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PubMed2005

Procainamide is a specific inhibitor of DNA methyltransferase 1.

CpG island hypermethylation occurs in most cases of cancer, typically resulting in the transcriptional silencing of critical cancer genes. Procainamide has been shown to inhibit DNA methyltransferase activity and reactivate silenced gene expression in cancer cells by reversing CpG island hypermethylation. We report here that procainamide specifically inhibits the hemimethylase activity of DNA methyltransferase 1 (DNMT1), the mammalian enzyme thought to be responsible for maintaining DNA methylation patterns during replication. At micromolar concentrations, procainamide was found to be a partial competitive inhibitor of DNMT1, reducing the affinity of the enzyme for its two substrates, hemimethylated DNA and S-adenosyl-l-methionine. By doing so, procainamide significantly decreased the processivity of DNMT1 on hemimethylated DNA. Procainamide was not a potent inhibitor of the de novo methyltransferases DNMT3a and DNMT3b2. As further evidence of the specificity of procainamide for DNMT1, procainamide failed to lower genomic 5-methyl-2'-deoxycytidine levels in HCT116 colorectal cancer cells when DNMT1 was genetically deleted but significantly reduced genomic 5-methyl-2'-deoxycytidine content in parental HCT116 cells and in HCT116 cells where DNMT3b was genetically deleted. Because many reports have strongly linked DNMT1 with epigenetic alterations in carcinogenesis, procainamide may be a useful drug in the prevention of cancer.

Allosteric Regulation↗
PubMed1987

Comparative effects of procainamide and its N-acetylated metabolite in conscious dogs with atrioventricular block: plasma concentration-response relationships.

The effects of procainamide and its metabolite N-acetylprocainamide (NAPA) on atrial effective refractory period (AERP), atrial rate, ventricular rate, and mean blood pressure were investigated in conscious dogs with chronic atrioventricular block and implanted atrial pacing electrodes. Procainamide at cumulative doses of 4.3, 13.0, and 30.3 mg/kg and NAPA at equimolar doses of 5.1, 15.3, and 35.7 mg/kg (i.e., at plasma levels covering the assumed therapeutic range) concentration-relatedly lengthened AERP, as reflected by the decrease of maximal atrial frequency determined by pacing. Procainamide was 1.2-1.5 times more potent than NAPA in this regard. Both drugs increased atrial rate in relation to their plasma concentrations--procainamide 1.2 times more than NAPA. Procainamide decreased ventricular rate at the two highest doses, while NAPA decreased it only at the highest dose after having increased it at the lowest. Procainamide lowered mean blood pressure at the lowest dose and increased it 15 min after the highest, whereas NAPA produced an increase in mean blood pressure for each dose. Taken together, these results on atrial rate, ventricular rate, and mean blood pressure indicate that the two drugs possess distinct pharmacological properties--i.e., procainamide exhibits slightly more marked direct vagolytic and depressor effects than does NAPA and exerts quite different blood pressure effects from those of NAPA. Thus, these data suggest that NAPA, especially when present at high levels, may markedly affect expected responses in patients being treated with procainamide.

Acecainide↗
PubMed1992

Proarrhythmic effects of procainamide and tocainide in a canine infarction model.

A canine model of myocardial infarction (MI) was used to study the type and frequency of ventricular antiarrhythmic and proarrhythmic effects due to procainamide and tocainide and the risk factors associated with development of proarrhythmia. An anterior MI was created by a 2-h occlusion of the left anterior descending artery (LAD) with complete reperfusion. Programmed ventricular stimulation was performed on two occasions after MI, on days 4-6 and on days 8-10, before drug and during antiarrhythmic drug infusion at three dose levels. The antiarrhythmic drugs were given in a randomized cross-over design. Only procainamide caused a dose-dependent increase in QRS, JTc, and right ventricular effective refractory period (ERP). Neither procainamide nor tocainide made sustained ventricular tachycardia (VT) noninducible, but procainamide slowed the tachycardia rate. Both drugs successfully made ventricular fibrillation (VF) noninducible: procainamide in 78% of trials and tocainide in 50% of trials. Proarrhythmia (development of inducible VT during drug when not present before drug or inability to terminate VT during drug administration) developed in 29% of dogs that received procainamide and 25% of dogs that received tocainide. There was no apparent correlation of QRS, JTc, and right ventricular ERP after drugs and proarrhythmia due to procainamide or tocainide. There was no significant difference in the size of MI between dogs with one or more proarrhythmic response to either drug and dogs that had no proarrhythmia. In this model, procainamide and tocainide had no antiarrhythmic efficacy for VT, but had moderate proarrhythmia potential that was unpredictable.

Animals↗
PubMed1990

Procainamide-cimetidine drug interaction in elderly male patients.

Thirty-six hospitalized male patients receiving oral sustained-release procainamide every six hours for the treatment of ventricular arrhythmias were studied at steady-state before and after oral cimetidine 300 mg every six hours for three days. Average age and weight were 73 +/- 12 (SD) years and 76 +/- 10 kg. Patients did not have a myocardial infarction within the last two years or congestive heart failure and had calculated creatinine clearances (CrCl) between 35 and 75 mL/min/70 kg. Ten patients had urine collections that permitted computation of the ratio between the renal clearance of procainamide and CrCl (PA/CrCl) and the renal clearance of n-acetyl-procainamide (NAPA) and CrCl (NAPA/CrCl). The average steady-state procainamide and NAPA concentrations increased 55% and 36%, respectively, during cimetidine treatment (P less than .01). Twelve patients experienced mild to severe symptoms of what may have been procainamide toxicity. Apparent procainamide oral clearance decreased 41% while patients received cimetidine (P less than .01). PA/CrCl and NAPA/CrCl ratios decreased by 33% and 21%, respectively, during cimetidine therapy (P less than .05). Cimetidine therapy given to older male patients taking procainamide can cause steady-state concentrations of procainamide to rise to toxic levels. Patients prescribed this combination should be monitored carefully for adverse side effects.

Aged↗
PubMed1982

Cimetidine and procainamide secretion by proximal tubules in vitro.

Previous studies have shown that organic bases, including some drugs, are secreted by renal proximal tubules. The present studies examined the transport of the organic bases cimetidine and procainamide by rabbit proximal straight tubules perfused in vitro. Both drugs were secreted into the tubule lumen. [3H]cimetidine secretion was reduced by quinidine, procainamide, and N-acetylprocainamide. Previous studies showed that cimetidine secretion was reduced by other organic bases. Hypothermia and ouabain inhibited [3H]procainamide secretion as was shown previously for cimetidine secretion. [3H]procainamide secretion was also reduced by quinidine, cimetidine, procainamide, and N-acetylprocainamide but not by probenecid. High concentrations of cimetidine (10(-3) M) had no effect on the rates of fluid or total CO2 absorption. When analyzed in terms of Michaelis-Menten kinetics, the effect of cimetidine on procainamide secretion and procainamide on cimetidine secretion was consistent with competitive inhibition. The results suggest that both cimetidine and procainamide are secreted into the lumen of proximal straight tubules predominately by an organic base transport mechanism. These studies raise the possibility that some of these drugs might compete for a common secretory mechanism in renal tubules and reduce the elimination of each other.

Absorption↗
PubMed1983

The response to procainamide during electrophysiologic study for sustained ventricular tachyarrhythmias predicts the response to other medications.

We evaluated 126 patients with inducible sustained ventricular tachyarrhythmias to assess whether the response to procainamide during electrophysiologic study could predict responses to other conventional antiarrhythmic agents and combinations of agents. Thirty of 42 patients in whom tachycardia was not inducible after the administration of procainamide and 69 of 84 patients in whom ventricular tachycardia was inducible after procainamide underwent serial electrophysiologic studies. Forty-three of 67 antiarrhythmic regimens (64%) tested in the patients in whom ventricular tachycardia could not be induced after procainamide prevented induction of ventricular tachycardia, compared with 10 of 145 regimens (7%) tested in the patients in whom ventricular tachycardia could be induced after procainamide. Sixty of the 69 patients in whom ventricular tachycardia remained inducible after procainamide had ventricular tachycardia induced on all other conventional antiarrhythmic regimens tested. By comparison, of the 30 patients in whom ventricular tachycardia became noninducible after procainamide, 25 had no ventricular tachycardia inducible on at least one other antiarrhythmic regimen tested. Thus, the response to procainamide accurately predicted the response to other conventional antiarrhythmic agents during electrophysiologic study.

Adolescent↗
PubMed1994

Modulation of procainamide's effect on cardiac conduction in dogs by extracellular potassium concentration. A quantitative analysis.

BACKGROUND: Antiarrhythmic drugs are known to have state-dependent interactions with cardiac sodium channels, and these have potentially important implications for drug effects on cardiac conduction, particularly in situations of changed resting potential and heart rate. Recent advances in theoretical approaches permit beat-to-beat changes in sodium channel block to be inferred from conduction changes in vivo and allow for an analysis of state-dependent drug action from conduction changes occurring on the onset of pacing at different rates. The purpose of the present study was to use this method to analyze the interaction between hyperkalemia and procainamide's sodium channel-blocking action in terms of resulting changes in left ventricular conduction. METHODS AND RESULTS: Epicardial mapping with a 56-electrode array was used to assess ventricular conduction in open chest, anesthetized mongrel dogs with Formalin-induced atrioventricular block. Procainamide was infused as a series of loading and maintenance infusions until at least 20% conduction slowing was obtained at the shortest basic cycle length (300 milliseconds). Results in a control set of normokalemic dogs were compared with results in dogs with moderate hyperkalemia produced by a loading and maintenance infusion of potassium chloride. Plasma procainamide concentration was measured by high-performance liquid chromatography, and the constancy of serum potassium concentration was verified with ion-sensitive electrode measurement. Although hyperkalemia itself (mean +/- SEM potassium concentration, 6.64 +/- 0.66 mmol/L) did not alter conduction, it resulted in substantially increased conduction slowing by procainamide despite substantially lower plasma drug concentrations (102 +/- 10 mumol/L) compared with normokalemic dogs (potassium concentration, 3.87 +/- 0.24 mmol/L; procainamide concentration, 277 +/- 16 mumol/L). The onset of conduction slowing and block followed basic molecular theory, with an exponential time constant that was faster at longer cycle lengths and total block that increased as cycle length decreased. Piecewise exponential analysis of block during the rested and depolarized phases of the action potential showed that the enhancement of procainamide's action by hyperkalemia was due almost exclusively to increased rested-phase block. Hyperkalemia produced a bradycardia-dependent and slight reduction in action potential duration and antagonized the action potential-prolonging effect of procainamide, particularly at shorter cycle lengths. CONCLUSIONS: Hyperkalemia strongly enhances procainamide-induced conduction slowing by increasing the interaction between the drug and sodium channels during the rested phase of the cardiac cycle. These results indicate the applicability of basic molecular theories of antiarrhythmic drug action to understanding drug-induced changes in conduction velocity in vivo and highlight the potential importance of heterogeneous magnification of sodium channel-blocking drug action by the spatially variable hyperkalemia that occurs with acute myocardial ischemia. The latter could play an important role in the known proarrhythmic potential of sodium channel-blocking drugs in patients with coronary artery disease.

Animals↗
PubMed1997

Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation: electrophysiological determinants of enhanced conversion efficacy.

BACKGROUND: The selective class III antiarrhythmic agent ibutilide prolongs action potential duration and terminates atrial flutter (AFL) and fibrillation (AF), but the mechanism of its antiarrhythmic efficacy in humans has not been fully characterized. This study compared the antiarrhythmic effects of ibutilide with the class IA agent procainamide in humans during AFL and AF. Antiarrhythmic drug actions and electrophysiological characteristics of AFL and AF that enhanced pharmacological termination were investigated. METHODS AND RESULTS: Right atrial monophasic action potentials were recorded during 148 episodes of AFL (n=89) or AF (n=59) in 136 patients treated with intravenous ibutilide (n=73) or placebo (n=22) as participants in randomized, double-blinded comparative studies or intravenous procainamide (n=53) in a concurrent open-label study. The conversion rates in AFL with ibutilide, procainamide, and placebo were 64% (29 of 45 patients), 0% (0 of 33), and 0% (0 of 11), respectively, whereas in AF the rates were 32% (9 of 28), 5% (1 of 20), and 0% (0 of 11), respectively. In AFL, ibutilide increased atrial monophasic action potential duration (MAPD) more (30% versus 18%, P<.001) and prolonged atrial cycle length (CL) less (16% versus 26%, P<.001) than procainamide. Ibutilide shortened and procainamide prolonged action potential diastolic interval during AFL (-12% versus 51%, P<.001). Ibutilide increased MAPD/CL ratio, whereas procainamide tended to decrease this ratio (13% versus -6%, P<.01). In AF, ibutilide and procainamide induced similar increases in atrial CL (48% versus 45%), but ibutilide induced a greater increase in MAPD (52% versus 37%, P<.05). Independent electrophysiological predictors of pharmacological arrhythmia termination were increase in MAPD/CL ratio (P=.005) in AFL and longer baseline mean MAPD (P=.011) in AF. Termination of AFL with ibutilide was characterized by significant increases in beat-to-beat atrial CL, MAPD, and diastolic interval variability. Ibutilide was significantly more effective in converting AF when the mean atrial CL was > or = 160 ms (64% versus 0%, P<.001) or MAPD was > or = 125 ms (57% versus 0%, P=.002) at baseline. CONCLUSIONS: Enhanced conversion efficacy of ibutilide compared with procainamide in AFL is correlated with a relatively greater prolongation of atrial MAPD than atrial CL, and termination of AFL by ibutilide is characterized by oscillations in atrial CL and MAPD. Conversion of AF by ibutilide is enhanced by a longer baseline mean atrial CL or MAPD.

Adult↗
PubMed1991

Inhibitory effects of procainamide on sympathetic nerve activity in humans.

In experimental animals, procainamide causes hypotension and reductions in efferent vasoconstrictor sympathetic outflow that may result from ganglionic blockade or central nervous system sympathetic inhibition. To test the hypothesis that procainamide decreases sympathetic nerve activity (SNA) in humans, we recorded postganglionic SNA in seven normal subjects in the baseline state and during infusions of procainamide HCl at 50 mg/min (loading) and 8 mg/min (maintenance). At the end of the loading infusion, mean arterial pressure (MAP) had decreased from 88.5 +/- 2.4 (mean +/- SEM) to 81.5 +/- 3.2 mm Hg (p less than 0.05), central venous pressure from 6.7 +/- 0.7 to 5.4 +/- 0.9 mm Hg (p less than 0.05), forearm vascular resistance (FVR) from 28 +/- 4.8 to 22.3 +/- 5.1 resistance units (p less than 0.05), and SNA from 259 +/- 47 to 94 +/- 26 units/min (p less than 0.05). These changes persisted during the maintenance infusion. Increased levels of SNA, FVR, and MAP provoked by the cold pressor test were reduced significantly by intravenous procainamide. In eight other subjects, intravenous procainamide HCl (15 mg/kg at 50 mg/min) caused dose-dependent inhibition of SNA that reversed as blood concentrations fell during drug washout. To determine if procainamide causes direct vasodilation, in nine subjects, graded infusions were delivered into the brachial artery at doses that produced no systemic effect. Ipsilateral FVR tended to increase during local intra-arterial infusion of procainamide. These data show that intravenous procainamide causes hypotension, vasodilation, and sympathetic withdrawal. Vasodilation does not result from a direct vasorelaxant effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

Interindividual variability in 5-Fluorouracil metabolism and procainamide N-acetylation in human liver cytosol.

We investigated the enzymatic kinetics and interindividual variability of the metabolism of 5-fluorouracil and procainamide by human liver cytosol and/or microsomes. The Km values for the 5-fluorouracil dihydropyrimidine dehydrogenase (DPD) and procainamide N-acetyltransferase activities in pooled liver cytosol, and procainamide hydrolysis in pooled liver microsomes were 3.9, 1670, and 969 microM, respectively, and the intrinsic clearance (Vmax/Km) values for these reactions were 128, 0.192, and 0.0059 microl/min/mg protein, respectively. The cytosolic activities of 5-fluorouracil metabolism and procainamide N-acetylation ranged from 145 to 790 (469+/-156, mean+/-S.D., n=22) and <1 to 152 (52+/-48, n=12) pmol/min/mg protein, respectively, and the DPD activity of 5-fluorouracil was neither gender-related nor age-dependent. Procainamide N-acetylation activities among 12 human cytosol samples were highly correlated with sulfamethazine N-acetylation activities, suggesting that procainamide N-acetylation is catalyzed by N-acetyltransferase-2. These results suggest that the N-acetylation reaction is more important than the hydrolysis in the metabolic pathway of procainamide, and that there are large interindividual differences in the enzyme activities towards the respective metabolic pathways of 5-fluorouracil and procainamide in human liver.

Acetylation↗
PubMedDate not supplied

Conversion from intravenous procainamide to oral sustained release tablets in cardiac patients.

There is as yet no established method for converting from intravenous to oral sustained release procainamide (Procan SR; Parke-Davis Canada Inc). The pharmacokinetics of simultaneous discontinuation of intravenous procainamide and administration of oral sustained release procainamide was studied in six patients with ventricular tachyarrhythmias. Patients were converted after ensuring that steady-state concentrations were achieved with intravenous procainamide. Serum procainamide levels were obtained at the time of conversion and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 6.0 h after conversion. The mean steady-state concentration (23.7 +/- 8.9 mumols/L) and the adjusted mean serum procainamide concentration with Procan SR (25.3 +/- 7.9 mumols/L) were not significantly different. This indicated that the serum procainamide concentration obtained with the intravenous infusion was not compromised when the patients were switched to oral therapy. Although mean percentage serum procainamide concentration fluctuation was 102.6 +/- 92.5, all patients tolerated the conversion well. Therefore, the method used in this study is an acceptable method of conversion.

Administration, Oral↗
PubMed1988

Procainamide-DNA interaction.

The interactions of procainamide with DNA were studied by neutral and alkaline sucrose gradient sedimentation and sequential action of 2 enzymes: a mammalian repair endonuclease and bacterial DNA polymerase I. Sucrose gradient sedimentation shows that in the absence of photosensitization, the interaction of procainamide with DNA did not modify DNA sedimentation in alkaline or neutral sucrose gradients. In contrast, when a photosensitized DNA procainamide mixture was placed on sucrose gradients, the peak appearing on alkaline sucrose gradient after treatment with endonuclease was shifted toward the lower molecular weights, indicating that strand breaks had developed in the photosensitized procainamide DNA. Incubation of a [32P] labeled photosensitized procainamide-DNA complex with a repair endonuclease and DNA polymerase I released the label in the acid soluble fraction, indicating that only the photosensitized procainamide-DNA complex was susceptible to the endonucleolytic attack. There was only negligible release of the label in the acid soluble fraction without exposure of the DNA-procainamide mixture to light. The incorporation into DNA of [3H]-TTP (tritium labeled triphosphates) in presence of DNA polymerase I was inhibited when the photosensitized procainamide-DNA complex was used as substrate. However, after treatment of the photosensitized DNA complex with the repair endonuclease, the incorporation of [3H]-TTP was increased and reached values close to that observed with DNA unexposed to light, suggesting that the endonuclease functions as a repair enzyme.

Animals↗
PubMedDate not supplied

The formation of procainamide hydroxylamine by rat and human liver microsomes.

A method is described, using HPLC and electrochemical detection, which permits the direct quantitation of procainamide hydroxylamine. Procainamide hydroxylamine was formed from procainamide by hepatic microsomes from both rat and human, with rat microsomes showing higher apparent formation rates. The apparent Km for formation of procainamide hydroxylamine was 0.044 mM for rat liver microsomes, with an apparent Vmax of 2.81 nmol/min/mg of protein. Estimates of Km from three human microsomal samples were 6.29, 2.89, and 6.88 mM. Vmax estimates were 0.31, 0.74, and 0.74 nmol/min/mg of protein, respectively, roughly an order of magnitude less than that observed for the rat. Microsomal formation in both species was inhibited by boiling the microsomes, eliminating NADPH from the incubation system, by preincubation with SKF 525A, cimetidine, or n-octylamine, or by gassing the microsomal incubation mixture with carbon monoxide. These observations suggest that procainamide hydroxylamine formation is cytochrome P-450 mediated. Procainamide hydroxylamine could not be detected in the blood of rats treated with a single dose of procainamide, 100 mg/kg, po. One potential reason for the inability to detect this metabolite in blood is indicated by the rapid disappearance in vitro of procainamide hydroxylamine added to whole blood. Most of this disappearance appears to be due to an interaction with hemoglobin.

Adult↗
PubMed1988

Stability of procainamide hydrochloride in neutralized 5% dextrose injection.

The stability of procainamide hydrochloride in neutralized 5% dextrose injection was studied. Sixty-four admixtures were prepared by adding either 2 mL (for 0.4% admixtures) or 4 mL (for 0.8% admixtures) of procainamide hydrochloride to 250 mL of 5% dextrose injection in plastic containers. The pH of 32 of these admixtures (16 of each type) was adjusted to 7.5. These 32 admixtures represented the neutralized group, and the remaining 32 represented the control group. The admixtures were stored at either 23-25 degrees C (room temperature) or 5 degrees C (refrigeration) for 24 hours. Procainamide hydrochloride concentrations in each sample were determined by high-performance liquid chromatography immediately after the admixtures were prepared and at various intervals during storage. Procainamide concentrations decreased over time in 5% dextrose injection. The decrease was significantly less for admixtures in neutralized 5% dextrose injection, those stored under refrigeration, and those with an 0.8% concentration of drug. Decreases in procainamide hydrochloride concentrations in the control admixtures might have been caused by procainamide-dextrose complexation. Initial concentrations of procainamide hydrochloride in 5% dextrose injection can be adequately maintained over a 24-hour storage period by neutralizing the 5% dextrose injection or storing the admixture at 5 degrees C. However, because it is impractical to maintain the necessary temperature condition during a 24-hour infusion, neutralization might be the most viable alternative when extended stability of procainamide hydrochloride in 5% dextrose injection is required.

Chemistry, Pharmaceutical↗
PubMed1985

Reactivity and possible significance of hydroxylamine and nitroso metabolites of procainamide.

We have demonstrated previously that procainamide is metabolized to a hydroxylamine. The reactivities of this hydroxylamine and of the closely related nitroso derivative toward biological molecules were investigated with the objective of exploring possible mechanisms of procainamide-induced lupus. The hydroxylamine of procainamide was found to bind covalently to microsomal protein to a much greater degree than did procainamide and, in contrast to procainamide, it did not require metabolic activation. However, the hydroxylamine is readily converted nonenzymatically to the nitroso derivative, and reducing agents such as ascorbate and NADPH, which reduce the nitroso derivative to the hydroxylamine, blocked covalent binding. This suggests that the nitroso derivative is the reactive species for covalent binding. Furthermore, glutathione had been shown previously to block covalent binding of procainamide metabolites, and the nitroso derivative, but not the hydroxylamine, reacted rapidly with glutathione forming a sulfinamide derivative. The covalent binding of the nitroso derivative to microsomal protein appears to involve sulfydryl groups, because it, like the glutathione adduct, was readily cleaved by mild acid. In contrast, the nature of the covalent binding to albumin and histone protein appears different from that to microsomal protein in that most of the binding was stable to mild acid. The reactivity toward DNA was much less than that to protein. The observation that both the reactivity of nitrosoprocainamide and the specificity of antinuclear antibodies in procainamide-induced lupus are to histone protein rather than the DNA supports the hypothesis that this reactive metabolite plays a role in the etiology of procainamide-induced lupus.

Albumins↗
PubMed1997

Intravenous Procainamide for Predicting the Response of Sustained Ventricular Tachycardia to Type III Antiarrhythmic Drugs.

The use of serial electrophysiology studies to guide antiarrhythmic drug therapy in patients with ventricular tachycardia is both costly and time consuming. Intravenous procainamide administered during of the initial electrophysiology study has previously been shown to be useful in predicting the efficacy of oral antiarrhythmic medications (type I and III). The purpose of this study is to confirm that ventricular tachycardia suppression after intravenous procainamide correlates with suppression on oral class III antiarrhythmic medications (amiodarone and sotalol). This study included all patients with sustained ventricular tachycardia who underwent an initial electrophysiology study including an acute suppression trial with intravenous procainamide and a subsequent restudy on oral amiodarone or sotalol. The response to intravenous procainamide was then compared with these type III antiarrhythmic medications. Between January 1993 and May 1995, 360 patients underwent electrophysiology studies for suspected or documented ventricular arrhythmias. One hundred patients (28%) had an inducible sustained ventricular tachycardia, and 26 patients received both intravenous procainamide and subsequently oral amiodarone or sotalol. Acute infusion of procainamide provided a highly specific method for predicting suppression of oral amiodarone and sotalol (82% and 100% respectively). However, several patients who were not suppressed by intravenous procainamide were suppressed by oral sotalol resulting in lower overall predictive accuracy 12/15 (80%) for amiodarone vs. 5/11 (45%) for sotalol treated group. We conclude that the acute infusion of procainamide may help to predict ventricular tachycardia suppression after oral amiodarone and sotalol. A larger prospective trial is warranted to confirm this finding.

Journal Article↗
PubMed1975

Polymorphic acetylation procainamide in man.

N-Acetylprocainamide (NAPA) and procainamide plasma and urine concentrations were determined by thin-layer chromatography (TLC) densitometry in people of known acetylator phenotype (dapsone phenotyping) taking procainamide for more than 3 days. The plasma NAPA/procainamide ratio 3 hr after the last dose for fast acetylators (mean plus or minus SD) is 1.8 plus or minus 0.59 (N equal to 8) and for slow acetylators, 0.61 plus or minus 0.09 (N equal to 6) P smaller than 0.001). The renal clearance of NAPA averaged 1.2 times the simultaneously measured endogenous creatinine clearance, whereas procainamide clearance was approximately double the creatinine clearance. There was no difference between slow and rapid acetylators in the renal clearance of either drug or the urine pH, indicating that the difference in plasma NAPA/procainamide ratios between these two groups is due to differences in their rates of acetylation. Therefore, procainamide is probably acetylated by the polymorphic N-acetyltransferase in man. Reflecting the blood level differences, the NAPA/procainamide ratio in urine (collected 99 to 180 min after last dose) was found to be higher in rapid than in slow acetylators. The plasma protein binding of NAa and of procainamide are similar. Since NAPA seems to have an antiarrhythmic potency similar to procainamide, NAPA probably contributes to the antiarrhythmic activity of procainamide therapy, especially in genetic rapid acetylators.

Acetylation↗
PubMed1977

Cumulation of N-acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function.

N-Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 microgram/ml 3 hr after a dose of procainamide which is well above the 3-hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 microgram/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 microgram/ml) and 38 days (0.9 microgram/ml) after procainamide was stopped, indicating a half-life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.

Acetylation↗