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PubMed1999

Involvement of CYP2D6 activity in the N-oxidation of procainamide in man.

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.

Adult↗
PubMed1964

THE GANGLION BLOCKING ACTION OF PROCAINAMIDE.

In cats and rabbits procainamide (20 to 50 mg, intravenously) produced a fall of blood pressure of 20 to 50 mm Hg which reached a maximal effect within 1 min and lasted for about 5 min. Procainamide reduced the pressor responses to nicotine and to carotid arterial occlusion and reduced the depressor response to vagal stimulation, but did not antagonize the actions of adrenaline or noradrenaline on blood vessels. The contractions of the nictitating membrane to stimulation of the preganglionic cervical sympathetic nerve were partially or completely blocked by 20 to 50 mg of procainamide given intravenously. The ganglion blocking effect was more abrupt in onset and more slow to recover than that due to hexamethonium and had about 1/250th of the activity of the latter. Procainamide (1 mg) reduced the acetylcholine output of the perfused superior cervical ganglion to below 30% of the control value and blocked transmission completely. Small doses (10 mug) reduced the acetylcholine output but hardly affected ganglionic transmission. Procainamide, injected into the perfused superior cervical ganglion, blocked contractions elicited by stimulation of the preganglionic cervical sympathetic nerve for a longer period than those produced by acetylcholine injected into the perfusion circuit to the ganglion; the reverse was true for hexamethonium. Procainamide reduced the size of action potentials recorded from the superior cervical ganglion without altering the resting potential of the ganglion. The ganglion blocking activities of procainamide and hexamethonium often potentiated each other, especially when the preparation had been set up for several hours. On the guinea-pig isolated ileum preparation, procainamide (0.5x10(-4) g/ml.) antagonized responses due to acetylcholine, histamine and, most effectively, to nicotine. On the isolated heart, procainamide (1 mg) almost abolished the bradycardia produced by acetylcholine; 10 mg slowed and weakened the heart, while 100 mg stopped it. We conclude that procainamide, like procaine, blocks ganglionic transmission by (1) depressing the release of acetylcholine from preganglionic nerve endings; and (2) competing, with the acetylcholine which is released, for receptor sites on the ganglion cells. The amounts required to produce significant effects in vivo and in vitro are comparable. The methods available for detecting this type of ganglion blocking action are discussed.

Acetylcholine↗
PubMed1988

Effects of procainamide and lidocaine on electrically inducible ventricular tachycardia studied with programmed ventricular stimulation in post myocardial infarction.

The effects of procainamide and lidocaine, representative of class IA and IB antiarrhythmic agents, on electrically inducible ventricular tachycardia (VT) were studied using programmed ventricular stimulation in 47 post myocardial infarction patients at an average of 1.5 months after the onset. The mean doses of administered procainamide and lidocaine were 1050 mg and 161 mg, and their mean plasma concentrations were 7.5 micrograms/ml and 3.1 micrograms/ml respectively. The induction of sustained VT was suppressed in 15 of 29 patients (52%) by procainamide, but in none by lidocaine. The induction of nonsustained VT was suppressed in 6 of 18 patients (33%) by procainamide, and in 1 of 8 patients (13%) by lidocaine. The efficacy rate of procainamide was significantly higher than that of lidocaine in suppression of VT induction (21/47 vs 1/14 p less than 0.01). Procainamide significantly prolonged the effective refractory period of the right ventricle as well as the HV and QRS interval, however lidocaine did not affect them significantly. On the other hand, the worsening effect which changed nonsustained VT inducible in the baseline into sustained VT inducible post drug administration was demonstrated in 8 of 18 procainamide cases (44%), and in 3 of 8 lidocaine cases (38%). Between the procainamide effective and ineffective or worsening patients, there were no differences found in the electrophysiologic variables either in the baseline or post procainamide administration. We concluded that procainamide was more effective than lidocaine for the prevention of potential life-threatening VT induction in post myocardial infarction patients, although its efficacy was considerably limited, and to confirm the effectiveness and exclude the worsening effects of the class IA and IB antiarrhythmic agents, drug testing using programmed ventricular stimulation appeared to be valuable.

Cardiac Pacing, Artificial↗
PubMedDate not supplied

Influence of midazolam on pharmacokinetic parameters of procainamide in rabbits.

The majority of antiarrhythmic drugs have very narrow therapeutic range, and they may cause some side effects at doses used for curing cardiac arrhythmias. These drugs may enter different interactions. Procainamide also may interact with other drugs. Also some other drugs may change pharmacokinetics of procainamide, for example the iv anesthetics influence on pharmacokinetic parameters of procainamide. The aim of the study was to investigate the influence of midazolam on the plasma concentrations and pharmacokinetic parameters of procainamide in rabbits during two hours of observation. Procainamide was administered in rabbits at a dose of 13 mg/kg iv, and midazolam at 0.2 mg/kg iv. Procainamide levels were determined by immunofluorescence polarization method using ABBOTT reagents. Levels of procainamide were determined in the plasma at 5, 10, 15, 30, 45, 60, 90 and 120 min after the administration of procainamide. After administration of midazolam with procainamide, a decrease in plasma concentration of procainamide, together with its increased elimination, was observed.

Adjuvants, Anesthesia↗
PubMed1992

Procainamide inhibits sympathetic nerve activity in rabbits.

Procainamide has been used extensively for the treatment of ventricular arrhythmias. It is widely held that the sympathetic nervous system plays an important role in the pathogenesis of ventricular arrhythmias. We investigated the possibility that procainamide has effects on the sympathetic nervous system by determining the responses to procainamide of postganglionic renal and preganglionic lumbar nerve activity in rabbits with sinoaortic and vagal denervation. Bolus administration of procainamide (3, 7, and 15 mg/kg) resulted in dose-dependent decreases in renal sympathetic nerve activity (26%, 38%, and 57%, respectively). These boluses resulted in plasma levels of procainamide of 13.3, 23.6, and 41.7 micrograms/ml, respectively. The same doses of procainamide resulted in decreases in lumbar nerve activity of 36%, 36%, and 41%, respectively. In a separate group of rabbits pretreated with hexamethonium (n = 8), 15 mg/kg procainamide reduced lumbar nerve traffic by 38%. Infusion of procainamide at 1 mg/kg/min over 20 minutes (n = 9) resulted in a decrease in renal sympathetic nerve activity of 20% with a plasma level of 11 micrograms/ml. Sham-treated rabbits (n = 8) exhibited an 18% increase in traffic over a comparable period of time. We conclude that procainamide inhibits lumbar and renal sympathetic nerve activity through effects on the brain or spinal cord. The influence of procainamide on sympathetic nerve activity may contribute importantly to its efficacy in the therapy of ventricular arrhythmias.

Animals↗
PubMed1975

Elimination of procainamide in end stage renal failure.

To investigate the effect of end stage renal insufficiency and hemodialysis on the serum half-life of procainamide, 500 mg of procainamide was given orally to control subjects and dialysis patients on interdialysis days. Procainamide was assayed by spectrophotometry and spectrophotofluorometry. Mean half-life in normal subjects was 3.2 hr by spectrophotometry and 3.5 hr by spectrophotofluorometry. Mean half-life in patients was 11.3 hr by spectrophotometry and 16.0 hr by spectrophotofluorometry (p less than 0.001 compared to control subjects). Half-life of procainamide during dialysis in patients given 500 mg of procainamide 1 hr before dialysis was 4.3 hr and 9.6 hr on a nondialysis day (p less than 0.001). Both methods of assay gave higher levels of procainamide when the metabolite, N-acetylprocainamide, was present in serum and the extract allowed to stand in 1 N HCl, but spectrophotometry was less affected. Thus, end stage renal insufficiency greatly prolongs the half-life of procainamide, procainamide is readily dialyzable, and N-acetylprocainamide is hydrolyzed in 1 N HCl to procainamide during routine serum determinations.

Acetylation↗
PubMed1996

Effects of ofloxacin on the pharmacokinetics and pharmacodynamics of procainamide.

Procainamide is a class I antiarrhythmic agent that undergoes active tubular secretion through the organic cation transport system, with approximately 50% of a dose excreted in the urine as unchanged drug. The remainder is metabolized to an active metabolite, n-acetyl procainamide (NAPA). Ofloxacin is a fluoroquinolone antibiotic that is excreted in the urine as unchanged drug via active tubular secretion and glomerular filtration. To test the hypothesis that ofloxacin may interfere with the renal elimination of procainamide, 9 healthy volunteers were randomly assigned to receive 1 g of oral procainamide as a single dose with or without pretreatment with 400 mg of ofloxacin twice a day for 5 doses. Blood and urine samples were obtained and pharmacokinetic parameters for procainamide were determined for each treatment period. Standard 12-lead and signal-averaged electrocardiographic recordings were used for pharmacodynamic analysis. The mean area under the concentration-time curve (AUC) and peak plasma concentration (Cmax; mug/mL) for procainamide increased by 27% and 21%, respectively, and the plasma clearance for procainamide decreased by an average of 22% with coadministration of ofloxacin. Ofloxacin did not significantly influence the pharmacokinetics of NAPA, nor were pharmacodynamics of procainamide significantly affected by coadministration of ofloxacin. These results suggest that procainamide concentrations should be monitored closely when coadministered with ofloxacin.

Administration, Oral↗
PubMed1980

Production and characterization of specific antibody for radioimmunoassay of procainamide.

The production and characterization of a specific antibody for use in the radioimmunoassay of procainamide are described. Cross-reactivity was measured by a nonequilibrium competitive procedure. Procainamide analog concentrations resulting in 50% inhibition were: procainamide, 1.59 nmoles/ml; N-acetylprocainamide, 3.55 nmoles/ml; a propyl analog of procainamide, 398 nmoles/ml; procaine, 316 nmoles/ml; lidocaine, greater than 8000 nmoles/ml; and practolol, greater than 16,000 nmoles/ml. Variations in the ability to inhibit binding of labeled procainamide were related to structural similarities and differences. The affinity constant of the antibody for procainamide was 2.9 x 10(8) liters/mole as measured from a Scatchard plot. The assay allows the direct measurement of procainamide in a 0.1-ml aliquot of diluted serum. The advantages of this method over currently available techniques are its sensitivity, specificity, and simplicity. Furthermore, prior extraction of serum samples is not required. As little as 1 ng of drug/ml of serum can be detected by this method. The accuracy and precision were determined by adding known amounts of procainamide to human serum and then assaying five replicates of each concentration. The within-day and between-day coefficients of variation were 2 and 5%, respectively. The proposed method was used to determine the serum concentration after an intravenous dose of procainamide. A comparison of the radioimmunoassay results with values obtained by a GLC procedure showed excellent agreement.

Adult↗
PubMed1988

Pharmacodynamics of intravenous procainamide as used during acute electropharmacologic testing.

No previous studies have determined the pharmaco-dynamics of intravenous procainamide when administered in a dose of 15 mg/kg and at a rate of 50 mg/min, as is common practice during electropharmacologic testing. In this study, 30 patients received procainamide in this fashion; the right ventricular effective refractory period and the QRS duration at a ventricular pacing rate of 120/minute were then determined every minute for 20 minutes. Ten patients received no maintenance infusion of procainamide (group A), 10 received a 4 mg/min maintenance infusion (group B) and 10 received an 8 mg/min maintenance infusion (group C). Ten additional patients received no procainamide and served as control subjects (group D). The plasma procainamide concentration was measured at 1, 5, 10, 15 and 20 minutes after the loading dose was administered. A stable plasma procainamide concentration was not present in group A, B, or C until 15 minutes after infusion of the loading dose. The effective refractory period and QRS duration increased compared with baseline at 1 minute, decreased between 1 and 10 minutes and then remained essentially unchanged between 10 and 20 minutes in all 3 treatment groups. Concentration-effect relation was linear in each treatment group. The plasma procainamide concentrations in group C were significantly greater than in group A; however, the effects on refractoriness and QRS duration were similar in both groups. These findings indicate that with a procainamide dosing method commonly used during electropharmacologic testing, the plasma procainamide concentration decreases significantly during the first 15 minutes after the loading dose is administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Procainamide-induced slowing of ventricular tachycardia with insights from analysis of resetting response patterns.

To investigate the mechanism of slowing of the rate of ventricular tachycardias (VTs) by procainamide, resetting response patterns were characterized in 24 VTs in 22 patients. All patients had coronary artery disease and inducible sustained VT during procainamide therapy. Only tachycardias with the same surface QRS morphology before and after procainamide were studied: all were slowed by procainamide. The mean cycle length was 292 +/- 61 ms before and 374 +/- 61 ms after procainamide (p less than 0.05). The mean effective refractory period, measured at the right ventricle, was 241 +/- 21 ms before and 261 +/- 24 ms after procainamide (p less than 0.05). During procainamide therapy, single and double extrastimuli were delivered during VT and resetting response patterns identified. Patterns were characterized as flat, increasing or flat plus increasing. Resetting was seen in 17 (71%) of these VTs and resetting response patterns were identified in 16 (94%) of these. The resetting response pattern was flat in 7, flat plus increasing in 5 and increasing in 4. The finding of some flat portion at the end of resetting response patterns in 12 VTs after procainamide indicates that the reentrant impulse conducts through fully recovered tissue within the circuit. It suggests that procainamide slowed these VTs by slowing conduction velocity in fully recovered tissue due to sodium channel blockade and not by prolongation of action potentials and refractory periods.

Cardiac Pacing, Artificial↗
PubMed1991

Paired comparisons of efficacy of intravenous and oral procainamide in patients with inducible sustained ventricular tachyarrhythmias.

Thirty-eight patients who had inducible sustained ventricular tachycardia during baseline programmed electrical stimulation underwent electrophysiologic testing after both intravenous and oral administration of procainamide. Each had presented clinically with documented sustained ventricular tachycardia or out of hospital cardiac arrest not associated with acute myocardial infarction. In 23 patients (61%) (Group I) the arrhythmia became noninducible during an intravenous infusion of procainamide. Oral procainamide was subsequently administered and retesting was carried out after dose titration to match plasma concentration at the end of the intravenous study. Among the 23 patients in Group I the mean (+/- SD) plasma procainamide level was 7.2 +/- 2.8 micrograms/ml after intravenous dosing and 7.9 +/- 2.5 micrograms/ml after oral dosing (p = 0.09). In 15 (65%) of the 23 patients, sustained ventricular arrhythmia was inducible on oral therapy with comparable plasma procainamide levels (intravenous = 6.3 +/- 2.1 micrograms/ml, oral = 7.5 +/- 2.1 micrograms/ml). The other eight patients (35%) had concordant responses to repeat testing with comparable intravenous (mean 9.0 +/- 3.3 micrograms/ml) and oral (8.8 +/- 3.1 micrograms/ml) plasma procainamide levels. In the additional 15 patients (Group II) sustained ventricular tachyarrhythmia remained inducible on intravenous procainamide therapy and the patients were retested on oral therapy with similar plasma concentration (p = 0.05). In seven patients (47%) sustained ventricular tachyarrhythmia was noninducible on treatment with oral procainamide (mean plasma level 7.6 +/- 2.7 micrograms/ml) after failure of intravenous procainamide (mean plasma level 10.3 +/- 2.3 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1996

Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia.

Efficacy of procainamide and lidocaine in terminating spontaneous monomorphic ventricular tachycardia (VT) was assessed in a randomized parallel study. Patients with acute myocardial infarction and those with poor hemodynamic tolerance of VT were excluded. Procainamide 10 mg/kg was given intravenously with an injection speed of 100 mg/min, and lidocaine was administered at an intravenous dose of 1.5 mg/kg in 2 minutes. Fourteen patients were randomized to lidocaine and 15 to procainamide. Termination occurred in 3 of 14 patients after lidocaine and in 12 of 15 patients after procainamide (p <0.01). Procainamide stopped 8 of 11 VTs not responding to lidocaine, and lidocaine stopped 1 of 1 not responding to procainamde. Of a total of 41 VT episodes, 4 of 15 responded to lidocaine and 20 of 26 to procainamide (p <0.01). Because of VT recurrences, 16 patients could be studied repeatedly with drugs given in the reversed order. This resulted in a total of 55 trials of 79 drug injections. Lidocaine terminated 6 of 31 VTs and procainamide 38 of 48 (p <0.001). The protocol was stopped in 4 cases because of adverse effects. A comparison of the QRS width and QT interval before and at the end of the injection revealed significant lengthening of these values after procainamide but no change after lidocaine. In conclusion, procainamide is superior to lidocaine in terminating spontaneously occurring monomorphic VT.

Anti-Arrhythmia Agents↗
PubMed1998

Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation.

OBJECTIVES: This multicenter study compared the efficacy and safety of ibutilide versus procainamide for conversion of recent-onset atrial flutter or fibrillation. BACKGROUND: Ibutilide fumarate is an intravenous (IV) class III antiarrhythmic agent that has been shown to be significantly more effective than placebo in the pharmacologic conversion of atrial flutter and fibrillation to sinus rhythm. Procainamide is commonly used for conversion of recent-onset atrial fibrillation to normal sinus rhythm. METHODS: One hundred twenty-seven patients (age range 22 to 92 years) with atrial flutter or fibrillation of 3 h to 90 days' (mean 21 days) duration were randomized to receive either two 10-min IV infusions of 1 mg of ibutilide fumarate, separated by a 10-min infusion of 5% dextrose in sterile water, or three successive 10-min IV infusions of 400 mg of procainamide hydrochloride. RESULTS: Of the 127 patients, 120 were evaluated for efficacy: 35 (58.3%) of 60 in the ibutilide group compared with 11 (18.3%) of 60 in the procainamide group had successful termination within 1.5 h of treatment (p < 0.0001). Seven patients were found to have violated the protocol and were not included in the final evaluation. In the patients with atrial flutter, ibutilide had a significantly higher success rate than procainamide (76% [13 of 17] vs. 14% [3 of 22], p=0.001). Similarly, in the atrial fibrillation group, ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38], p=0.005). One patient who received ibutilide, which was found to be a protocol violation, had sustained polymorphic ventricular tachycardia requiring direct current cardioversion. Seven patients who received procainamide became hypotensive. CONCLUSIONS: This study establishes the superior efficacy of ibutilide over procainamide when administered to patients to convert either atrial fibrillation or atrial flutter to sinus rhythm. Hypotension was the major adverse effect seen with procainamide. A low incidence of serious proarrhythmia was seen with the administration of ibutilide occurring at the end of infusion.

Aged↗
PubMed1988

Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue.

Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.

Acetylation↗
PubMed1988

Trimethoprim alters the disposition of procainamide and N-acetylprocainamide.

The steady-state pharmacokinetics and pharmacodynamics of procainamide and its active N-acetyl metabolite (NAPA) were assessed alone and in combination with trimethoprim. Eight healthy men received oral sustained-release procainamide, 500 mg every 6 hours for 3 days, alone and with oral trimethoprim, 200 mg daily for 4 days. Concomitant trimethoprim significantly increased the plasma AUC(0-12) of both procainamide and NAPA (63% and 52%, respectively), with concurrent decreases in their renal clearances (47% and 13%, respectively) and a 39% increase in the mean urinary recovery of NAPA (as percentage of procainamide and NAPA recovery). After trimethoprim coadministration, there was also a trend toward a decrease in the apparent acetylation clearance of procainamide (19%, p = 0.057). The change in procainamide and NAPA renal clearances after trimethoprim coadministration strongly correlated with their baseline renal clearances (r = 0.84 and r = 0.74, respectively, p less than 0.0001). There was small but significant increase in the corrected QT interval with procainamide administration, which increased further with trimethoprim coadministration. We conclude that trimethoprim increases the plasma concentrations of procainamide and NAPA by decreasing their renal clearances and allowing more conversion of procainamide to NAPA.

Acecainide↗
PubMed1994

Effects of procainamide and lidocaine on defibrillation energy requirements in patients receiving implantable cardioverter defibrillator devices.

INTRODUCTION: In acute canine studies, lidocaine, but not procainamide, increases defibrillation energy requirements. We evaluated the effects of lidocaine or procainamide on defibrillation energy requirements in 27 patients undergoing intraoperative testing for implantable cardioverter defibrillator device placement. METHODS AND RESULTS: Patients were tested off antiarrhythmic drugs and again following either lidocaine (200 to 250 mg loading and 3 mg/min maintenance infusions) or procainamide (1 gm loading and 3 to 4 mg/min maintenance infusions). The defibrillation testing protocol consisted of initial testing at 15 J, followed by higher or lower energies to determine the lowest energy producing three consecutive successful defibrillations. Overall, the mean defibrillation energy increased from 14 +/- 5 J to 18 +/- 7 J during lidocaine (plasma concentration 5.1 +/- 1.6 micrograms/mL; P < 0.02) but were similar at baseline (12 +/- 5 J) and during procainamide infusion (13 +/- 6 J) (plasma concentration: procainamide 10.7 +/- 7.2 micrograms/mL; N-acetyl procainamide 1.0 +/- 0.4 micrograms/mL). A positive linear correlation was found between lidocaine plasma concentration and percent change in defibrillation energy (lidocaine: r = 0.61; P = 0.01). Procainamide raised the defibrillation energy in three patients, two with supratherapeutic plasma concentrations. The increase in defibrillation energy equaled or exceeded 25 J in four patients after lidocaine and in one patient after procainamide. CONCLUSION: The data suggest that at high plasma concentrations, lidocaine and procainamide adversely affect defibrillation energy requirements consistent with an adverse, concentration-dependent effect of sodium channel blockade on defibrillation energy requirements in patients.

Aged↗
PubMed1985

Circadian changes in procainamide and N-acetylprocainamide kinetics in the rat.

The aim of this study was to investigate the possible influence of the time of administration on procainamide and N-acetylprocainamide (NAPA) kinetics in the rat. A single 50 mg kg-1 i.p. dose of procainamide was given to Wistar AF SPF adult male rats maintained under controlled environmental conditions (LD: 06.00h-18.00h) at four different fixed times i.e. 10.00, 16.00, 22.00 and 04.00h. Procainamide and NAPA plasma levels were determined by an immunoenzymatic method. Our data showed significant 24 h variation of the following pharmacokinetic parameters: highest elimination half-lives at 10.00h (t1/2 beta = 0.736 +/- 0.020h) for procainamide and at 04.00h (t1/2 beta = 3.55 +/- 0.08h) for NAPA (P less than 0.001); highest apparent volume of distribution at 04.00h for procainamide (Vd = 2.35 +/- 0.17 litre) (P less than 0.05); highest ratio AUC NAPA/AUC procainamide at 04.00h (1.039 +/- 0.056) (P less than 0.001). Procainamide clearance and Cmax and AUC for procainamide and NAPA were not significantly dependent on time of day. These data indicate a 24 h variation in the metabolism of procainamide which is converted to NAPA, the N-acetylation being greatest at 04.00h.

Acecainide↗
PubMed1985

Procainamide transport in rabbit renal cortical brush border membrane vesicles.

Previous studies in canine and rat renal cortical brush border membrane vesicles (BBMV) and some results in isolated perfused rabbit proximal tubules indicate that organic cations may be transported across the apical cell membrane by an organic cation/proton exchange process. To determine more directly whether organic cations are transported across the apical cell membrane of rabbit proximal tubules, [3H]procainamide uptake in BBMV was studied. Procainamide uptake was linearly related to the inverse of the media osmolarity, indicating uptake into an intravesicular space. A proton gradient directed from vesicle interior outwardly stimulated and an opposite gradient inhibited procainamide uptake. pH-stimulated uptake was inhibited by the proton ionophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP) and was also reduced by an inwardly directed sodium gradient. pH-stimulated procainamide uptake was inhibited by other organic cations including the quarternary ammonium ion tetramethylammonium, indicating that the effect of proton gradients was not due to changes in nonionic diffusion. pH-stimulated procainamide uptake at 10 s was saturable with an apparent Km of 5.4 X 10(-4) M and Vmax of 4.7 X 10(-10) mol X mg protein-1. Uptake of [3H]procainamide was enhanced when BBMV were preloaded with nonradioactive procainamide but this was prevented by FCCP and valinomycin. Finally, an outwardly directed potassium gradient in the presence of valinomycin failed to significantly stimulate procainamide uptake. These results are consistent with a mechanism of secretion that involves electroneutral exchange of procainamide for protons across the apical cell membrane of rabbit proximal tubules.

Animals↗