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PubMed1997

Role of CYP2D6 in the N-hydroxylation of procainamide.

Sequential oxidations at the arylamine moiety of the procainamide molecule leading to the formation of N-hydroxyprocainamide and its nitroso derivative may be responsible for lupus erythematosus observed in patients treated with the drug. The objective of the present study was to characterize major cytochrome P450 isozyme(s) involved in the N-hydroxylation of procainamide. Firstly, incubations were performed with microsomes from either lymphoblastoid cells or yeast transfected with cDNA encoding for specific human cytochrome P450 isozymes. Experiments performed with these enzyme expression systems indicated that the highest formation rate of N-hydroxyprocainamide was observed in the presence of CYP2D6 enriched microsomes. Additional experiments demonstrated that the formation rate of N-hydroxyprocainamide by CYP2D6 enriched microsomes was decreased from 45 +/- 4% to 93 +/- 1% by quinidine at concentrations ranging from 30 nM to 100 microM (all p < 0.05 vs control) and by approximately 75% by antibodies directed against CYP2D6. Secondly, incubations were performed with microsomes prepared from 15 human liver samples. Using this approach, an excellent correlation was observed between the formation rate of N-hydroxyprocainamide and dextromethorphan O-demethylase activity (CYP2D6; r = 0.9305; p < 0.0001). In contrast, no correlation could be established between N-hydroxyprocainamide formation rate and caffeine N3-demethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), S-mephenytoin N-demethylase (CYP2B6), tolbutamide methlhydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), chlorzoxazone 6-hydroxylase (CYP2E1), dextromethorphan N-demethylase (CYP3A4), testosterone 6 beta-hydroxylase (CYP3A4/5) or lauric acid 12-hydroxylase (CYP4A11) activities. Furthermore, formation rate of N-hydroxyprocainamide was decreased in a concentration-dependent manner by quinidine (300 nM to 100 microM) and by antibodies directed against CYP2D6 but not by furafylline 20 microM (CYP1A2), ketoconazole 1 microM (CYP3A4), sulfaphenazole 10 microM (CYP2C9) or antibodies directed against CYP1A1/1A2, CYP2C, CYP2A6, CYP2E1 or CYP3A4/3A5. In conclusion, the results obtained in the present study demonstrate that CYP2D6 is the major human cytochrome P450 isozyme involved in the formation of the reactive metabolite of procainamide, namely N-hydroxyprocainamide.

Anti-Arrhythmia Agents↗
PubMed1999

Transesophageal pacemaker therapy in atrial flutter after procainamide pretreatment.

Transesophageal atrial stimulation was applied in 56 patients to terminate atrial flutter. Extrastimulation and atrial burst techniques were applied using programmable stimulator (Medtronic 5328) and hexapolar esophageal electrode catheters. Thirty patients were randomized to receive digoxin pretreatment (group A), and 26 patients were randomized to receive procainamide pretreatment (group B). Efficacy of each pretreatment was evaluated by observing the change in the rhythm. In group A, transesophageal pacemaker therapy successfully converted atrial flutter to sinus rhythm in 13 patients and to atrial fibrillation in 14 patients, whereas the arrhythmia remained unchanged in the 3 remaining patients in the digitalized group. In group B, after procainamide pretreatment, sinus rhythm appeared in 19 and atrial fibrillation in 5, and no change was observed in the remaining 2 patients. Procainamide is more efficacious than digoxin (P < 0.05) in facilitating cardioversion by transesophageal stimulation.

Adult↗
PubMed1978

Massive doses of procainamide for ventricular tachyarrhythmias due to myocardial infarction.

Three patients are described in whom malignant ventricular arrhythmias appeared in connection with a reinfarction some days after hospitalization for an acute myocardial infarction and in whom massive doses of procainamide, up to 7.5 g/day i.v., were necessary to prevent these arrhythmias. The serum concentration of procainamide was 2--4 times higher than the recommended upper level, but no side-effects were observed. With the dose given, one would have expected still higher serum concentrations. Several reasons for this finding are discussed, including the effects of renal function, intestinal leakage, storage of the drug in tissues and hitherto unknown metabolic pathways of procainamide in patients, who are slow acetylators.

Acute Disease↗
PubMed1993

The effect of methyldopa and procainamide on suppressor cell activity in relation to red cell autoantibody production.

Kirtland et al (1980) suggested that methyldopa caused the production of red cell (RBC) autoantibodies by causing a persistent increase in lymphocyte cyclic AMP, which inhibited suppressor T cell function, leading to unregulated autoantibody production in some patients. They showed that significantly higher lymphocyte cyclic AMP concentrations were generated by lymphocytes from healthy donors after adding methyldopa, and by lymphocytes from patients who were receiving methyldopa compared to lymphocytes from healthy donors without methyldopa present. They also showed that methyldopa affected suppressor cell activity. We measured the effect of methyldopa and procainamide on suppressor cell activity, using a similar approach to Kirtland et al (1980). Suppressor cell activity was measured by measuring the amount of IgG, produced in vitro, by B cells following mitogen stimulation preceded by a 24 h incubation period. We found no significant increase in the amount of IgG generated by normal donor lymphocytes, when methyldopa or procainamide was present during the preincubation period. This is in contrast to the findings of Kirtland et al (1980). We also measured the amount of IgG generated in vitro by mitogen-stimulated lymphocytes from patients (with and without positive direct antiglobulin tests) taking methyldopa and compared this to the amount of IgG generated by lymphocytes from normal donors and patients (with and without positive direct antiglobulin tests). The results were similar for each group. This does not agree with the findings of Kirtland et al (1980) who found that lymphocytes from patients taking methyldopa produced more IgG in vitro than lymphocytes from normal donors. Our results do not support the hypothesis that methyldopa and procainamide induce autoantibodies by affecting suppressor cell function.

Autoantibodies↗
PubMed1992

Hypersensitivity reaction associated with acute hepatic dysfunction following a single intravenous dose of procainamide.

Rare cases of hepatotoxicity have been attributed to the antiarrhythmic agent procainamide. We here describe the case of a patient who had a hypersensitivity reaction to procainamide with fever, chills, arthralgia, abdominal pain and acute elevations of serum aminotransferase activities and bilirubin concentration. The reaction occurred after the patient had received a large intravenous dose during cardiac electrophysiological testing. This case should alert physicians to potential hepatotoxic reactions to procainamide, particularly with the increasing popularity of cardiac electrophysiological testing, during which this drug is commonly used.

Drug Hypersensitivity↗
PubMed1977

Procainamide-induced systemic lupus erythematosus with hypocomplementemia.

Procainamide-induced systemic lupus erythematosus (SLE) is a well recognized clinical syndrome believed to be characterized by normocomplementemia. However, in 7 cases of drug-induced SLE recorded in the literature, hypocomplementemia was found. The present report concerns a well documented case of procainamide-induce SLE with hypocomplementemia. The patient improved and complement values returned to normal after procainamide therapy was discontinued and replaced by digitalis and steroid therapy.

Aged↗
PubMed1994

Electrical proarrhythmia with procainamide: a new ICD-drug interaction.

A 78-year-old man with a transvenous cardioverter defibrillator system developed frequent shocks during oral procainamide therapy. Electrophysiologic evaluation demonstrated failure to terminate ventricular tachycardia with maximal energy shocks, but consistent termination by low energy discharges. Procainamide had no effect upon the defibrillation threshold. The failure of therapy with disopyramide and mexiletine to reproduce this observation suggests either a previously unreported electrophysiologic effect of, or idiosyncratic response to, procainamide.

Aged↗
PubMed1997

Mechanisms underlying different surface ECG morphologies of recurrent monomorphic ventricular tachycardia and their modification by procainamide.

INTRODUCTION: Distinct surface ECG morphologies (ECGMs), from one episode to the next, of recurrent monomorphic ventricular tachycardia (VT) in the same patient complicate endocardial catheter mapping and the success of ablative therapy. This study investigates the incidence and mechanisms of multiple ECGMs during recurrent monomorphic VTs in a canine model of experimental myocardial infarction (MI). METHODS AND RESULTS: Computerized ECG analysis and simultaneous endocardial and epicardial activation mapping with a 64 bipolar electrode array were used to analyze the relation between site of VT origin, local activation sequence, and surface ECGM in 72 VT episodes induced in 9 of 17 dogs with experimental MI. Pairwise comparisons of all VTs induced in the same animal were done in drug-free state (47 VTs) and after intravenous procainamide (25 VTs). In drug-free state, VT pairs with similar surface ECGMs manifested endocardial breakthrough sites (BSs) within a distance < 10 mm in 46 (100%) of 46 VT pairs compared to 43 (45%) of 95 VT pairs with different surface ECGMs (P < 0.0001). Of all 89 VT pairs with endocardial BSs within < 10 mm, similar endocardial activation patterns were found in 34 (74%) of 46 pairs with similar ECGMs in contrast to 6 (14%) of 43 pairs with different ECGMs (P < 0.001). Similar comparisons of VT pairs induced after intravenous procainamide administration showed that the endocardial BSs were located within < 10 mm in 9 (75%) of 12 VT pairs with similar and in 17 (49%) of 95 with different surface ECGMs, respectively (P = NS). CONCLUSIONS: In the same heart, similar surface ECGMs of recurrent VT are highly predictive of closely spaced endocardial BSs in drug-free state, but not after procainamide administration. Nearly half of the VTs with different surface ECGMs still originate from closely spaced endocardial BSs but commonly manifest a change in the endocardial activation spread from this site. Thus, assumptions about different mechanisms and sites of VT origin based on different surface ECGMs should be made with caution.

Animals↗
PubMed1978

Reversible severe anaemia and granulocytopenia caused by procainamide. A case report.

A 64-year-old male developed severe anaemia during procainamide therapy. At the same time granulocytopenia was found. Discontinuation of procainamide led to complete recovery. Severe anaemia due to the use of procainamide is not well known. The available data indicate a maturation block of the erythropoiesis as the possible cause of the anaemia, perhaps in combination with an autoimmune haemolysis.

Agranulocytosis↗
PubMed1975

Antinuclear antibodies during procainamide treatment and drug acetylation.

Acetylator capacity was determined in two groups of patients who had received procainamide for more than three months. In seven patients antinuclear antibodies (A.N.A.) were detected during treatment, and these changes disappeared (in six patients) or were less pronounced (one patient) after withdrawal of the drug. These patients tended to have faster acetylation rates, and five were phenotypically "rapid" acetylators. Five patients who did not develop A.N.A. during treatment had less rapid (P less than 0.05) rates of acetylation, and four were "slow" acetylators. We suggest that the immunological changes which may occur during procainamide treatment may be associated with the acetylated metabolite of procainamide rather than the parent compound and that it might be possible to identify patients at risk.

Acetylation↗
PubMed1980

Efficacy of intravenous procainamide infusion in converting atrial fibrillation to sinus rhythm. Relation to left atrial size.

The efficacy of intravenous procainamide, infused at 30 mg/min to a maximum dose of 20 mg/kg, in converting atrial fibrillation was evaluated under electrocardiographic and blood pressure control in 21 patients. Nine patients had atherosclerotic heart disease, seven had valvular lesions, five had hypertension, and six had no apparent heart disease. Nine patients (converters), who reverted to sinus rhythm at a mean dose of procainamide of 13.3 +/- 3.6 mg/kg (mean plasma concentration, 7.4 +/- 3.9 micrograms/ml) had normal echocardiographic left atrial diameters. All but one of the remainder, the 12 non-converters, who received a mean drug dose of 13.1 +/- 3.5 mg/kg (mean plasma concentration 13.9 +/- 7.6 micrograms/ml), had atrial diameters exceeding 4.0 cm. QRS and QTc intervals were not altered significantly in converters, but were prolonged significantly in non-converters. No serious side effects from the infusion were encountered. Intravenous procainamide infusion appears to be a safe and rapidly effective method of converting recent-onset atrial fibrillation to sinus rhythm in patients with normal left atrial dimensions.

Adult↗
PubMed1980

Hemodynamic effects of combined treatment with lignocaine, procainamide and practolol in acute myocardial infarction.

In the treatment of refractory ventricular tachyarrhythmias antiarrhythmic drugs must sometimes be combined. An electrophysiologically appropriate combination is lignocaine and procainamide and, when needed, a beta-blocking agent. The hemodynamic effects of this treatment were studied in 6 patients in the acute phase of myocardial infarction. After a control period, an infusion of lignocaine was started and 1 h later procainamide/placebo was added in a double-blind system and finally also practolol/placebo. The drugs were given intravenously in ordinary doses. Hemodynamics were studied by bedside catheterization. During triple treatment heart rate and aortic pressures fell significantly whereas right atrial mean pressure increased compared to the control period. Stroke volume, cardiac output and pulmonary artery pressures were unchanged. Most of the changes appeared when practolol was added. Following the procainamide injection a transient fall in aortic pressures was noted. Lignocaine gave no hemodynamic effects. The number of ventricular premature beats was reduced in all patients and no patient had ventricular tachycardia during treatment. In these patients it was possible to combine lignocaine, procainamide and practolol in the acute phase of myocardial infarction. However, 3 patients developed hypotension, 1 sinus bradycardia and 1 had a short run of nodal tachycardia. It is concluded that this kind of combined treatment, because of its potential risks, should be restricted to critical clinical situations and then it ought to be hemodynamically controlled.

Adult↗
PubMed1976

Effects of procainamide on the dispersion of recovery of excitability during coronary occlusion.

In 14 mongrel dogs, refractory periods were determined in nonischemic and acutely ischemic zones of myocardium during control conditions, 15 minutes after coronary ligation, and 10 and 20 minutes after a procainamide infusion. Following coronary ligation, refractory periods in the nonischemic area remained unchanged (100.8% of control) while in the ischemia area they decreased to 88.6% of control (P less than 0.02) causing a dispersion of refractoriness of 12.2%. After the administration of procainamide, refractory periods lengthened in the nonischemic as well as in the ischemic areas but the changes were such that the temporal dispersion caused by the coronary ligation was reduced from 12.2% to 5.5% (P less than 0.01) after 10 minutes, and to 5.0% (P less than 0.02) after 20 minutes of drug infusion. It is concluded that procainamide exerts different overall effects on the nonischemic and acutely ischemic canine myocardium. It is postulated that this action may play a role in the suppression of re-entrant arrhythmias.

Animals↗
PubMed1977

The relationship between the metabolism of procainamide and sulfamethazine.

The metabolism of sulfamethazine (SMZ), which is acetylated by a binodally distributed enzyme, and procainamide (PA) was compared in 21 normal volunteers, each given a single oral dosted metabolites, N-acetyl-procainamide (NAPA) and Ac-SMZ, were measured. Subjects with less than 64% Ac-SMZ in the 0-8 hour collection were termed "slow" and those with more than 64% were termed "fast" SMZ acetylators. Slow SMZ acetylators had 9.8 to 43.8% (24.1 +/- 10.13) NAPA recovered, and fast SMZ acetylators, 22.0 to 42.6% (33.7 +/- 7.29) NAPA, P less than 0.01. In addition, the calculated half-life of PA metabolism for slow SMZ acetylators was 9.0 to 33.8 hours (18.4 +/- 8.82) and for fast SMZ acetylators was 8.1 to 14.4 hours (10.9 +/- 2.19), P less than 0.01. For four subjects, SMZ acetylation phenotype did not correlate with the half-life of SMZ or PA metabolism; and in two, SMZ acetylation phenotype and half-life of metabolism did not correlate with the same PA indices. Even though slow SMZ acetylators have less NAPA recovered than fast SMZ acetylators, it is not yet clear that procainamide is metabolized by a bimodally distributed enzyme as is sulfamethazine.

Acetylation↗
PubMed1981

Hemodynamic effects of n-acetylprocainamide compared with procainamide in conscious dogs.

We examined the hemodynamic actions of clinically relevant i.v. doses (20 mg/kg and 10 mg/kg) of n-acetyl procainamide (NAPA) in conscious dogs preinstrumented with a left ventricular (LV) micromanometer, LV and aortic catheters, and ultrasonic crystals for measurement of LV internal diameter shortening (% delta D). Within 30 seconds after the 20-mg/kg dose, there were significant increases in heart rate (27 +/- 7 beats/min, mean +/- SEM; n = 6), maximum dP/dt (655 +/- 206 mm Hg/sec), and % delta D (2.2 +/- 0.9%; all p less than or equal to 0.05). However, by 6 hours after the dose there were reductions compared with control in peak LV pressure (19 +/- 9 mm Hg), dP/dt (610 +/- 210 mm Hg/sec), and % delta D (2.3 +/- 0.6%; all p less than or equal to 0.05). In contrast, equimolar doses of procainamide or drug vehicle alone evoked no response, as did NAPA after pretreatment with reserpine (0.25 mg/kg/day for 2 days) or hexamethonium (10-15 mg/kg). These data suggest NAPA produces a biphasic hemodynamic response with enhancement of LV performance early and a decrease later; this response is different from that of the parent compound, procainamide. These effects are likely mediated by the adrenergic nervous system at either a ganglionic or a central level.

Acecainide↗
PubMed1992

A quantitative analysis of use-dependent ventricular conduction slowing by procainamide in anesthetized dogs.

BACKGROUND: Use-dependent effects of antiarrhythmic drugs on phase 0 sodium current result in rate-dependent conduction slowing with important potential clinical consequences. The purpose of the present study was to determine whether state-dependent interactions of procainamide with sodium channels can be analyzed based on conduction changes in vivo. METHODS AND RESULTS: Procainamide infusions were used to produce stable drug concentrations causing greater than or equal to 25% conduction slowing at a basic cycle length (BCL) of 300 msec in morphine/chloralose-anesthetized dogs with formalin-induced atrioventricular block. Computer-based epicardial activation mapping was applied to assess the time course and pattern of conduction over a wide range of BCLs before and after drug administration. Action potential duration was measured from recordings of monophasic action potentials. The onset and steady-state values of fractional sodium channel block estimated from conduction changes were fitted to equations obtained from a stepwise exponential analysis. The rate constant for the onset of block (lambda *) decreased, as predicted, with decreasing cycle length. The slope of the relation between lambda * and recovery time at each BCL averaged 0.29 +/- 0.03 sec-1, resulting in a calculated recovery time constant (3.4 seconds) similar to values previously obtained by direct measurement. Estimates of binding and unbinding rate constants for the sodium channel during the action potential plateau and after repolarization were of the same order as previous results obtained using microelectrode methods in vitro. CONCLUSIONS: Use-dependent conduction changes produced by procainamide in vivo closely follow the predictions of mathematical models of drug-channel interactions, and underlying kinetic interactions with the sodium channel inferred from conduction changes agree with previous, more direct observations. These results support the relevance of basic concepts about antiarrhythmic drug actions on sodium channels for understanding drug effects on conduction in vivo and advance analytical tools that can be used to explore the latter in humans.

Action Potentials↗
PubMed1993

Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice.

Human antigen-specific CD4+ T cells become autoreactive after treatment with various DNA methylation inhibitors, including 5-azacytidine, procainamide, and hydralazine. This suggests a mechanism that could contribute to the development of some forms of autoimmunity. In this report we have asked whether T cells treated with DNA methylation inhibitors can induce autoimmunity. Murine CD4+ T cells were treated with 5-azacytidine or procainamide and were shown to respond to syngeneic antigen-presenting cells, similar to CD4+ human T cell clones treated with these drugs. Functional characterization demonstrated that cells treated with either drug spontaneously lysed syngeneic macrophages and secreted IL-4, IL-6, and IFN-gamma. Adoptive transfer of 5-azacytidine- or procainamide-treated cells into unirradiated syngeneic recipients induced an immune complex glomerulonephritis and IgG anti-DNA and antihistone antibodies. These experiments demonstrate that T cells treated with either of two distinct DNA methyltransferase inhibitors are sufficient to induce a lupus-like disease. It is possible that the lysis of macrophages, together with the release of cytokines promoting B cell differentiation, contributes to the autoantibody production and immune complex deposition. These results suggest that environmental agents that inhibit DNA methylation could interact with T cells in vivo to produce a lupus-like illness, a mechanism that could have relevance to drug-induced and idiopathic lupus.

Animals↗