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PubMed1997

Facilitating influence of procainamide on conversion of atrial flutter by rapid atrial pacing.

In a prospective, double-blind, randomized, placebocontrolled study we investigated the facilitating influence of intravenous procainamide on conversion of atrial flutter by rapid atrial pacing. Fifty consecutive patients with spontaneous sustained atrial flutter were 1:1 randomized into two homogenous groups: group A received 10 mg.kg-1 procainamide intravenously, group B placebo. After infusion there was a significant (P < 0.01) lengthening of the flutter cycle with respect to baseline in group A, exceeding the flutter cycle length of the control group (P < 0.05). The overall success rate of rapid atrial pacing in restoring sinus rhythm was significantly higher after pre-treatment with procainamide compared to placebo (100% vs 76%; P < 0.05): 20 patients of group A reverted immediately after pacing to sinus rhythm, the remaining five after a brief episode of atrial fibrillation. In the placebo group, 16 patients showed a prompt conversion to sinus rhythm and three after transient atrial fibrillation. In the remaining six patients, due to sustained pacing-induced atrial fibrillation, direct current cardioversion was necessary. After administration of procainamide a less aggressive stimulation protocol with significantly (P < 0.01) longer paced cycles to interrupt atrial flutter was achievable. In conclusion, intravenous procainamide augments the efficacy of atrial pacing to convert atrial flutter to sinus rhythm.

Adult↗
PubMed1979

Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia.

The use of procainamide or procaine for treatment of malignant hyperthermia is commonly recommended. The skeletal muscle relaxant dantrolene has also been indicated for treatment of this complication during anesthesia. In the present study, effects of procainamide and dantrolene were compared in malignant hyperthemia-susceptible (MHS) pigs in vivo and on MHS muscle from human patients in vitro. The ED50 for dantrolene block of indirectly evoked twitch tension was 0.85 mg/kg in MHS pigs. A final cumulative dose of 2 mg/kg resulted in 68 per cent block of the twitch response. In contrast, procainamide at a final cumulative dose of 14 mg/kg had no effect on twitch response of the MHS pigs. Dantrolene, 3 micrometer, in vitro (approximately 0.8 mg/kg in vivo) was effective in preventing or reversing the abnormal halothane-induced contracture response of human MHS muscle strips. Procainamide, 0.11 mM, a dose approximating clinical levels (about 22 mg/kg), had no effect on basal twitch response or on the abnormal halothan-induced contracture of MHS human muscle. These results confirm the effectiveness of dantrolene and the lack of effectiveness of procainamide in the treatment of malignant hyperthemia.

Animals↗
PubMedDate not supplied

Metoprolol or propranolol does not alter the kinetics of procainamide.

Eight healthy volunteers received a single 500 mg intravenous dose of procainamide hydrochloride by 30-min infusion on three occasions in random sequence. The three modes of administration were (a) control, without concurrent drugs; (b) during coadministration of propranolol, 80 mg three times daily; and (c) during coadministration of metoprolol, 100 mg two times daily. Procainamide kinetics were determined from multiple serum concentrations measured by enzyme-multiplied immunoassay (EMIT) during 10 h after each dose. A metaproterenol infusion study verified a high degree of beta-blockade during trials 2 and 3. Mean procainamide half-life during the three trials (1.9, 2.2, and 2.3 h, respectively) tended to show prolongation during beta-blocker treatment, but the overall difference was of borderline significance (0.05 less than p less than 0.1). Total procainamide clearance (16.2, 14.1, and 13.7 ml/min/kg) did not differ significantly between the three trials, nor was there a significant change in area under the serum concentration curve for N-acetylprocainamide, the major metabolite. Thus the kinetics of procainamide in healthy persons are not importantly altered by typical therapeutic doses of two beta-adrenergic blockers.

Adult↗
PubMed1993

Sustained atrial flutter around the tricuspid valve in pigs: differentiation of procainamide (class IA) from flecainide (class IC) and their rate-dependent effects.

The wavelength theory considers two determinants of reentry, i.e., refractoriness and conduction velocity. It does not take excitability into account primarily. We evaluated frequency-dependence of excitability and refractoriness before and after flecainide or procainamide administration in relation to termination of reentrant atrial flutter. After making a Y-shaped lesion in the right atrium, we induced 62 flutters (cycle length 171 +/- 15 ms) by electrical stimulation in 15 pigs. Strength-interval curves were determined to assess excitability and refractoriness. Multiple cycle lengths were used to establish rate-dependent changes. Flutter cycle length increased after flecainide (to 290 +/- 67 ms) or procainamide (to 295 +/- 54 ms). The flutters always terminated abruptly (flecainide dose 103 +/- 104 mg, plasma concentration 370 +/- 21 ng/ml; procainamide dose 1,150 +/- 686 mg, concentration 51 +/- 24 mg/l). Flecainide caused an increase in diastolic thresholds from 0.3 +/- 0.2 to 0.8 +/- 0.5 mA (p < 0.006) and procainamide from 0.5 +/- 0.3 to 0.9 +/- 0.5 mA (p < 0.02). The increase in threshold was frequently dependent. Procainamide increased refractoriness at longer cycle lengths (> or = 250 ms), but this effect was abolished at shorter cycle lengths, indicating that only after significant slowing of the rate, prolongation of refractoriness may appear. Thus, both drugs interrupt reentrant flutter mainly by reducing excitability. Subclassification into IA and IC may be less relevant at high rates. Construction of strength-interval curves and assessment of rate-dependent "postrepolarization refractoriness" should be considered when one studies drugs that influence excitability.

Animals↗
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↗
PubMed1987

Interaction of steady-state procainamide with H2-receptor antagonists cimetidine and ranitidine.

This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on steady-state procainamide pharmacokinetics. Six healthy men were given 500 mg sustained-release procainamide every 6 h, for a total of 13 doses, on three occasions. Subjects were randomly assigned to three treatments by a Latin-square design: cimetidine 1,200 mg/day, ranitidine 300 mg/day, and no H2-receptor antagonist (control) for 4 days. Cimetidine significantly increased the procainamide area under the serum concentration-time curve by 43%, decreased renal clearance by 36%, and decreased the ratio of systemic clearance of procainamide to bioavailability by 28%. Ranitidine did not significantly alter procainamide steady-state pharmacokinetics.

Acecainide↗
PubMed1998

Effect of age, gender, and race on steady state procainamide pharmacokinetics after administration of procanbid sustained-release tablets.

Procainamide hydrochloride is a Class 1A antiarrhythmic agent administered intravenously or orally for treatment of symptomatic ventricular premature depolarizations (VPD), nonsustained ventricular tachycardia, and life-threatening ventricular arrhythmias. A new sustained-release formulation, Procanbid, which allows for twice-daily dosing was recently approved for marketing in the United States. This paper describes the population pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), the major metabolite, in healthy volunteers and patients with VPD by combining Cmax, tmax, Cmin, and AUC(0-12) values at steady state from six multiple-dose studies in which one 1000-mg or two 500-mg Procanbid tablets were administered. Means of parameters by race and gender were inspected for trends likely to be of clinical relevance. Procainamide and NAPA pharmacokinetic parameters observed after administration of Procanbid tablets were similar in blacks and whites, and in men and women. However, differences in body size should be considered when determining the Procanbid dose for women. Participant age had significant impact on NAPA pharmacokinetics in this study population and should be considered in dose selection. Age effects on procainamide were not detected in the study population, which was heavily weighted toward younger subjects, but are anticipated in the older population of patients for which procainamide is indicated. Procanbid formulation performance was not altered by patient demographics.

Acecainide↗
PubMed1975

Procainamide absorption studies to test the feasibility of using a sustained-release preparation.

Using in vitro techniques it was confirmed that whilst the release of procainamide from the conventional formulation (Pronestyl) was rapid, that from the sustained-release preparation (Cardiorytmin Retard) occurred over a prolonged period. 2 The peak plasma procainamide concentrations after single doses of Cardiorytmin Retard were relatively lower and occurred later than those after single doses of Pronestyl. Furthermore, after reaching a peak, the fall in plasma procainamide concentration was less rapid after the sustained-release preparation. Early urinary recovery of procainamide in patients and in healthy volunteers was greater after Pronestyl than after Cardiorytmin Retard, though overall recovery in urine was similar. These findings indicate that the absorption of the sustained-release preparation is slower, though the overall bioavailabilities of the two preparations are almost the same. 3 These results confirm the feasibility of using a sustained-release procainamide preparation, such as Cardiorytmin Retard, since it would be possible to administer the same amount of drug in fewer daily doses without plasma concentrations becoming ineffective towards the end of each dosing interval.

Adult↗
PubMed1982

Ethanol-induced increase in procainamide acetylation in man.

1 The effect of ethanol on procainamide pharmacokinetics was studied in humans by two different experimental designs. In one, ethanol was given 1.5 h after taking the drug followed by hourly drinks, while in the other ethanol was given 2 h before and subsequently after taking the drug. 2 In both studies, ethanol caused a significant reduction of T1/2 and a significant increase in total clearance of procainamide, while the apparent volume of distribution of procainamide, as well as the renal clearance of both procainamide and N-acetylprocainamide were unaffected by ethanol treatment. 3 Ethanol treatment increased the percentage of N-acetylprocainamide measured in blood and urine and the ratio of AUCNAPA/AUCPA significantly. 4 The T1/2 and total clearance of procainamide was significantly different in slow and rapid acetylators.

Acetates↗
PubMed1978

Intermittent atrioventricular block: procainamide administration as a provocative test.

Twelve patients with clinical features suggesting possible intermittent high degree atrioventricular block were studied. All 12 patients had basic 1:1 atrioventricular conduction but nine had an electrocardiographic pattern of bifascicular distal conduction disease (right bundle branch block with left anterior or posterior hemiblock, or left bundle branch block). Intracardiac conduction was assessed by recording of the His bundle electrocardiogram and atrial pacing techniques, before and 20 minutes after intravenous administration of procainamide, in a dose of up to 10 mg/kg. Before procainamide administration, seven of the 12 patients had a prolonged H-V interval (greater than 55 ms). Procainamide administration lengthened the H-V interval in all 12 patients by 5--40 ms. In five patients, procainamide induced second or third degree AV block below the level of the bundle of His. It was concluded that the administration of procainamide may be a useful provocative test of distal conduction in patients with possible intermittent AV block.

Aged↗
PubMed1985

Effects of lidocaine, procaine, procainamide and quinidine on electrophysiological properties of cultured embryonic chick hearts.

The effects of lidocaine, procaine, procainamide and quinidine were studied on organ-cultured embryonic chick (2-3 day-old) ventricular cells. Lidocaine (10(-5) - 10(-4)M), in a dose-dependent manner, reduced the rate of pacemaker discharge, the action potential amplitude (APA), the maximum rate of rise (Vmax) of the upstroke of the action potential and the action potential duration at 50% repolarization (APD50). These changes occurred without alterations in the maximum diastolic potential (MDP). Extracellular electrical field stimulation could still evoke action potentials in cells arrested by 10(-4)M lidocaine, but 10(-3)M lidocaine completely abolished electrical activity. Procaine, procainamide and quinidine, at 5 X 10(-5)M to 10(-3)M, depolarized the cells to around -30 mV and reduced APA and Vmax. Procaine and procainamide increased APD50, but quinidine shortened it. All the effects described disappeared completely in about 40 min of superfusion with drug-free Tyrode solution. Isoprenaline (5 X 10(-7)M) and adrenaline (10(-6)M) restored spontaneous firing of preparations arrested by any of the antiarrhythmic agents and repolarized ventricular cells depolarized by procaine, procainamide or quinidine. Propranolol (5 X 10(-7)M) did not affect the depolarization produced by procaine (5 X 10(-4)M), but antagonized its reversal by isoprenaline. In contrast, isoprenaline (10(-6)M) did not produce recovery of automaticity of preparations arrested by verapamil (10(-5)M). Histamine (10(-5)M) or strontium (10 mM) were not able to restore rhythmic activity in cells arrested procaine. Application of long (10-15 s duration) hyperpolarizing currents did not reverse the blocking effect of procaine, procainamide and quinidine. The input resistance increased during the procaine-induced depolarization. It is suggested that the four agents studied block the slow Na+ channels responsible for the upstroke of the action potential in young chick heart cells. A drug-induced decrease in PK may occur in those cells arrested at low levels of membrane potential.

Action Potentials↗
PubMed1999

Rate dependent effects of procainamide on the threshold current for pacing in the setting of postrepolarization refractoriness in dogs.

Normally, ventricular APD exceeds the VERP. However, under specific circumstances this relation may change and can become inverse. This phenomenon of postrepolarization refractoriness may be caused by a decrease in excitability. The threshold current (TC) for pacing has never been quantified as a possible explanation for these observations. Using a MAP pacing catheter in the right ventricular apex, the rate dependent behavior of TC, VERP, and APD before and after procainamide (dose 20 mg/kg in 10 min + 5 mg/min infusion) was determined in 17 dogs with chronic complete AV block. Initially, TC was determined with 0.1 mA accuracy. Using a pacing current of at least twice TC, VERP and APD showed a similar, rate dependent shortening for PCLs 800, 575, and 350 ms. Procainamide treatment led to an equal, rate independent VERP and APD increase: no post repolarization refractoriness. Subsequently, accuracy for TC determination was increased to 0.01 mA. Comparing PCLs 800 and 250 ms, TC doubled from 0.05 +/- 0.01 to 0.10 +/- 0.09 mA during control and almost tripled from 0.06 +/- 0.02 to 0.17 +/- 0.10 mA (P < 0.05) after procainamide. Using a fixed pacing current of exactly twice TC found at 800 ms PCL during control, VERP exceeded APD after procainamide treatment at 300 and 250 ms PCL: postrepolarization refractoriness. Increasing the pacing current to twice the rate dependent TC, the relation between VERP and APD normalized: no postrepolarization refractoriness. We conclude that after procainamide, rate dependent TC increase is of major importance for the phenomenon of postrepolarization refractoriness.

Animals↗
PubMed2004

Massive cell vacuolization induced by organic amines such as procainamide.

Procaine and some other basic drugs reportedly induce vacuolization of various cell types. We addressed the concentration-effect and structure-activity relationships as well as the mechanism of this effect using three cell lines. Massive vacuolization occurs over several hours in primary cultures of rabbit pulmonary artery smooth muscle cells (SMCs) and COS-1 cells in response to procaine and loosely related amine compounds (procainamide, N-acetyl-procainamide, metoclopramide, lidocaine, triethylamine, nicotine) used at 2.5 mM. Furthermore, chloroquine, propranolol, diphenhydramine, and neutral red are active in this respect at 100 to 250 microM in SMCs and COS-1 cells. Human embryonic kidney 293 cells mildly responded to triethylamine, nicotine, and propranolol only. Tetraethylammonium was uniformly inactive, as well as many other drugs in all three cell types (concentrations up to 2.5 mM). Procainamide does not induce apoptosis in SMCs treated for up to 48 h, although the vacuolization is sustained and proliferation and migration are reduced during this period. Procainamide-induced vacuolization is reversible on drug washing, largely prevented by bafilomycin A1 cotreatment, and has a tentatively identified Golgi origin (uptake of ceramide-C5). Procainamide and neutral red are concentrated in SMCs in a bafilomycin A1-sensitive manner. The preventive effect of bafilomycin A1 suggests that the vacuoles originate from the osmotic swelling of acidic organelles in which the charged basic drugs are trapped at low pH. Drug transport at the plasma membrane may be limiting for this type of response, as suggested by the cell type selectivity of agents and the inhibitory effect of some drugs such as quinidine.

Animals↗
PubMed2005

Levofloxacin and ciprofloxacin decrease procainamide and N-acetylprocainamide renal clearances.

Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05). During ciprofloxacin treatment, only procainamide and NAPA renal clearances decreased significantly.

Acecainide↗
PubMed1997

Effects of procainamide on the excitable gap composition in a canine model of atrial flutter.

The effects of increasing concentrations of procainamide on the composition of the excitable gap were determined in a canine model of atrial flutter. Using the model of a Y-shaped lesion in the right atrium, reentry around the tricuspid valve was induced by burst pacing in 10 open-chest chloralose-anesthetized dogs. Diastole was scanned with a single premature stimulus and the relationship between the coupling interval of the premature beat and the return cycle length (CL) determined a reset-response curve that described the excitable gap. This was repeated up to the maximum flutter CL while infusing procainamide (30 mg/kg) over 1 h. Procainamide progressively prolonged the flutter CL from 131 +/- 21 (+/-SD) to 188 +/- 46 ms (p < 0.01) and the effective refractory period from 96 +/- 19 to 149 +/- 47 ms (p < 0.01). At peak plasma levels of 77 +/- 33 mumol/L the drug terminated flutter only in two dogs. Neither the duration (35 +/- 10 to 39 +/- 13 ms) nor the composition of the excitable gap changed on drug. A fully excitable portion (7 +/- 3 ms or 20 +/- 11% of the excitable gap) persisted on procainamide (7 +/- 3 ms or 19 +/- 9% of the excitable gap). It was concluded that procainamide prolongs the atrial flutter CL and the effective refractory period but does not change either the duration or composition of the excitable gap even at plasma concentrations that significantly exceed those recommended in man.

Action Potentials↗
PubMed1986

The effects of procainamide on conduction in anisotropic canine ventricular myocardium.

Although conduction velocity in cardiac tissue is dependent on fiber orientation, the influence of commonly used antiarrhythmic agents on conduction longitudinal and transverse to such fibers is unknown. We evaluated the effects of procainamide on conduction velocity and intracellular potentials in vitro during conduction longitudinal and transverse to fiber orientation in epicardial strips obtained from areas of uniform fiber orientation from 15 adult mongrel dogs. Ventricular epicardial strips demonstrated marked anisotropy. At a pacing cycle length of 1000 msec, mean conduction velocity longitudinal to fiber orientation averaged 0.602 +/- 0.051 m/sec and mean conduction velocity transverse to fiber orientation was 0.186 +/- 0.024 m/sec, resulting in a ratio of longitudinal to transverse conduction velocities of (theta L/T) 3.27 +/- 0.38. After the addition of procainamide, conduction velocity decreased to 0.532 +/- 0.062 m/sec longitudinal to fiber orientation and to 0.174 +/- 0.023 m/sec transverse to fiber orientation resulting in a decrease of theta L/T to 3.09 +/- 0.37 (p less than .05 vs control). Before the addition of procainamide, when pacing at progressively shorter cycle lengths, conduction velocity longitudinal to fiber orientation was relatively unchanged, whereas conduction velocity transverse to fiber orientation decreased resulting in an increase in theta L/T. After the addition of procainamide, conduction velocity at shorter pacing cycle lengths decreased both longitudinal and transverse to fiber orientation demonstrating the well-known use-dependent effect of procainamide. However, in contrast to control conditions, conduction velocity longitudinal to fiber orientation was slowed by a greater extent than the conduction transverse to fiber orientation, resulting in an even greater decrease in theta L/T. To investigate the effect of differences in drug binding during propagation in different directions, we examined conduction velocity during alternations in pacing direction and compared it with velocity during steady-state pacing. At a pacing cycle length of 1000 msec, no difference was observed between the initial conduction velocity after changing pacing directions and the steady-state conduction velocity. At pacing cycle lengths shorter than 1000 msec, when changing from transverse to longitudinal conduction, there was an initial drop in normalized conduction velocity that was present on the first beat of longitudinal conduction; however, with continued pacing in a longitudinal direction there was a further decrease in conduction velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1988

Effects of procainamide on intra-atrial [corrected] electrograms during atrial fibrillation: implications [corrected] for detection algorithms.

The effects of antiarrhythmic drugs on electrograms have implications for arrhythmia-detection algorithms in implantable antitachycardia devices. Filtered and unfiltered intra-atrial electrograms were analyzed in eight patients who received procainamide (50 mg/min iv, up to 1000 mg) during 11 episodes of atrial fibrillation. Continuous recordings were made before, during, and after the infusion. The recordings were digitized, divided into 4.27 sec segments, and analyzed for atrial rate, median frequency and amplitude probability density function. Significant differences were noted before and after infusion of procainamide for atrial rate (498 +/- 97 vs 356 +/- 146 beats/min; p less than .005), median frequency (5.50 +/- 1.22 vs 4.24 +/- 0.99 Hz; p less than .0005), and density (58.3 +/- 13.9% vs 69.1 +/- 15.0%; p less than .005). Pre- and postprocainamide values were compared with published criteria for detection of atrial fibrillation. Before procainamide, only 2.3%, 5.7%, and 3.4% of the data segments failed to meet criteria for atrial fibrillation by rate, frequency content, and density, respectively. In contrast, after procainamide, 50%, 36.4%, and 28.4% of the data segments failed to meet these same criteria, despite electrograms still meeting morphologic criteria for atrial fibrillation. Thus procainamide resulted in changes sufficient to cause failure of published criteria for detection of atrial fibrillation. These findings have broad implications for the function of antitachycardia devices in patients receiving antiarrhythmic drug therapy.

Adult↗
PubMed1988

Procainamide infusion test: inability to identify patients with Wolff-Parkinson-White syndrome who are potentially at risk of sudden death.

Persistence of preexcitation in sinus rhythm with procainamide infusion has been reported to occur in patients with a short anterograde accessory pathway effective refractory period (AERPAP) and this test has been proposed as a reliable noninvasive method to identify patients with the Wolff-Parkinson-White syndrome who are at risk of sudden death. However, sudden death correlates best with a shortest preexcited RR interval during atrial fibrillation (SRRPE) of 260 msec or less. We infused 10 to 12 mg/kg procainamide to 56 patients to determine whether persistence or loss of preexcitation in sinus rhythm identified patients with SRRPEs of 260 or less or greater than 260 msec, respectively. Atrial fibrillation was induced in 53 patients. Of these, 32 patients had persistence of preexcitation with procainamide infusion and SRRPE in this group of patients was shorter than that in patients in whom preexcitation was lost (194 +/- 44 vs 235 +/- 55 msec, p less than .05). However, preexcitation persisted after procainamide infusion in only 31 of 46 (67%) patients with SRRPEs of 260 msec or less. Furthermore, 15 of 21 patients who lost preexcitation had SRRPEs of 260 msec or less and two of these patients had a history of ventricular fibrillation. The correlation between AERPAP and SRRPE was studied in a separate group of 79 patients with single accessory pathways. There was a significant (p less than .001) but poor (r = .58) correlation between these two variables. Thus, the procainamide test regarding accessory pathway refractoriness often cannot be extrapolated to SRRPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗