore, it is unlikely that the flutter is due to reentry over a pathway involving the AV node; rather, the arrhythmia seems to be caused by reentrant excitation of the leading circle type.

Acecainide↗
PubMed1987

Comparative effects of procainamide and its N-acetylated metabolite in conscious dogs with atrioventricular block: plasma concentration-response relationships.

The effects of procainamide and its metabolite N-acetylprocainamide (NAPA) on atrial effective refractory period (AERP), atrial rate, ventricular rate, and mean blood pressure were investigated in conscious dogs with chronic atrioventricular block and implanted atrial pacing electrodes. Procainamide at cumulative doses of 4.3, 13.0, and 30.3 mg/kg and NAPA at equimolar doses of 5.1, 15.3, and 35.7 mg/kg (i.e., at plasma levels covering the assumed therapeutic range) concentration-relatedly lengthened AERP, as reflected by the decrease of maximal atrial frequency determined by pacing. Procainamide was 1.2-1.5 times more potent than NAPA in this regard. Both drugs increased atrial rate in relation to their plasma concentrations--procainamide 1.2 times more than NAPA. Procainamide decreased ventricular rate at the two highest doses, while NAPA decreased it only at the highest dose after having increased it at the lowest. Procainamide lowered mean blood pressure at the lowest dose and increased it 15 min after the highest, whereas NAPA produced an increase in mean blood pressure for each dose. Taken together, these results on atrial rate, ventricular rate, and mean blood pressure indicate that the two drugs possess distinct pharmacological properties--i.e., procainamide exhibits slightly more marked direct vagolytic and depressor effects than does NAPA and exerts quite different blood pressure effects from those of NAPA. Thus, these data suggest that NAPA, especially when present at high levels, may markedly affect expected responses in patients being treated with procainamide.

Acecainide↗
PubMed1988

Effects of N-acetylprocainamide and recainam in the pharmacologic conversion and suppression of experimental canine atrial flutter: significance of changes in refractoriness and conduction.

The electrophysiologic determinants of the pharmacologic conversion and the prevention of atrial flutter are poorly defined. This study investigated the effects of pharmacologically induced changes in atrial conduction velocity and refractoriness, in the conversion and suppression of atrial flutter induced in the open-chest anesthetized dog by intercaval crush and rapid atrial pacing. The effects of an intravenous infusion of the new class III antiarrhythmic drug N-acetylprocainamide (30 mg/kg over 15 min) and the class Ic antiarrhythmic drug recainam (10 mg/kg over 20 min followed by 10 mg/kg/h) were evaluated. N-acetylprocainamide restored sinus rhythm in 10 of 15 (66%) dogs, while recainam converted only 2 of 10 (20%). N-acetylprocainamide prevented reinduction in 3 (20%), while recainam was effective in none. In the atria, N-acetylprocainamide induced significant increases in effective refractory period (+27%, p less than 0.01), functional refractory period (+22%, p less than 0.01), and in atrial flutter cycle length (+13%, p less than 0.01). Recainam increased effective refractory period (+28%, p less than 0.01), functional refractory period (+20%, p less than 0.01), conduction time at atrial paced cycle length of 150 msec (+70%, p less than 0.01) and atrial flutter cycle length (+56%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed1989

Pharmacokinetic and pharmacodynamic interaction of N-acetyl procainamide and procainamide in humans.

Procainamide is a sodium channel blocker which prolongs QRS and QTc intervals, yet its major active metabolite, N-acetylprocainamide (NAPA), generally prolongs only QTc and has very different electrophysiologic and antiarrhythmic actions. In greater than 50% of patients receiving chronic treatment with procainamide, plasma concentrations of NAPA exceed those of procainamide. In this study, we examined the hypothesis that NAPA might alter the disposition kinetics or pharmacologic actions of procainamide. Ten patients with frequent ventricular extrasystoles received intravenous (i.v.) infusions of procainamide alone (study day 1), procainamide and NAPA (study day 2), and NAPA alone (study day 3) at least 48 h apart. On study days 1 and 2, procainamide was administered at a constant rate for 4 h. On study days 2 and 3, NAPA was administered as a loading and maintenance infusion designed to reach a target pseudo-equilibrium plasma concentration of 8 micrograms/ml. NAPA increased procainamide elimination half-life (t1/2) from 275 +/- 42 min (mean +/- SD) on day 1 to 340 +/- 74 min on day 2 (p less than 0.01). A significant correlations was noted between the change in procainamide total clearance on day 2 relative to day 1 and the initial procainamide total clearance on day 1 (r = -0.77, p = 0.009). Findings were similar when procainamide fractional urinary excretion was considered (r = -0.89, p = 0.007). NAPA did not alter procainamide-induced QRS prolongation, but potentiated procainamide-induced QTc prolongation. The antiarrhythmic response to procainamide was not significantly altered by NAPA in seven of nine patients. One patient had greater arrhythmia suppression when NAPA and procainamide were combined than when either was administered alone. In one patient, NAPA apparently antagonized procainamide-induced arrhythmia suppression, but this effect was not reproducible. We conclude that accumulation of NAPA during procainamide therapy can alter both procainamide elimination as well as its electrophysiologic actions.

Acecainide↗
PubMed1991

Electropharmacodynamics of N-acetylprocainamide in the immature mammalian heart--evidence for a prominent class III effect in the newborn.

The electrophysiologic effects of N-acetylprocainamide (NAPA), a metabolite of procainamide reported to exert significant Class III antiarrhythmic effects in the adult heart, were evaluated in 12 neonatal mongrel canines (ages 7-14 days). Following transvascular placement of quadripolar electrical catheters in the right atrium and ventricle, and a tripolar catheter in the region of the His bundle, electrophysiologic assessments were made of sinus and AV nodal function and atrial and ventricular refractoriness utilizing intracardiac stimulation and recording techniques following cumulative intravenous doses of 20 and 40 mg/kg of NAPA (serum concentrations 13.1 +/- 1.9 and 25.6 +/- 3.4 micrograms/ml). NAPA resulted in an overall increase in sinus cycle length of 18%. No changes were observed in the paced cycle length resulting in AV nodal Wenckebach. Consistent with NAPA's reported Class III action, NAPA increased the effective and functional refractory periods of the ventricle by 35 and 34%, respectively (p less than 0.001). Even larger increases were observed in atrial refractoriness (effective 75%, functional 57%, p less than 0.001). In separate experiments (n = 6), the effects of intravenous NAPA (40 mg/kg) on the duration of the monophasic action potential recorded from the neonatal atrium and ventricle were determined. NAPA increased APD90 of the atrium by approximately 50% and that of the ventricle by 60%, thus confirming a significant effect on myocardial repolarization in the neonate.

Acecainide↗
PubMed1992

Electrophysiologic interactions of procainamide and N-acetylprocainamide in isolated canine cardiac Purkinje fibers.

The study objective was to characterize the electrophysiologic interactions of procainamide (PA) and its metabolite, N-acetylprocainamide (NAPA), in canine Purkinje fibers. Cell (N = 43) action potentials were measured in Tyrode's solution (K+ = 4.0 mM, 36 degrees C) at a basic cycle length of 1,000 ms using standard microelectrode techniques. Six PA concentrations (0.020-0.32 mM) and six NAPA concentrations (0.010-0.24 mM) were studied alone and in combination. PA caused concentration-dependent decreases in Vmax and APD50 but did not alter APD90, ERP, or RMP. NAPA caused a small but not significant concentration-dependent decrease in Vmax, no change in RMP, and significant concentration-dependent increases in APD50, APD90, and ERP. Low NAPA concentrations increased, intermediate concentrations did not affect, and high NAPA concentrations again increased PA's effect on Vmax. PA-NAPA combinations resulted in concentration-dependent changes in APD50 that were intermediate between the effects of PA or NAPA alone. PA did not significantly alter NAPA's effects on APD90 at NAPA concentrations less than or equal to 0.040 mM, while it antagonized NAPA's effect at higher concentrations. The effects of PA-NAPA combinations on ERP were generally similar to their effects on APD90. The electrophysiologic effects of PA-NAPA combinations in normal canine Purkinje fibers are complex functions of the relative and absolute concentrations of the two compounds.

Acecainide↗
PubMed1979

Clinical evaluation of the EMIT procainamide and N-acetylprocainamide assay.

Procainamide and its major metabolite, N-acetylprocainamide, were measured by the homogeneous enzyme immunoassay technique (EMIT). The reagents for the EMIT assays were supplied as a separate matched set for each assay. There is no cross-reactivity by procainamide in the assay for N-acetylprocainamide or by N-acetylprocainamide in the assay for procainamide. Within-day precision determined by replicate analysis of samples in the therapeutic range gave a coefficient of variation of less than 5% for each assay. The day-to-day coefficient of variation was less than 6% for each assay. Quantitative results obtained by the enzyme immunoassay on serum samples from patients receiving procainamide were compared with the results obtained by a high pressure liquid chromatography procedure. For the procainamide assay the correlation coefficient (r) was 0.983; for the N-acetylprocainamide assay the correlation coefficient was 0.981. There was no false positives or false negatives. The immunoassay requires 50 microliters of serum and the enzyme activity is measured in a spectrophotometer. An individual determination requires only 1 min to perform; therefore, the procedure can be used for either emergency or routine analysis.

Acecainide↗
PubMed1981

Plasma concentrations of desethyl N-acetylprocainamide in patients treated with procainamide and N-acetylprocainamide.

We describe a method for routinely measuring plasma concentrations of procainamide (PA), N-acetylprocainamide (NAPA) and desethyl N-acetylprocainamide (NAPADE) by high-performance liquid chromatography (HPLC). The method has been used together with mass spectrometry of the appropriate chromatographic fraction to demonstrate that NAPADE is a metabolite of NAPA. In addition, comparison of NAPADE concentrations in the plasma of patients receiving PA and NAPA indicates that NAPA is not an intermediate for most of the NAPADE formed from PA. We propose that the principal route of NAPADE formation from PA occurs by initial dealkylation to form rho-amino-N-[2-(ethylamino)ethyl]benzamide (PADE), a hypothetical PA metabolite that has yet to be identified.U

Acecainide↗
PubMed1983

Improved liquid chromatographic determination of procainamide and N-acetylprocainamide in serum.

A liquid chromatographic method for the determination of procainamide (PA) and N-acetylprocainamide (NAPA) in serum has been developed. This method utilizes isocratic conditions, ambient temperature, and a conventional fixed-wavelength 280-nm detector. Sample pretreatment involves extraction of PA and NAPA, along with p-amino-N-(2-dipropylaminoethyl)-benzamide hydrochloride as internal standard, into an organic phase and reextraction into an aqueous acidic phase. Using this sample pretreatment, interferences due to commonly used drugs are eliminated. The method accurately measures PA and NAPA to levels as low as 1 mg/L.

Acecainide↗
PubMed1986

High performance liquid chromatography of procainamide and N-acetylprocainamide in human blood plasma.

Procainamide is used in antiarrhythmic therapy, and the need to monitor the drug concentration as well as its major plasma metabolite, N-acetyl-procainamide, is well established. An assay designed for the routine clinical therapeutic drug monitoring laboratory has been developed. A 0.5-ml aliquot of blood plasma is treated with 0.1 ml of internal standard solution, and the mixture is alkalinized. The drug, its metabolite, and the internal standard, N-propionyl procainamide are extracted with methylene chloride. After evaporation to dryness and addition of 0.3 ml of mobile phase, a volume of 0.1 ml is injected onto a liquid chromatograph equipped with spectrofluorimetric detection, which has a better specificity than UV absorptiometric detection. The between-day coefficient of variation was 3.5% for procainamide and 5% for N-acetylprocainamide. The sensitivity of this technique permits detection of 0.1 micrograms/ml of procainamide and 0.25 micrograms/ml of N-acetylprocainamide. Several drugs that are often present in patients receiving procainamide were shown not to interfere.

Acecainide↗