N-acetylprocainamide Research Articles

Arrhythmia Control by Selective Lengthening of Cardiac Repolarization: Role of N-Acetylprocainamide, Active Metabolite of Procainamide

In recent years, data has become available to support the concept that a selective lengthening of the cardiac action potential (a Class III antiarrhythmic action) by whatever mechanism with an attendant increase in the effective refractory period constitutes a distinct antiarrhythmic mechanism. Such an action is exemplified clinically by hypocalemia and hypothyroidism and pharmacologically by amiodarone, sotalol and bretylium, all of which have other associated features. The N-acetylation of procainamide leads to the pharmacologically active compound, N-acetylprocainamide (NAPA). The loss of propensity to block depolarization with the preservation of the effect on repolarization in the case of NAPA makes the compound a class III antiarrhythmic agent. The process of N-acetylation has also led to longer elimination half-life and predominantly renal excretion with linear kinetics but with the preservation of the antiarrhythmic properties of the parent compound. The electrophysiologic data are consistent with the results of studies which have demonstrated that NAPA has the potential to suppress premature ventricular contractions and prevent spontaneously occurring as well inducible ventricular tachycardia in patients with heart disease. The effects on atria indicate that the drug has the potential to electively reverse atrial flutter and fibrillation to normal rhythm and maintain stability of sinus rhythm. The overall experimental and clinical data warrant further evaluation of NAPA as an antiarrhythmic agent.

Procainamide Toxicity in a Patient With Acute Renal Failure

A patient developed acute renal failure while receiving oral procainamide (PA). This lead to severe PA and N-acetyl procainamide (NAPA) toxicity. Rebound of NAPA plasma levels postdialysis prolonged the toxicity, which was treated with hemodialysis, hemoperfusion, and combined hemodialysis-hemoperfusion. Because of the potential for PA and NAPA toxicity in patients with renal insufficiency, especially in patients with changing renal function due to acute renal failure, it is recommended that the use of PA be curtailed in this population and that another substitute antiarrhythmic agent be used.

Effects of lupus-inducing drugs on the B to Z transition of synthetic DNA.

Five drugs associated with systemic lupus erythematosus were studied for their effect on the salt-induced right-handed (B) to left-handed (Z) transition of poly(dG-me5dC) X poly(dG-me5dC). Using circular dichroism spectroscopy, procainamide and hydralazine were found to reduce the midpoint of B to Z transition from 0.8M NaCl to 0.5M NaCl and to increase the rate of this transition at 1M NaCl. Isoniazid and D-penicillamine had less effect on the midpoint of transition and practically no effect on the kinetics. N-acetyl procainamide (a structurally related control for procainamide) and L-canavanine had no effect. Procainamide caused slight reduction in the helix-coil transition (melting) temperature of calf thymus DNA. At a concentration of 1:1 (DNA phosphate:drug ratio), procainamide and hydralazine also caused the aggregation of calf thymus DNA. Since altered DNA conformations, such as Z-DNA, are more immunogenic, these results suggest that the induction or stabilization of Z-DNA by these drugs might be important in the pathogenesis of at least some cases of systemic lupus erythematosus.

Electrophysiologic evaluation of the antiarrhythmic effects of N-acetylprocainamide for ventricular tachycardia secondary to coronary artery disease

Antiarrhythmic properties of N-acetylprocainamide (NAPA), an active metabolite of procainamide, were studied in 12 patients with coronary artery disease who presented with cardiac arrest or documented sustained ventricular tachycardia (VT). Programmed electrical stimulation (PES) studies were performed in 10 men and 2 women, aged 52 to 80 years (mean 63), who had a left ventricular ejection fraction of 16 to 69% (mean 33). All patients tested had inducible VT provoked by PES without antiarrhythmic therapy. Patients were then tested with procainamide, 1,000 mg administered intravenously. VT could be provoked after procainamide treatment in 8 of 10 patients. Twenty-four to 36 hours later NAPA was administered, 18 mg/kg body weight intravenously, and PES was performed after 20 minutes. NAPA did not significantly change heart rate, mean arterial blood pressure, electrocardiographic intervals and AH or HV conduction times. The QT interval lengthened, but not significantly. The mean serum NAPA levels were 15.7 ± 4 μg/ml in the group protected by NAPA and 16.2 ± 4 μg/ml in the group not protected by NAPA. Five patients were discharged with NAPA therapy, 1.5 g orally every 8 hours. Two patients have been maintained with chronic NAPA therapy (10 ± 3 months), and 2 patients had breakthrough VT on follow-up Holter monitoring and alternative therapy was given. One patient died while taking oral therapy. NAPA demonstrates antiarrhythmic efficacy in preventing induction of VT by PES in a high-risk group of patients. During chronic oral therapy in some patients, NAPA appears to be well tolerated, with antiarrhythmic efficacy that may be enhanced with further upward dose titration.

An Evaluation of the TDx Fluorescence Polarization Immunoassays for Procainamide and n-Acetylprocainamide

The TDX fluorescence polarization assays (FPIA) for procainamide (PA) and n-acetylprocainamide (NAPA) were evaluated. Coefficients of variation for within- and between-assay precision studies were less than 6%. Both methods correlated well with a referenced HPLC technique; r2 values for PA and NAPA were 0.980 and 0.986, respectively.

Torsades de Pointes Due to N‐Acetylprocainamide

A 66-year-old female with chronic renal failure received five doses of procainamide and developed marked QT interval prolongation and recurrent episodes of torsades de pointes, which were temporally related to high serum n-acetylprocainamide (NAPA) levels and not to procainamide levels. Repeated hemodialysis was effective in lowering NAPA levels. Torsades de pointes is a potential hazard of NAPA accumulation during procainamide administration to patients with renal insufficiency.

Torsade de pointes associated with elevated N-acetylprocainamide levels

N-acetylprocainamide (NAPA), the major metabolite of procainamide, has been shown to have separate antiarrhythmic and side effects from procainamide.l Torsade de pointes, a type of polymorphous ventricular tachycardia characterized by “twisting” of ventricular complexes around the isoelectric line and usually associated with QT prolongation,2 has been reported to occur with administration of procainamide.3 However, only recently has it been associated with NAPA.* Because procainamide is such a widely used antiarrhythmic agent, this association has important clinical implications. The following case confirms this association of torsade de pointes with NAPA. A 57-year-old black man was admitted to the St. Louis Veterans Administration Medical Center on June 21, 1982, with a diagnosis of biventricular heart failure. There were no symptoms or history suggestive of coronary artery disease or cardiac arrhythmias. He was taking no medications. The admission ECG showed sinus rhythm, right bundle branch block, and a QT interval of 0.46 second. Two-dimensional echocardiography showed marked fourchamber enlargement and severe diffuse left ventricular hypokinesis. He improved on treatment with digoxin, furosemide, and hydralazine. On June 25, however, he had a cardiopulmonary arrest, with a slow idioventricular rhythm but no ventricular tachycardia. He was intubated and stabilized but required mechanical ventilation. A

N-acetylprocainamide kinetics during intravenous infusions and subsequent oral doses in patients with coronary artery disease and ventricular arrhythmias.

The kinetics of N-acetylprocainamide (NAPA) were studied in 5 patients (all men, mean age = 62) with coronary artery disease and ventricular arrhythmias during loading infusions of 0.22-0.45 mg/kg/min, prolonged (19-48 hrs) intravenous infusions 2.5-5.2 mg/min, and in 4 of the patients, during subsequent oral doses 1.5-3 g every 8 hrs. Serum, concentrations of NAPA were determined by high-performance liquid chromatography. The individual concentration-time profiles could, with one exception, be described by a two-compartment, open, kinetic model with apparent first-order elimination. The kinetic variables were: initial distribution volume (Vc) 0.20 +/- 0.11 l/kg (mean +/- SD); steady-state distribution volume (Vss) 1.58 +/- 0.55 l/kg; distributional clearance (Cle) 133 +/- 23 ml/(kg X hr); absorption rate constant (Ka) 0.354 +/- 0.173 hr-1; and fraction of dose reaching systemic circulation (F) 1.00 +/- 0.14. The data for one patient who had received increasing oral dosages of 1.5, 2, 2.5 and 3 g every 8 hours resulted in systematic underprediction of observed concentrations at the two highest oral dosing rates. This suggests the possibility of some degree of nonlinearity or time-dependent change in the kinetic behavior of NAPA. Only low concentrations of procainamide, less than 1 mg/L, were found at the end of the infusions.

Polymorphic ventricular tachycardia and ventricular fibrillation due to N-acetyl procainamide

Worsening of ventricular arrhythmias has been reported during therapy with class I antiarrhythmic agents. 1 N-acetyl procainamide (NAPA), the first metabolite of procainamide, has been implicated as a cause of polymorphic nonsustained ventricular tachycardia (VT) in 1 patient. 2 Sudden death has occurred during NAPA therapy, but recurrent ventricular fibrillation (VF) resulting from NAPA treatment alone has not been documented previously. 3,4 The following case demonstrates this phenomenon.

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.

Torsade de pointes induced by N-Acetylprocainamide

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.

The pharmacokinetics of oral procainamide (1 g) were investigated in six healthy subjects during chronic dosing with ranitidine 150 mg twice daily, and in three of the subjects when ranitidine 750 mg was administered over 12 h. The procainamide area under the plasma concentration-time curve was significantly (PQ0.02) increased by ranitidine (27.761.5 vs 31.561.8 mg l-1 h) with a significant reduction in renal clearance (379632 vs 309630 ml/min, PQ0.02). There was no change in half-life. The N-acetylprocainamide (NAPA) area under the plasma concentration-time curve was also significantly (PQ0.02) elevated by ranitidine (8.661.2 vs 9.761.3 mg 1-1 h) due to a reduction in renal clearance from 187630 to 168628 ml/min. The larger dose of ranitidine produced greater alterations in the procainamide and NAPA pharmacokinetics. Ranitidine reduced the absorption of procainamide by 10% and by 24% at the higher dose level. Two-hourly renal clearance values of procainamide were significantly (PQ0.05) reduced in the 2 to 10 h period and for NAPA between 0 to 6 and 8 to 10 h. The larger ranitidine dose reduced the renal clearances of procainamide and NAPA over the control period at each 2-hourly time period. The reductions in renal clearance are most likely mediated by competition for the renal tubular cationic secretory pathway. Clinical implications arising from this study suggest a reduction in procainamide dosage may be necessary in a small, select number of patients with high plasma ranitidine concentrations, e.g., the elderly; furthermore, failure of therapeutic response for some drugs may be due to ranitidine-induced impaired gastrointestinal absorption.

Fluoroimmunoassays for procainamide and N-acetylprocainamide compared with a liquid-chromatographic method.

We measured procainamide and its active metabolite, N-acetylprocainamide (NAPA), in 80 sera from 37 patients by a new fluorimmunoassay procedure and an established "high-performance" liquid-chromatographic method. Additive and proportional differences between the methods were 0.07 mg/L and 9%, respectively, for procainamide and 0.62 mg/L and 16% for NAPA. Between-day CVs by the chromatographic and immunoassay methods, respectively, were 3.9% and 2.2% for procainamide at a concentration of 6 mg/L, and 5.1% and 1.2% for NAPA (14 mg/L). We applied a modification of the fluoroimmunoassay for determination of procainamide concentrations, using sera obtained during a pharmacokinetic study, and demonstrated excellent agreement with the chromatographic method.

Population pharmacokinetics of procainamide from routine clinical data.

Routine clinical pharmacokinetic data collected from patients receiving procainamide were analysed to estimate population pharmacokinetic parameters. 116 plasma concentration determinations for procainamide and 14 timed urine collections for the drug and its major metabolite N-acetylprocainamide (NAPA) were obtained from 39 patients, mostly males. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. Estimates of the influence of weight, height, renal function, and the presence of congestive heart failure (CHF) on the renal clearance (CLR), acetylation clearance (CLA), miscellaneous metabolic clearance (CLO), and volume of distribution (Vd) of procainamide were obtained. The mean (SE) CLR, CLA, CLO and Vd for procainamide in a 70kg patient with normal renal function were estimated to be 14.4 (2.3) L/h, 10.1 (1.7) L/h, 1.2 (1.3) L/h, and 136.0 (20.0) L, respectively. These pharmacokinetic parameters vary linearly with bodyweight; height adds no information if weight is known. The presence of CHF has no significant effect on either CLO or Vd, but reduces CLA and CLR by 11% (p less than 0.01). Even after adjustments for CHF, renal function and weight, the total clearance and Vd of procainamide vary unpredictably among individuals, with a coefficient of variation between 30 and 40%, and less than 50%, respectively.

Electrophysiologic properties and antiarrhythmic mechanisms of intravenous N-acetylprocainamide in patients with ventricular dysrhythmias

To define electrophysiologic properties and antiarrhythmic mechanisms of N-acetylprocainamide (NAPA), we studied 16 patients with symptomatic ventricular dysrhythmias. Electrophysiologic studies were performed before and after intravenous infusion of NAPA at 20 mg/kg over 20 minutes, achieving plasma concentrations of 24 ± 3.2 to 35.5 ± 4.5 μg/ml. NAPA did not significantly change sinus cycle length or atrioventricular (AV) conduction times (PA, AH, HV, and QRS), but it lengthened the QTc interval ( p < 0.001) during sinus rhythm. Programmed atrial stimulation revealed that NAPA had no discernible effects on AV nodal conduction; however, it exerted depressive effects on the His-Purkinje system in 9 of 16 patients. In 7 of 16 patients who manifested frequent ventricular premature beats (VPBs), NAPA abolished VPBs in only three of them; NAPA induced progressive prolongation of the premature coupling interval before complete abolition of VPBs. In 8 of 16 patients who had inducible repetitive ventricular response (RVR) because of reentry within the His-Purkinje system, NAPA narrowed or abolished the RVR zone in 3 patients and slowed the RVR rate with widening of the RVR zone in the remaining 5 patients. In 2 of 16 patients with slow ventricular tachycardia (VT), NAPA had no antiarrhythmic effects. By contrast, in the other 2 of 16 patients in whom sustained VT could be reproducibly elicited with programmed ventricular stimulation, NAPA slowed the rate of VT and suppressed VT inducibillity. We conclude that electrophysiologic properties of NAPA are slightly different from those of procainamide and that NAPA is not uniformly effective for suppressing ventricular dysrhythmias, but its antiarrhythmic mechanisms are similar to those of procainamide.

Significance of acetylator phenotype in pharmacokinetics and adverse effects of procainamide.

The pharmacokinetics and development of antinuclear antibodies (ANAs) during procainamide (PA) therapy were studied in 35 patients with ventricular arrhythmias. Sixteen of the subjects were rapid and 19 were slow acetylators. Twenty-six of them (13 rapid and 13 slow acetylators) received PA therapy (2.4g sustained-release PA X HCl daily in three doses) for at least 16 weeks. On maintenance therapy, rapid acetylators had insignificantly lower serum PA concentrations and slightly higher N-acetylprocainamide (NAPA) concentrations than slow acetylators. The unchanged PA fraction (PA/PA + NAPA) in the rapid acetylators was somewhat lower than in the slow acetylators. Rapid acetylators excreted more NAPA in urine than did slow acetylators (p less than 0.05), whereas the difference in PA excretion was not significant. More than 80% of the given drug was excreted as PA and NAPA. Spontaneous or exercise-induced arrhythmias were recorded in 6 rapid and 8 slow acetylators. ANAs (titre at least 20) appeared in 6 rapid and 8 slow acetylators. The mean time until ANA development in rapid acetylators was only marginally longer than in slow acetylators. The results suggest that acetylation phenotyping is not of great significance in predicting the development of ANAs during PA therapy.

Simultaneous analysis of antiarrhythmic drugs and metabolites by high performance liquid chromatography: Interference studies and comparisons with other methods

Our previously described HPLC method for the simultaneous analysis of several antiarrhythmic drugs and metabolites in serum [Clin. Biochem. 14. 113-118 (1981)] was correlated with an enzyme immunoassay technique (EMIT) for quinidine, procainamide, N-acetyl procainamide, and disopyramide. Correlation coefficients in each case was greater than 0.95. Our method compared favorably with a fluorescent procedure for the quantitation of propranolol in plasma. Interference studies with 34 drugs indicated that the measurements of quinidine and monodealkyldisopyramide were affected by quinine and lidocaine, respectively. Carbamazepine and glutethimide interfered with propranolol, but additional clean-up extractions removed these interferences.

Procainamide elimination kinetics in pediatric patients.

Procainamide kinetics were studied in six children after a single intravenous dose. Two-compartment kinetic analysis of serum concentration-time curves of five children, who received a dose of 5.5 +/- 0.9 mg/kg (mean +/- SD), revealed the following values for kinetic parameters: distribution half-life, 10.3 +/- 3.4 min; elimination half-life, 1.7 +/- 0.1 hr; elimination constant, 1.2 +/- 0.3 hr-1; plasma clearance 19.4 +/- 2.0 ml/min/kg, and steady-state volume of distribution, 2.2 +/- 0.3 l/kg. A sixth patient, who received an accidental overdose of 28 mg/kg, had altered elimination kinetics due to drug-induced hypotension. N-acetylprocainamide (NAPA) was detected in serum samples obtained soon after procainamide dosing and peak concentrations were attained at 1 to 2 hr. NAPA levels were lower than corresponding procainamide concentrations at most sampling periods. The findings of short elimination half-life and rapid plasma clearance of procainamide in children suggest that continuous intravenous infusion may be necessary to maintain therapeutically effective plasma concentrations in these patients.

N-Acetylprocainamide kinetics and clinical response during repeated dosing.

Kinetics of and clinical responses to N-acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythmic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24-hr ambulatory ECGs. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r = 0.94, SEE = 3.6 mg/l). The capability for defining patient-specific estimates for drug disposition with six or seven serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 hr -1 +/- 0.017) and volume of distribution (1.25 l/kg +/- 0.28) were of the same order as in earlier single-dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not found to be clinically effective in any of the 10 patients, although two patients demonstrated a greater than 70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequently required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient-specific kinetic models that may have applications to other antiarrhythmic drugs.

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.