SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
INTRODUCTION: Although intravenously administered procainamide has been used extensively during electropharmacologic testing for more than 10 years, there is little information available on the effects of incremental dosing of procainamide in patients with inducible, monomorphic ventricular tachycardia (VT). METHODS AND RESULTS: Twenty-nine patients with coronary artery disease had sustained monomorphic VT reproducibly induced in the baseline, drug-free state. Programmed stimulation was repeated 5 minutes after loading infusion (50 mg/min) of 7.5 and 15 mg/kg (all patients) and 22.5 mg/kg of procainamide (15 patients), while maintaining continuous infusion of 0.055, 0.11, and 0.165 mg/kg per minute after each increment in dose, respectively. Corresponding procainamide plasma concentrations were 5.6 +/- 2, 10.5 +/- 3, and 14.5 +/- 3 mg/L before, and 4.7 +/- 2, 9.6 +/- 3, and 14.6 +/- 4 mg/L after electrophysiologic study at each increment in dose of procainamide, respectively. Each incremental dose of procainamide resulted in significant prolongation of tachycardia cycle length and QRS duration during sinus rhythm and right ventricular pacing. Five (17%), 7 (24%), and 1 (7%) patients, respectively, had no inducible sustained VT following the incremental dosing of procainamide. Three of five patients who had no inducible VT at 7.5 mg/kg had VT induced again at a higher dose of procainamide. Four of 24 patients whose VT remained inducible at 7.5 mg/kg of procainamide had no VT induced at 15 mg/kg of procainamide. Twelve (41%), 15 (52%), and 6 (40%) patients, respectively, no longer had VT with baseline morphology induced following the incremental dosing of procainamide. VT with new morphology compared to baseline was induced in more than 40% of patients at one or more of the three different procainamide dosing regimens. The mean cycle length of VTs with new morphology was significantly shorter than the cycle length of tachycardias with baseline morphology at each particular dose of procainamide. CONCLUSION: Similar serum procainamide concentrations before and after programmed stimulation can be achieved at the described dosing regimen. Although 7.5 and 15 mg/kg of procainamide are both effective in suppressing induction of all VT in 20% to 25% of patients, non-inducibility at a particular dose of procainamide does not predict noninducibility at a respectively higher or lower dose. New morphologies of VT that are frequently faster than VTs with baseline morphology at a particular dose of procainamide can be induced in approximately half of the patients, and the clinical significance of these arrhythmias remains to be determined.
Procainamide administration often results in excessively high serum N-acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N-acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two-way crossover study was to determine if para-aminobenzoic acid (PABA) inhibits N-acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48-hour period after initiation of the infusion. Urine was collected over a 72-hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0-00, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0-00 and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety of efficacy of procainamide in patients.
OBJECTIVE: To evaluate the effect of prophylactic procainamide on the frequency of postoperative atrial fibrillation in patients undergoing myocardial revascularization. DESIGN: Prospective, randomized, double-blind, placebo-controlled pilot study. SETTING: Surgical intensive care unit and wards at a university hospital affiliate. PATIENTS: A total of 46 patients undergoing myocardial revascularization. INTERVENTIONS: Twenty-two patients received procainamide (procainamide group) and 24 patients received placebo (control group). Procainamide was administered to the procainamide group within 1 hr of the patient's arrival in the intensive care unit and consisted of an intravenous loading dose (12 mg/kg) followed by a maintenance dose (2 mg/min) of procainamide. The control group received a similar volume of placebo. When the patient was able to take oral medication, the study drug was administered orally in a weight-adjusted dosage. MEASUREMENTS: Electrocardiograms (EKGs) were continuously monitored. Procainamide and N-acetyl procainamide serum concentrations were measured, and the dosages in the procainamide group were adjusted by an independent observer. The study drug was continued for 5 days or until an event occurred that resulted in dismissal from the study. MAIN RESULTS: The procainamide group and control group had similar preoperative demographic descriptors and operative variables, except for the mean left ventricular ejection fraction, which was lower in the control group than in the procainamide group (60% vs. 68%, p = .03 [Wilcoxon rank-sum test]). There were no hospital deaths. The number of episodes of postoperative atrial fibrillation was significantly reduced in the procainamide group (5 episodes in 129 patient days at risk [3.9%/day at risk]) compared with the control group (17 episodes in 161 patient days at risk [10.6%/day at risk], p = .04 [Fisher's exact test]). Complication rates were similar in both groups. CONCLUSIONS: In a pilot trial, prophylactic procainamide reduced the number of episodes of atrial fibrillation in patients after coronary artery bypass grafting. Procainamide also decreased the number of patients who experienced postoperative atrial fibrillation. However, due to the small sample size, this latter difference was not statistically significant. Further studies are needed to confirm this encouraging trend.
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.
1. Previous studies suggest that procainamide is a substrate for organic cation/proton antiport. In order to study the coupling between procainamide flux and proton flux in greater detail we investigated the effects of extracellular procainamide addition upon intracellular pH in cultured monolayers of renal OK cells. Intracellular pH was monitored by use of BCECF as a probe. 2. Apical addition of procainamide (10 mM) caused a significant alkalinisation of intracellular pH. Basolateral addition of procainamide was equally effective in raising intracellular pH. A similar alkalinisation was found in two other renal cell lines: MDCK strain 1 and LLCPK1. 3. In contrast, both tetraethylammonium and N-methylnicotinamide, archetypal substrates for organic cation/proton antiport were without effect upon intracellular pH. 4. At physiological pH values, procainamide exists as a neutral weak base (B) and its conjugate weak acid (BH+). To test which species of procainamide was responsible for the alkalinisation, experiments in which [B] was kept constant whilst [BH+] was varied from 1.15 mM to 7.25 mM were performed. The results suggested that the neutral weak base (B) was the permeant species. 5. Procainamide efflux from procainamide-loaded cell monolayers resulted in a significant acidification of intracellular pH. As with procainamide uptake, this result could be ascribed to the movement of neutral weak base. 6. These effects of procainamide upon intracellular pH are consistent with nonionic diffusion of procainamide rather than an interaction of procainamide with the organic cation/proton antiporter. In addition, the results suggest that organic cation/proton antiport is not highly expressed in OK cells.
The short-term effects of incremental doses of procainamide (7.5, 15, 22.5, and 30 mg/kg) on right ventricular effective refractory period, intraventricular conduction, and induction of ventricular tachycardia were determined in 31 patients who had a history of sustained, unimorphic ventricular tachycardia. QRS duration during incremental ventricular pacing was used as an index of rate-dependent changes in intraventricular conduction. The mean plasma procainamide concentrations corresponding to the incremental doses were 5.5 +/- 1.2 (+/- SD), 9.0 +/- 1.6, 12.6 +/- 2.2, and 16.3 +/- 3.2 mg/liter. Each incremental dose of procainamide up to a dose of 30 mg/kg resulted in a significant increment in right ventricular effective refractory period and each dose up to 22.5 mg/kg potentiated a rate-dependent prolongation of QRS duration. After the 7.5 mg/kg dose of procainamide, induction of ventricular tachycardia was suppressed in eight of 31 patients. After higher doses of procainamide, induction of ventricular tachycardia was suppressed in two additional patients. In three of 10 patients in whom the induction of ventricular tachycardia was suppressed by 7.5, 15, or 22.5 mg/kg of procainamide, sustained unimorphic ventricular tachycardia was again inducible after a higher dose of procainamide. In three of 31 patients, only nonsustained ventricular tachycardia was inducible after a 7.5 to 22.5 mg/kg dose of procainamide; however, in two of these three patients, sustained ventricular tachycardia was again inducible after administration of a higher dose of procainamide. In conclusion, during electropharmacologic testing with procainamide, it is worthwhile to test a dose of 7.5 mg/kg, because this dose is often effective in patients who respond to this drug. However, the results of this study indicate that procainamide may be effective in suppressing the induction of sustained ventricular tachycardia at a relatively low plasma concentration, but not at a higher plasma concentration. Therefore, during long-term therapy with procainamide it may be important to avoid plasma procainamide concentrations not only lower, but also higher than the concentration that results in the suppression of induction of tachycardia.
Many of the cytotoxic substrates of the multidrug transporter are organic cations. Cimetidine, procainamide, and tetraethylammonium bromide were used in a Chinese hamster ovary model of multidrug resistance, to study handling of noncytotoxic cationic transport probes. Cimetidine and procainamide, but not tetraethylammonium, accumulated to a greater extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the resistant CHRC5 (C5) cell line. Accumulation of both cimetidine and procainamide was significantly increased by verapamil in C5 but not AB. Procainamide accumulation in both AB and C5 was temperature dependent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, tamoxifen, rhodamine, and ethidium also increased procainamide accumulation in C5 but not AB. Azide in glucose-free medium increased procainamide accumulation in C5, and this was reversed when glucose, but not 3-O-methylglucose, was added. Procainamide efflux rates were similar in AB and C5 and not affected by verapamil or azide. The initial rate of procainamide uptake was higher in AB than in C5, and both verapamil and azide increased the initial rate of procainamide uptake in C5. Thus, differences in accumulation of the noncytotoxic transport probe procainamide in the colchicine-sensitive and colchicine-resistant components of the Chinese hamster ovary cell line mimic the accumulation of known cytotoxic substrates for the multidrug transporter, such as colchicine, vinblastine, and doxorubicin. The differential accumulation of procainamide is due to differences in rates of drug influx, rather than efflux. Since procainamide influx is passive and decreased accumulation in the resistant line appears to parallel M(r) 170,000 glycoprotein presence and activity, we would speculate that decreased procainamide accumulation may be due to an indirect effect of the M(r) 170,000 glycoprotein, such as its effect on intracellular pH.
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)
We evaluated the efficacy of a single oral dose of procainamide to terminate paroxysmal tachycardia, when procainamide was taken shortly after onset of tachycardia, a regimen we have termed "periodic procainamide." In 12 patients (mean age 15 years) with non-life-threatening tachycardia (orthodromic reciprocating tachycardia, 8/12; ventricular tachycardia, 3/12; atrial flutter, 1/12) in whom intravenously administered procainamide (15 mg/kg at 1 mg/kg/min) terminated tachycardia, efficacy of a single oral dose of procainamide (25 mg/kg) to terminate tachycardia was tested during electrophysiologic study. After oral administration of procainamide, tachycardia was terminated and could not be reinitiated in 11 of 12 patients (9/12 less than 75 min, 2/12 greater than 120 min after administration). Time of tachycardia termination approximately coincided with the time of peak serum concentration of procainamide after the single oral dose. Delayed response or failure of procainamide to terminate tachycardia was associated with delayed and diminished peak serum procainamide concentration. After evaluation, 10 responders were instructed to take a single dose of procainamide when tachycardia occurred. During a mean follow-up of 9 months (range 2 to 17) seven of 10 patients had an opportunity to use periodic procainamide on one to more than 100 occasions; four of 10 patients have not had recurrence of tachycardia. Tachycardia was successfully terminated in six of seven patients using the periodic regimen and could not be terminated on the first out-of-hospital use in one of seven patients. Success of periodic procainamide was predicted during evaluation by rapid termination of tachycardia after oral administration.
The extent to which the procainamide-dextrose complex reverts to free procainamide hydrochloride in plasma was studied in vitro. The procainamide-dextrose species was formed, isolated using preparative liquid chromatography, and then added to six different lots of pooled plasma that were maintained at physiological temperature (37 +/- 0.1 degrees C). At zero, four, and eight hours after preparation of the samples, 1-mL portions were removed from each sample, extracted, and assayed for procainamide hydrochloride using high-performance liquid chromatography. The mean procainamide hydrochloride concentrations at zero, four, and eight hours after preparation were 2.67, 4.81, and 1.38 g/mL, respectively. Each lot of pooled plasma was statistically analyzed to determine if a significant amount of procainamide hydrochloride reappeared. Analysis of variance showed significant difference between the concentrations of free procainamide hydrochloride in the samples at zero, four, and eight hours (p less than 0.02). Follow-up with Duncan's multiple comparisons test determined that the mean procainamide hydrochloride concentrations immediately after preparation were not significantly different from those at eight hours, but the mean procainamide hydrochloride concentrations at four hours were significantly different from those at eight hours (p less than 0.01). A paired Student's t test comparing the data from zero and eight hours showed a significant reduction in mean procainamide hydrochloride concentrations with time (p less than 0.05). The procainamide-dextrose complex in vitro does not revert to free procainamide hydrochloride in plasma at physiological temperature during the first eight hours.
Procainamide is a class I antiarrhythmic drug. Most studies of the cellular electrophysiologic effects of procainamide have been done with concentrations well above the therapeutic range. We studied the effects of therapeutic concentrations (10 mg/L) of the drug on transmembrane action potentials recorded from isolated canine cardiac tissues. In normal false tendon Purkinje fibers with maximal diastolic potentials (MDPs) of -93 +/- 1 mV, procainamide decreased action potential duration (APD)-20mV and slightly prolonged APD100%. The dV/dtmax was not decreased. In normal subendocardial Purkinje fibers with MDPs of -92 +/- 1 mV, procainamide 10 mg/L significantly decreased dV/dtmax but did not affect APD-20mV. In normal muscle cells from left ventricular endocardium, procainamide 10 mg/L increased only APD100%. The effects of procainamide on partially depolarized Purkinje fibers varied. In normal subendocardial Purkinje fiber preparations superfused with 7.5 mM KCl-Tyrode's solution, the mean maximal diastolic potentials were -73 +/- 2 mV, and procainamide 10 mg/L slightly decreased action potential amplitude (APA) and increased APD-60mV. In contrast, in 24-h infarct zone Purkinje fibers with MDPs of -75 +/- 4 mV, procainamide 10 mg/L decreased APA and dV/dtmax and prolonged APD100%. In one experiment on an infarct preparation, procainamide also induced 2:1 block at cycle lengths shorter than approximately 400 ms. The results of these experiments indicate that therapeutic concentrations of procainamide exert selective effects on action potentials in partially depolarized zones of infarcted hearts. This action may explain why procainamide can abolish some reentrant arrhythmias.
UNLABELLED: The influence of procainamide on inducible ventricular tachyarrhythmias was evaluated in 35 dogs with experimental myocardial infarction, and 9 normal dogs. Programmed stimulation was performed from the right ventricular apex via a percutaneously positioned electrode catheter, using up to five extrastimuli before and after intravenous administration of procainamide (15 mg/kg). Procainamide levels in postinfarct dogs were 8.5 +/- 0.7 micrograms/mL (range 5.3-13.6 micrograms/mL). Procainamide exerted its greatest effect in postinfarct dogs with reproducible baseline ventricular fibrillation. Six of nine dogs (P less than 0.05) with ventricular fibrillation had sustained monomorphic ventricular tachycardia (cycle length: 147 +/- 4 msec) induced after procainamide administration. This ventricular tachycardia required significantly more extrastimuli than baseline ventricular fibrillation (3 +/- 0.3 extrastimuli before vs 4 +/- 0.3 extrastimuli after procainamide). Procainamide never converted ventricular fibrillation to ventricular tachycardia in normal dogs. Procainamide had minimal effect on inducible ventricular tachycardia after myocardial infarction. Ventricular tachycardia induction was abolished in only 2 of 17 dogs despite significant prolongation of electrophysiological parameters. Ventricular tachycardia cycle length, and the number of extrastimuli required were unchanged by procainamide in this subgroup. CONCLUSION: Ventricular tachycardia is insensitive to the antiarrhythmic properties of procainamide in this model. In contrast, procainamide is able to convert postinfarction ventricular fibrillation to ventricular tachycardia, presumably by promoting sustained, organized reentry. This previously undescribed action is an unusual form of proarrhythmic effect, and suggests that this drug should be used cautiously in patients after myocardial infarction.
OBJECTIVE: To describe a possible case of procainamide-induced intrahepatic cholestatic jaundice that was recognized six weeks after the initiation of procainamide therapy and to summarize the five previously reported cases. CASE SUMMARY: A 77-year-old woman with a history of hypertension, insulin-dependent diabetes mellitus, temporal arteritis, and Wolff-Parkinson-White syndrome who had taken procainamide for six weeks presented to the hospital with disorientation and acute renal and hepatic dysfunction. In addition to disorientation, scleral icterus, and diffuse maculopapular rash, her physical examination was generally normal. There was no evidence of fever, nausea, vomiting, lymphadenopathy, or eosinophilia. Her liver enzyme concentrations increased significantly from baseline (beginning of procainamide therapy). Her N-acetylprocainamide (NAPA) concentration was elevated to 52 mg/L upon admission. Procainamide was discontinued and her NAPA concentration returned to within normal limits in two days. Diagnostic tests were performed to rule out active hepatitis, vasculitis, and liver malignancies. After procainamide was discontinued and prednisone treatment was started, she became more oriented and her liver enzyme concentrations slowly improved. DISCUSSION: Only five cases of procainamide-induced liver abnormalities have been previously reported; these included granulomatous hepatitis and intrahepatic cholestasis. The mechanism for liver dysfunction is not known; however, it is proposed to be a delayed hypersensitivity reaction. Clinical hallmarks of hypersensitivity include fever, eosinophilia, rash, and lymphadenopathy; nausea and vomiting also may be present. Of the five reported cases, all experienced fever and only one experienced pruritus. No patients had eosinophilia or lymphadenopathy. Because of the temporal increase in liver enzyme concentrations after six weeks of procainamide therapy, we believe that this case represents another possible procainamide-induced hypersensitivity reaction. CONCLUSIONS: Procainamide-induced liver dysfunction can occur from one day to six weeks after initiation of the drug and may subside one day to several weeks after discontinuation of therapy. Symptoms may include nausea, vomiting, rash, and fever. Liver enzyme concentrations are abnormal. It is important to recognize the possibility of such a reaction early so that procainamide therapy can be discontinued promptly to avoid further liver damage.
Ranitidine, procainamide and its active N-acetyl metabolite (NAPA) are renally secreted bases which can compete for carrier-mediated transport processes. The effect of ranitidine on the disposition of procainamide and NAPA was evaluated in 13 healthy men. Subjects were randomized to receive p.o. procainamide (1000 mg) alone (base line) and after p.o. ranitidine, 150 mg twice a day for 4 days. Blood and urine samples were collected at frequent intervals for 24 hr after the procainamide dose. There were no significant differences in the mean pharmacokinetic parameters of procainamide and NAPA after ranitidine coadministration compared to base line. However, individual changes did occur and regression analysis revealed a correlation between base-line procainamide renal clearance (CLR) and the change (delta) in CLR after ranitidine (r = 0.69, P less than .01). Subsequently, individuals were separated into Group I (n = 7) if they had a decrease or Group II (n = 6) if they had an increase in procainamide CLR after ranitidine. Mean +/- S.D. base-line procainamide CLR was 539 +/- 114 ml/min for Group I vs. 410 +/- 61 ml/min for Group II (P less than .01). During ranitidine coadministration, Group I had a 23% decrease in mean procainamide CLR (P less than .05), whereas Group II had a 21% increase (P less than .05). There were no significant differences in the metabolic clearance (CLM) of procainamide between the two groups at base line. However, Group I had a 45% increase (P less than .01) whereas Group II had a 41% decrease (P less than .05) in mean procainamide CLM with concomitant ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of the widely used antiarrhythmic agent, procainamide, was studied in rats with extrahepatic biliary obstruction produced by ligation of the common bile duct. Various biological fluids, including plasma, saliva, and urine, were analyzed for procainamide and/or its major metabolite, N-acetylprocainamide. Ligation of the common bile duct immediately prior to intravenous administration of 50 mg/kg procainamide did not alter plasma, saliva, or urine concentrations of procainamide, indicating that biliary excretion was of minor importance in the elimination of procainamide. However, bile duct ligation allowed to persist for 4 days significantly elevated plasma, saliva, and urine levels of procainamide. While the increase in urinary procainamide paralleled the increase observed in plasma, salivary concentrations did not. Bile duct ligation did not appear to impair nonmicrosomal acetylation of procainamide, although a significantly greater amount of unchanged drug was found in the urine after 24 hr. Pharmacokinetic analysis via the two-compartment open model showed that bile duct ligation caused a decrease in overall clearance from approximately 61.94 to 28.71 ml/kg/min. This reduction probably resulted from the decreased microsomal metabolism of procainamide. The significant reduction in the apparent volume of distribution from 3.76 to 2.72 liter/kg could be the result of reduced binding sites. There was also a significant increase in the elimination half-life of procainamide from 47.39 to 78.64 min in bile duct ligated rats.
The efficacy and tolerance of quinidine and procainamide used individually and in combination were studied in 19 patients with frequent ventricular premature complexes (VPCs). During single-drug treatment, the maximum tolerated dose of quinidine without extracardiac dose-related side effects was 1.6 +/- 0.21 g/day and that of procainamide was 4.1 +/- 1.05 g/day. During combination therapy with smaller doses (p less than 0.05) of quinidine (1.16 +/- 0.26 g/day) and procainamide (2.80 +/- 0.98 g/day), no patient had side effects. Before treatment, all patients had frequent (more than 60 per hour) VPCs and 17 had ventricular tachycardia on Holter monitoring. The frequency of VPCs was reduced to 22 +/- 19% with quinidine, 47 +/- 40% with procainamide and 9 +/- 11% with combination therapy (p less than 0.05, combination vs procainamide or quinidine alone). Individually, an effective regimen (more than 83% reduction of VPCs and abolition of ventricular tachycardia) was found in 5 patients (26%) receiving quinidine alone at maximal tolerated dose, in 4 (21%) receiving procainamide alone at maximal tolerated dose, and in 14 (74%) receiving combination therapy (p less than 0.01 vs quinidine or procainamide). Thus, the antiarrhythmic effects of quinidine and procainamide are additive. When quinidine or procainamide are additive. When quinidine or procainamide is ineffective because dose-related extracardiac side effects limit the maximal tolerated dose, combination therapy in smaller and tolerable doses avoids side effects and is more effective than either drug alone at the maximal tolerated dose.