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PubMed1986

Procainamide pharmacokinetics in patients on continuous ambulatory peritoneal dialysis.

The pharmacokinetics of procainamide in patients on continuous ambulatory peritoneal dialysis have been studied. A mean peak plasma concentration of 3.2 +/- 0.6 microgram/ml was achieved about 2 h after a single 500-mg oral procainamide hydrochloride dose. The procainamide elimination half-life ranged from 6.1 to 15.3 h. Apparent oral clearance, 183.7 +/- 63.2 ml/min, was less than half that observed in healthy adults suggesting markedly reduced dosage requirements. Continuous ambulatory dialysis patients exhibit similar procainamide pharmacokinetic parameters as do end stage renal disease patients, most notably a prolonged elimination half-life and reduced oral clearance.

Acecainide↗
PubMed1989

Thrombosis associated with procainamide-induced lupus anticoagulant.

A predisposition to thrombosis in patients with procainamide-induced lupus anticoagulants is previously unrecognized. We describe two patients treated with procainamide who experienced acute thromboembolic events temporally associated with development of the lupus anticoagulant. One patient had a deep venous thrombosis and pulmonary embolism, while the other patient had a cerebrovascular accident. In both patients, coagulation parameters corrected with interruption of procainamide therapy. We suggest that thrombosis may complicate treatment with procainamide in patients who develop the lupus anticoagulant.

Aged↗
PubMed1992

Acute effects of amiodarone on sodium currents in isolated neonatal ventricular myocytes: comparison with procainamide.

Recent studies suggest that amiodarone's acute clinical effects in infants and children are related predominantly to its class I antiarrhythmic activity. However, the effects of amiodarone on Na+ currents have not been investigated directly in immature cardiac cells. Accordingly, the tight seal whole cell voltage clamp technique was used to measure time- and voltage-dependent Na+ currents in acutely isolated neonatal ventricular myocytes from 2- to 5-day-old rabbits, before and after addition of amiodarone (0.1-10 microM). To evaluate the class I antiarrhythmic activity of amiodarone in this age group, the effects of amiodarone on Na+ currents were compared with those of procainamide. Similar to procainamide, amiodarone significantly decreased peak inward Na+ current in neonatal ventricular myocytes. Moreover, both amiodarone and procainamide shifted the steady-state inactivation curve to more negative membrane potentials and delayed recovery of the Na+ current from inactivation. Thus, the effects of amiodarone on the Na+ current in immature myocardium are qualitatively similar to those of procainamide, suggesting that amiodarone may act acutely as a class I antiarrhythmic agent in the newborn heart.

Amiodarone↗
PubMed1977

Effects of procainamide and quinidine sulfate in the Wolff-Parkinson-White syndrome.

Thirty-three patients with Wolff-Parkinson-White syndrome were studied electrophysiologically before and after administration of intravenous procainamide and oral quinidine sulfate. Procainamide prolonged the shortest R-R (SRR) interval between two consecutive pre-excited beats during atrial fibrillation 20-70 msec in 15 of 21 patients with no change observed in 6 of 21 patients. Quinidine sulfate prolonged the SRR 20-170 msec in all 16. In 14 of 18 patients where procainamide and quinidine were comparable, quinidine prolonged the SRR 30-100 msec more than procainamide.

Atrial Fibrillation↗
PubMed1981

Relationship between plasma levels of procainamide, suppression of premature ventricular complexes and prevention of recurrent ventricular tachycardia.

We compared the relationship between plasma levels of procainamide and suppression or prevention of various forms of ventricular arrhythmias in 18 patients, six of whom had premature ventricular complexes (PVCs) during acute myocardial infarction (AMI), six of whom had PVCs in the setting of stable chronic ischemic heart disease (CIHD), and six of whom had recurrent symptomatic ventricular tachycardia (VT) with chronic PVCs between episodes of VT. The mean plasma level of procainamide required for 85% suppression of PVCs in the AMI patients was 5.0 +/- 0.5 micrograms/ml, while that required for the CIHD patients was 9.3 +/- 0.7 micrograms/ml (p less than 0.05). The mean plasma level required for prevention of spontaneous episodes of symptomatic sustained tachycardia in the VT group was 9.1 +/- 3.4 micrograms/ml, while the mean level required for 85% suppression of PVCs in the same patients was 14.9 +/- 3.8 micrograms/ml (p less than 0.01). In the VT group, PVC frequency was decreased by a mean of only 36% (range 11-63%) at plasma levels of procainamide sufficient to prevent spontaneous VT. The relationship between plasma levels of procainamide and PVC suppression appears to be different in AMI and CIHD patients; furthermore, a high degree of PVC suppression is not a necessary endpoint of antiarrhythmic therapy when attempting to protect patients against recurrent symptomatic VT.

Acute Disease↗
PubMed1987

Enhancement of procainamide-induced rate-dependent conduction slowing by elevated myocardial extracellular potassium concentration in vivo.

Procainamide, a type 1A antiarrhythmic drug, blocks sodium channels and reduces the maximum rate of rise of the cardiac action potential (Vmax) in a rate-dependent fashion. In vitro, the magnitude of this rate-dependent reduction in Vmax is greater in tissue that is partially depolarized at rest than in tissue with a normal resting potential. Reductions in Vmax produced by drugs that block sodium channels are also directly related to the reductions in longitudinal conduction velocity of action potential propagation in papillary muscle preparations. We therefore sought to determine whether the rate-dependent conduction slowing induced by procainamide in the intact canine heart is enhanced in myocardial tissue abnormally depolarized by an elevated myocardial extracellular potassium concentration, [K+]o. QRS duration and epicardial activation times were measured as indexes of myocardial conduction. QRS duration and epicardial activation times were measured at control (4.0 mM) and at intermediate (6.5 mM) and high (9.2 mM) myocardial [K+]o in the presence or absence of a clinically relevant procainamide concentration (12.2 +/- 2.6 g/ml) at the longest obtainable interstimulus interval of 440 msec and at 330, 280, and 250 msec. Intermediate and high myocardial [K+]o alone induced rate-dependent conduction slowing as the frequency of stimulation increased (cycle length 440 msec to 330, 280, and 250 msec). In the presence of procainamide, rate-dependent conduction slowing was observed at all levels of myocardial [K+]o, and the amount of rate-dependent change in conduction time increased as the myocardial [K+]o was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1989

Predicting ventricular tachycardia cycle length after procainamide by assessing cycle length-dependent changes in paced QRS duration.

To determine if paced cycle length-dependent changes in the QRS duration correlate with the change in ventricular tachycardia (VT) cycle length after procainamide, we measured the QRS duration during sinus rhythm and during right ventricular pacing before and after procainamide (mean concentration, 9.9 micrograms/ml) in 18 patients with morphologically identical VT induced at both study periods. Pacing was performed at 600 msec or the longest cycle length that allowed for uninterrupted capture and at a cycle length that was within 50 msec of the VT cycle length observed during the control study (mean, 313 +/- 51 msec). After procainamide, the VT cycle length increased from 285 +/- 62 to 368 +/- 70 msec (percent change, 30 +/- 13%). The QRS duration during sinus rhythm increased from 125 +/- 25 to 145 +/- 29 msec (percent change, 16%). The QRS duration at both paced cycle lengths was the same in the baseline state (191 +/- 26 msec). However, the change in QRS duration after procainamide at the shorter paced cycle length compared to a 39 +/- 13 msec (18%) increase at the longer paced cycle, p less than 0.001. There was a significant correlation between the percent change in QRS duration at the shorter paced cycle length and the percent change in VT cycle length (r = 0.84, p less than 0.001) with the relation expressed by the regression equation: percent change in VT cycle length = -2.8 + 1.16 x percent change in QRS duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Rate-dependent changes in intraventricular conduction produced by procainamide in anesthetized dogs. A quantitative analysis based on the relation between phase 0 inward current and conduction velocity.

Antiarrhythmic drug effects on maximal upstroke velocity (Vmax) are frequency dependent, which implies that the effects of these drugs on conduction should also be rate dependent. Previous in vivo studies have been limited by assumptions about unchanging propagation pathway, and by the empirical use of a first-order recovery model. To explore time-dependent antiarrhythmic drug-induced conduction slowing in vivo, we used 56-electrode epicardial mapping in chloralose-anesthetized dogs with formalin-induced atrioventricular block. Interval-dependent changes in conduction time were assessed under control conditions and then after three loading and maintenance infusions of procainamide. Under control conditions, epicardial activation time (86 +/- 26 msec at a basic cycle length of 300 msec) was unchanged (87 +/- 24 msec) by pauses up to 6.6 +/- 2.2 seconds. Procainamide caused conduction slowing that dissipated as a function of recovery interval, with 94 +/- 6% recovery over a maximum pause of 6.7 +/- 1.5 seconds, but did not alter activation pattern. Drug-induced changes in conduction were evaluated by use of a mathematical model assuming phase 0 inward current proportional to conduction velocity squared. Conduction changes were better fitted by this "quadratic model" (least sum of squared deviations 3.9 x 10(-3) by mapping in five dogs, 2.7 x 10(-2) by use of QRS duration in nine dogs) than by a monoexponential model (sum of squared deviations 5.7 x 10(-3) by mapping, 3.4 x 10(-2) with QRS; p less than 0.01 vs. quadratic model for each). As predicted by theoretical analysis, recovery time constants from the quadratic model were similar to time constants for procainamide-induced changes in Vmax in vitro, and significantly longer than values obtained with a monoexponential model. Drug-induced changes in QRS duration were highly correlated with simultaneous changes measured by epicardial mapping (r = 0.95, p less than 0.001), indicating that QRS duration is a valid index of drug effects on ventricular conduction. We concluded that procainamide causes interval-dependent changes in ventricular conduction in vivo that are consistent with a proportional relation between phase 0 inward current and the square of conduction velocity. These observations have important potential implications for the dose-dependent and heart rate-dependent effects of antiarrhythmic drugs.

Action Potentials↗
PubMed1991

Circus movement atrial flutter in the canine sterile pericarditis model. Differential effects of procainamide on the components of the reentrant pathway.

To evaluate the mechanisms of action of procainamide on the components of the reentrant pathway, drug-induced changes in activation patterns, effective refractory periods (ERPs), and stimulation thresholds were analyzed in nine dogs with sterile pericarditis and sustained atrial flutter. Activation maps were based on 127 close bipolar recordings from a special "jacket" electrode. From the control map, 22 +/- 2 sites covering the slow zone and the normal zone of the reentrant circuit were selected to measure ERPs and thresholds. The excitable gap was estimated from the longest ERP during pacing at the tachycardia cycle length. During atrial flutter, epicardial activation proceeded as a single wave around an arc of functional conduction block in the proximity of the atrioventricular (AV) ring or around a combined functional/anatomic obstacle, with the arc being contiguous with one of the venae cavae. An area of slow conduction, which accounted for 53 +/- 15% of the revolution time within 35 +/- 15% of the total length of the reentrant pathway, was bordered by the arc of block and the AV ring or a caval vein and the AV ring, respectively. Procainamide (5-10 mg/kg i.v.) prolonged the cycle length of atrial flutter from 144 +/- 17 to 190 +/- 24 msec (p less than 0.05) and then terminated the arrhythmia in all studies. The increase in cycle length was due to an increase in conduction time in the slow zone by 37 +/- 11 msec (86 +/- 17% of the total cycle length increase). During the last reentrant beat, conduction failed in the slow zone, with the arc of block joining the AV ring. At termination, procainamide had prolonged conduction time, stimulation threshold, and ERP in the normal zone by 11 +/- 18%, 40 +/- 80%, and 5 +/- 15%, respectively, compared with 51 +/- 16%, 86 +/- 93%, and 14 +/- 21%, respectively, in the slow zone (p less than 0.05 for all three parameters). The duration of the excitable gap did not change significantly. We conclude that procainamide preferentially affected the slow zone of single loop reentrant circuits. The drug terminated circus movement atrial flutter without abolishing the excitable gap, and its effect on conduction seemed the major determinant of the antiarrhythmic action.

Animals↗
PubMed1977

Influence of glucagon on the cardiovascular effects of procainamide.

Effects of glucagon on procainamide-induced cardiac toxicity were studied in anesthetized dogs. Procainamide in doses of 50 and 100 mg/kg produced dose-dependent decreases in the blood pressure, cardiac output, left ventricular work index, and left ventricular systolic pressure; and increases in the left ventricular end diastolic and right atrial pressure, and total systemic vascular resistance. Glucagon antagonized most of the effects of procainamide on the cardiovascular system. Glucagon may be effective in antagonizing procainamide-induced cardiac toxicity.

Animals↗
PubMed1982

Pharmacokinetics of a sustained release procainamide preparation.

In summary, procainamide is a useful agent for suppressing premature depolarization frequency. Its short half-life of elimination requires a dosing frequency of every 3 hours with regular dosage forms or every 6-8 hours with a sustained action dosage. Because of the extreme unpredictability of plasma concentration, the dosage must be titrated in each patient with electrocardiographic monitoring serving as the most useful method of evaluating efficacy. Maximum and minimum plasma concentrations are helpful in monitoring the achievement of therapeutic plasma levels and adjusting the frequency of dosing, especially in the presence of impaired renal function or low cardiac output. Adverse effects of procainamide include anorexia, nausea, vomiting, fatigue, insomnia, visual hallucinations, and disorientation; these are minor and cease with discontinuation of the drug. Agranulocytosis has rarely been reported. Long-term treatment has resulted in the occurrence of a lupus-like syndrome that is reversible when the drug is stopped. Procainamide is excreted in breast milk and infants of mothers receiving procainamide should not be nursed.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

Comparative bioequivalence and efficacy of two sustained-release procainamide formulations in patients with cardiac arrhythmias.

This investigation evaluated the bioequivalence and efficacy of two sustained-release procainamide products. Ten patients with cardiac arrhythmias were randomized to product A (Procan-SR) or product B (Pronestyl-SR). After nine doses of study medication, plasma procainamide and N-acetylprocainamide concentrations were obtained to determine the area under the concentration versus time curve at steady state (AUCSS), mean plasma concentration (CSSav), the observed peak plasma concentration (CSSmax), the observed trough plasma concentration (CSSmin), and the apparent time to achieve CSSmax (tmax). The products were compared on a milligram-equivalent (adjusted) basis. Following completion of blood sampling, patients were crossed-over to the alternate product. There was no washout between treatments. After nine doses of the alternate test medications, blood sampling was repeated. Differences in AUCSS, CSSav, CSSmax, tmax, and intradose peak/trough ratios were not statistically significant. Within-group variability in AUCSS, CSSav CSSmax, and tmax was greater with product B, but this trend did not reach statistical significance. Antiarrhythmic efficacy was not significantly different between the two treatments. Although the greater bioequivalence, lesser variability, and the greater number of tablet dosage sizes would favor product A, patients stabilized on a particular brand of sustained-release procainamide should not be switched to another product without careful monitoring. One patient in this study developed nonsustained ventricular tachycardia with low procainamide plasma concentrations after being switched from product A to product B.

Acecainide↗
PubMed1983

The electrophysiological actions of lidocaine on ischemic ventricular muscle as compared with procainamide.

For the purpose to evaluate the effects of lidocaine on the ventricular arrhythmias occurring as complications of acute myocardial ischemia or infarction, the electrophysiological actions of lidocaine were estimated, as compared with those of procainamide, on the right ventricular papillary muscle of the rabbit heart superfused with hypoxic, hyperkalemic and/or acidic Krebs-Ringer solution. Lidocaine (1 to 5 x 10(-5)M) and procainamide (1.7 to 3.4 x 10(-5)M) depressed the maximum rate of action potential upstroke (Vmax) and prolonged both of the effective refractory period (ERP) and the diastolic interval needed for the premature Vmax to recover to 98% in magnitude of the basic Vmax (98% recovery time) dose-dependently, without decreasing the resting potential. Among the ischemic components, low pH (pH 6.9) and high potassium (10 mM) extracellular environments potentiated the depressant actions of lidocaine in synergic manner, but no significant enhancement of the actions of procainamide were observed under exposure to any components of ischemia. Mechanisms underlying the difference of the depressant actions on ischemic myocardium between lidocaine and procainamide were discussed in the light of recent concepts of actions of local anesthetics, and came to the conclusion that lidocaine is the most preferable antiarrhythmic agent for the management of ventricular arrhythmias during acute ischemia or infarction.

Action Potentials↗
PubMed1987

Effect of procainamide on the induction of ventricular fibrillation by sequential ventricular stimulation.

The effect of procainamide on ventricular vulnerability to fibrillation was studied in 13 anesthetized open-chest dogs. Epicardial electrograms were recorded through forty bipolar electrodes placed on the surface of exposed ventricles. Ventricular fibrillation (VF) was induced by sequential extrastimulation. The number of extrastimuli required to induce repetitive extrasystole (RE) or VF were defined as repetitive extrasystole threshold (RET) or ventricular fibrillation threshold (VFT). The epicardial electrograms at the onset of ventricular arrhythmia were divided every 100 msec after the last extrastimulation, and the ratio of recordings with activation time of more than 50 msec during each divided period was defined as "chaotic score". Intravenous injection of procainamide at the dose of 20 mg/kg failed to increase RET but successfully increased VFT from 4.4 +/- 0.9 to 7.0 +/- 1.8 in hearts with necrosis. Procainamide significantly reduced chaotic score from 36 +/- 12% to 14 +/- 7% at 5 sec after the induction of ventricular arrhythmias. We concluded that the antifibrillatory action of procainamide is based on a reduction of the number of chaotic multiple reentries, but not on the prevention of reentry per se.

Animals↗
PubMed1979

Myocardial contractility in patients with ischemic heart disease during long-term administration of quinidine and procainamide. Direct measurement of segmental shortening with radiopaque epicardial markers.

The purpose of this investigation was to determine whether long-term oral administration of commonly prescribed doses of quinidine sulfate and procainamide hydrochloride to patients with ischemic heart disease affects myocardial contractility. Segmental contractility, assessed by the systolic shortening fraction, the relative change in interclip distance from diastole to systole, was measured by cineradiography of metal clips that had been sutured to the epicardium at the time of coronary artery bypass surgery. Global contractility was assessed by gated blood-pool scintigraphy. Systolic shortening fraction determinations and scintigraphy were obtained following five to seven days' administration of procainamide (500 mg every four hours), quinidine (200 mg every six hours), or neither drug in a random sequence. Serum drug levels (milligrams per liter) were 1.8 +/- 0.8 (mean +/- 1 SD) for quinidine and 3.7 +/- 1.1 for procainamide, when measured one hour before the next dose. During quinidine administration, mean segment shortening fraction decreased only slightly, but significantly (P less than 0.02), from 12.4 percent to 10.6 percent. The clinical importance of so small a change is questionable. During procainamide administration, there was a very small, insignificant (P greater than 0.9), decrease in segmental shortening. Global left ventricular function was not significantly changed by either drug. It appears that both drugs can be used over long periods in commonly prescribed doses in patients with ischemic heart disease without a major overall deleterious effect on cardiac performance.

Blood Pressure↗
PubMed1988

Effects of procainamide and disopyramide on long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic heart.

Though the efficacies of procainamide and disopyramide in treating arrhythmias are well established, their precise mechanisms of antiarrhythmic action remain unclear. Arrhythmias which occur during acute myocardial ischemia can be explained partly on a metabolic basis. The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acids has been suggested as a cause of serious arrhythmias. The purpose of this study was to investigate changes in free carnitine, long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic canine heart following the administration of procainamide and disopyramide. The coronary artery was occluded for 40 min and myocardial samples were prepared from both nonischemic and ischemic areas. Procainamide and disopyramide prevented the accumulation of long chain acyl carnitine and long chain acyl CoA in the ischemic myocardium. The results showed that procainamide and disopyramide had beneficial effects on fatty acid metabolism. It was suggested that one of the antiarrhythmic mechanisms of these drugs might be the prevention of the accumulation of fatty acyl derivatives in the ischemic myocardium.

Acyl Coenzyme A↗
PubMedDate not supplied

Noninvasive diagnosis of cardiac allograft rejection: the effect of procainamide.

The surface electrocardiogram (ECG) has been used as a noninvasive technique for the diagnosis of cardiac allograft rejection. Alteration in conduction, R-wave amplitude, and rhythm have been associated with rejection. These ECG findings are modulated by the myocyte sodium channel, but are inconsistent and occur only during severe rejection episodes. The purpose of this study was to (1) characterize changes in cardiac electrophysiology during allograft rejection using the highly sensitive intramyocardial electrocardiogram and (2) determine whether pharmacological sodium channel blockade with procainamide enhances subtle ECG changes. Nine mongrel dogs underwent heterotopic heart transplantation in which four intramyocardial leads (one anteriorly and posteriorly on each ventricle) were attached. Leads exited to a subcutaneously placed ECG block which was transcutaneously accessed posttransplant to record direct intramyocardial electrocardiograms. Six animals were treated with procainamide, while three were not and served as controls. Daily measurements included the QRS, QT, and QTc intervals and the R-wave amplitude. Endomyocardial biopsies were performed weekly and also when significant decline in ECG amplitude occurred. Detailed ECG interval analysis failed to establish any correlation between conduction and rejection, even in the procainamide-treated group. Intramyocardial amplitude analysis, however, had a sensitivity of 100% and a specificity of 86% for the diagnosis of rejection. The results indicate that intramyocardial ECG interval analysis is not predictive of rejection even when prolonging conduction with procainamide. Amplitude analysis, however, remains an accurate noninvasive means for the early detection of cardiac allograft rejection and should allow more selective use of endomyocardial biopsy.

Animals↗
PubMed1988

Electrochemical determination of N-oxidized procainamide metabolites and functional assessment of effects on murine cells in vitro.

Because of the implication of N-oxidized metabolites of procainamide in the induction of drug-related lupus, we have studied the electrochemical behavior of these metabolites and developed an electrochemical synthesis of nitrosoprocainamide. This synthesis was developed using procainamide hydroxylamine as the starting material which was oxidized to the nitroso species at an applied potential of 700 mV vs Ag/AgCl using a carbon packed bed bulk electrolysis flow cell. Conversion efficiencies of greater than 95% were achieved with this method. Subsequent studies with a chemically diverse series of biocompounds were used to investigate possible reactions between the procainamide hydroxylamine and nitroso species and these selected molecules. Only antioxidants such as cysteine, glutathione and ascorbic acid were found to react with the nitroso compound as determined by electrochemical methods, and this reaction was characterized as primarily a simple redox reaction at physiological pH. Animal studies conducted with murine spleen cells incubated with mitogens and various procainamide compounds demonstrated that the N-oxidized metabolites are the active immunopharmacologic agents.

Acecainide↗