Therapeutic levels of intravenous procainamide in neonates: a retrospective assessment.

STUDY OBJECTIVES: To evaluate dosing and pharmacokinetic parameters of intravenous continuous-infusion procainamide in neonates, and to identify dosage regimens and factors leading to therapeutic procainamide levels and minimal adverse events. DESIGN: Retrospective, observational study. SETTING: Pediatric hospital. PATIENTS: . Twenty-one patients (seven preterm, 14 full term) younger than 30 days who received continuous-infusion procainamide therapy for more than 15 hours or had two consecutive therapeutic procainamide levels obtained while receiving therapy between June 1, 2002, and December 31, 2005. MEASUREMENTS AND MAIN RESULTS: Data on demographics, dosing, drug levels, and adverse effects were collected. Doses that achieved therapeutic levels were documented, and procainamide clearance was calculated and evaluated with regard to renal function and gestational age in patients who were at steady state. Mean clearance and mean N-acetylprocainamide (NAPA):procainamide ratios were compared between preterm and term neonates. No patients experienced hemodynamic instability or other adverse effects due to procainamide. Procainamide was given as a mean +/- SD 9.6 +/- 1.5-mg/kg bolus in 20 of 21 patients before continuous infusion. The mean +/- SD dose at which two therapeutic levels were achieved was 37.56 +/- 13.52 microg/kg/minute. Procainamide clearance was 6.36 +/- 8.85 ml/kg/minute and correlated with creatinine clearance (r=0.78, p<0.00001) and age at day of sampling (r=0.49, p<0.00001). The NAPA:procainamide ratio at steady state was 0.84 +/- 0.53; two patients were determined to be fast acetylators (ratio > 1). Preterm infants had lower mean clearance rates (p<0.001) but higher NAPA:procainamide ratios (p<0.01) than those of term infants. Five patients experienced seven supratherapeutic levels while receiving therapy; four of these patients were preterm, and all had creatinine clearances less than 30 ml/minute/1.73 m(2). Three patients had four pairs of levels obtained after discontinuation of procainamide, and elimination rate constant and half-life were calculated. CONCLUSION: Procainamide can be safely used in neonates, with no short-term adverse effects. The dosage regimen for intravenous procainamide required to achieve therapeutic levels in neonates is similar to that of older infants and children. Doses may need to be reduced in premature infants and in those with renal dysfunction.

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.

Comparative electrophysiologic effects of intravenous and oral procainamide in patients with sustained ventricular arrhythmias.

Thirty-three patients with sustained ventricular arrhythmias underwent electrophysiologic testing after intravenous and again after oral procainamide administration. Two groups were identified: group 1 included 15 patients with concordant serum procainamide concentrations with less than a 3 micrograms/ml difference after intravenous (mean 8.6 +/- 2.7) and oral (mean 8.8 +/- 2.7) procainamide administration, with mean N-acetylprocainamide concentrations of 1.0 +/- 0.6 and 6.2 +/- 2.8 micrograms/ml, respectively. Group 2 included 18 patients with discordant serum procainamide concentrations after intravenous (mean 9.5 +/- 5.9 micrograms/ml) and oral (mean 14.1 +/- 5.2 micrograms/ml) procainamide, with mean N-acetylprocainamide concentrations of 0.9 +/- 0.5 and 10.7 +/- 5.7 micrograms/ml, respectively. In group 1, response to programmed stimulation was the same after intravenous and oral procainamide administration, with no inducible ventricular arrhythmia in 5 of 15 patients. In group 2, 3 of 18 patients had no inducible arrhythmia after intravenous compared with 7 of 18 patients after oral procainamide administration. There was a different response to programmed stimulation after oral compared with intravenous procainamide in 6 of 18 patients in group 2 but in none of 15 patients in group 1 (p = 0.02). The effective procainamide concentration was greater than the ineffective concentration in five of the six patients with a discordant response, and the effective route of administration was oral in five of the six patients. The change in ventricular refractoriness in group 1 was similar after intravenous (28 +/- 23 ms) and oral (29 +/- 19 ms) procainamide, whereas in group 2, refractoriness was increased more after oral (33 +/- 21 ms) than intravenous (20 +/- 17 ms) procainamide administration and paralleled the difference in procainamide concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombocytopenia following sustained-release procainamide.

Procainamide hydrochloride-induced thrombocytopenia has infrequently been reported in the past. We report six cases of thrombocytopenia following the administration of the sustained-release form of procainamide. Three of these cases had platelet counts of less than 15,000/microL. The mean time to onset of thrombocytopenia from drug administration was 40 days (range, nine to 71 days). The mean time until normalization of the platelet counts after the drug therapy was stopped was 7.8 +/- 3.1 days (range, four to nine days). Oral prednisone therapy had little apparent benefit. The thrombocytopenia was not part of a systemic lupus erythematosus syndrome. We believe that thrombocytopenia is an important side effect of sustained-release procainamide therapy.

N-Acetyl-procainamide kinetics in the elderly.

Plasma and saliva N-acetyl-procainamide (NAPA) concentrations were measured by high-power liquid chromatography (HPLC) after intravenous infusion of 750 mg to 14 elderly patients (x age = 69 yr). The plasma NAPA disappearance curve can best be described by a two-compartment body model. Mean total body clearance was 10.6 1/hr, Vdss 125.8 1, and terminal half-life (t 1/2) 8.8 hr. A nonrenal clearance of 2.72 1/hr was calculated, that is, 19% of the expected total body clearance with normal kidney function. Saliva concentrations show huge inter- and intraindividual variability and are probably not usable for NAPA monitoring in older patients.

Intravenous N-acetylprocainamide disposition kinetics in coronary artery disease.

N-Acetylprocainamide (NAPA) disposition kinetics was studied in eight patients with coronary artery disease. NAPA was given over a 45-min period by intravenous infusion, and blood samples were drawn at specified times for 24 hr. NAPA plasma levels were determined by a specific high-pressure liquid chromatography (HPLC) procedure and the concentration-time data were fit to a three-compartment model. Mean (+/- SD) values for the elimination half-life, the total body clearance, and the steady-state volume of distribution were 9.53 +/- 3.22 hr, 1.98 +/- 0.40 ml/min/kg, and 1.30 +/- 0.18 1/kg. There was moderate intersubject variability in disposition. The data reported here differ from those reported for normal subjects.

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.

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.

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.

Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism.

We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 +/- 0.17 (mean +/- SD) for those with NAT2*4/*4, 0.37 +/- 0.06 for NAT2*4/*6A, 0.40 +/- 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.

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 NAPA's 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.

Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation.

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

The clinical pharmacology and antiarrhythmic efficacy of acetylprocainamide in patients with arrhythmias.

The actions of acetylprocainamide, the major metabolite of procainamide in man, were studied in a placebo-controlled oral-dose-ranging trial in 16 persons with arrhythmias. The occurrences of arrhythmias decreased in 15 patients receiving acetylprocainamide and increased subsequently in 10 of 13 patients given placebo. The frequency of arrhythmias was reduced by more than 75 percent in nine patients. Antiarrhythmic effects were dependent on dose and serum drug concentrations, with levels of 10 to 24 microgram/ml observed in patients with a reduction of more than 70 percent in premature ventricular complexes. The ratio of preejection period to left ventricular ejection time decreased during therapy. Side effects of light-headedness, insomnia, nausea and diarrhea occurred in six patients at serum levels ranging from 11 to 22 microgram/ml. The serum half-life of acetylprocainamide lengthened from 7 to 21 hours as the creatinine clearance decreased from 105 to 35 ml/min. Acetylprocainamide has antiarrhythmic efficacy, but causes side effects in human beings. This compound appears to contribute to the effects of procainamide therapy and may be useful as an antiarrhythmic drug.

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patient's procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

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 micrograms/ml in the group protected by NAPA and 16.2 +/- 4 micrograms/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.

Procainamide-induced sinus node dysfunction in patients with chronic renal failure.

Two patients with chronic renal failure developed transient sinus node dysfunction requiring insertion of a temporary pacemaker while receiving procainamide to control ventricular arrhythmias. Blood levels of procainamide were found to be elevated, although at these levels, sinus node dysfunction has not previously been reported. Following discontinuance of procainamide, sinus rhythm returned. A combination of factors, including elevated levels of N-acetyl procainamide, the metabolite of procainamide with anti-arrhythmic properties, are suggested as possible contributory causes for the ECG findings. Thus, procainamide may produce electrophysiologic features of "sick sinus syndrome" in patients with chronic renal failure even when blood levels of this substance are being monitored.

Pharmacokinetic and pharmacodynamic comparisons of twice daily and four times daily formulations of procainamide in patients with frequent ventricular premature depolarization.

A study was conducted to evaluate the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide (NAPA), as a function of dose and formulation and to characterize the relationship between ventricular premature depolarization (VPD) rate and plasma concentrations of procainamide and NAPA. A subset of patients (n = 43) with frequent VPD who were enrolled in a double-blind, multicenter, activity trial were assigned in randomized fashion to receive 1 of 4 dose levels (placebo or 1,000, 2,000, or 4,000 mg/day procainamide) and to receive Procanbid (Parke-Davis) tablets every 12 hours or Procan SR (Parke-Davis) tablets every 6 hours during the first week of a blinded crossover phase. Patients crossed over to the alternative formulation after one week. Maximum and steady-state average concentrations of procainamide and NAPA after administration of Procanbid tablets were equivalent to those after administration of an equivalent daily dose of Procan SR tablets. Corresponding trough concentrations of procainamide were lower after administration of Procanbid tablets than after administration of Procan SR tablets. Both formulations produced disproportionate increases in procainamide concentrations with increasing dose; concentrations of NAPA increased in proportion to dose. Assessment of the relationship between VPD rate and drug concentration in plasma indicated no substantive difference between the two formulations. It was concluded that administration of Procanbid tablets every 12 hours is essentially equivalent to administration of procainamide extended-release tablets (Procan SR) every 6 hours with respect to pharmacokinetics of procainamide and NAPA and to VPD suppression.

N-acetylprocainamide and ischemia-induced ventricular fibrillation in the dog.

Open-chest dogs anesthetized with pentobarbital were treated with saline or N-acetylprocainamide (20 mg/kg, i.v.) 10 min prior to simultaneous ligation of the left anterior descending and septal coronary arteries. Ventricular fibrillation occurred in 20 of 26 control dogs but in only 6 of 15 dogs treated with N-acetylprocainamide (P less than 0.05). Since N-acetylprocainamide significantly reduced spontaneous heart rate this may have contributed to its antifibrillatory effect.

High performance liquid chromatographic analysis of the antiarrhythmic drugs procainamide, disopyramide, quinidine, propranolol and metabolites from serum extracts.

We describe a method for the simultaneous high performance liquid chromatographic determination of several antiarrhythmic drugs and some of their metabolites after extraction from 2.5 mL of spiked pooled sera. The extracts were applied to a C8 reversed phase column. Nine compounds of interest were resolved within the 30 minute run. An initial mobile phase of 80% phosphate (25 mmol/L, pH 3.5), 20% organic (acteonitrile:methanol, 2:3) was maintained for 2 min at which time a linear gradient was used to change the mobile phase to 30% phosphate, 70% organic at 20 min after injection. This composition was maintained from an additional 5 min. Absorbance at 212 nm was used for detection. Peak area ratios of drug to internal standard (N-propionylprocainamide) were used for quantitation. The relative standard deviations (and mean solute concentrations) of daily duplicate determinations for 15 days are: procainamide, 5.1% (5.9 mg/L); N-acetylprocainamide, 9.3% (6.0 mg/L); Mono-N-dealkyldisopyramide, 3.7% (4.1 mg/L); disopyramide, 4.3% (4.0 mg/L); quinidine, 4.5% (6.5 mg/L); and propranolol, 5.1% (0.097 mg/L). Dihydroquinidine and 4-hydroxypropranolol were also resolved but not quantitated.

Evaluation of very rapid emit Qst methods for measuring serum procainamide and N-acetylprocainamide concentrations.

This study assessed the Emit Qst procainamide (PA) and N-acetylprocainamide (NAPA) assays. Accuracy and intraday precision were evaluated by repeatedly measuring PA and NAPA concentrations in spiked serum samples using Qst and high-performance liquid chromatography methods. Interday precision was evaluated by measuring concentrations in spiked samples over 4 weeks. Correlation between methods was assessed in patient samples, and proportional, constant, and random errors were estimated. Intraday coefficients of variation (CVs) were below 6.4% for PA and NAPA for both methods; interday CVs were below 7.8%. The proportional, constant, and random errors of the PA Qst assay in patient samples were 5.7%, -0.224 mg/L, and +/- 0.574 mg/L, respectively. The same errors in the NAPA Qst assay were 17.2%, 0.229 mg/L, and +/- 1.79 mg/L, respectively. The Qst assays are rapid, accurate, and precise methods for routine clinical measurement of PA and NAPA, although the proportional error in the NAPA assay should be recognized.