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A prospective, randomized, double-blind study to compare the efficacy in terminating postoperative atrial fibrillation of the class Ic drug propafenone versus class Ia drug procainamide was conducted. Intravenous propafenone was superior to procainamide in achieving rapid cardioversion and a better rate control with a lower incidence of symptomatic hypotension.
We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 +/- 0.17 (mean +/- SD) for those with NAT2*4/*4, 0.37 +/- 0.06 for NAT2*4/*6A, 0.40 +/- 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.
The risk of developing a syndrome resembling lupus erythematosus when taking procainamide has been well recognized for over 15 years, although the development of myopathy has been reported on one occasion only, in this instance without histopathological evidence of muscle inflammation. The patient reported in this paper developed a severe, rapidly progressive vasculitis, apparently limited to muscle, after taking procainamide for 42 months, his myopathy remitting rapidly after withdrawal of the drug and a short course of treatment with azathioprine. Although this man had no clinical evidence of SLE, he had impressive immunological evidence to support this diagnosis.
Scleritis developed in a patient using procainamide as part of a drug-induced lupus syndrome. Systemic findings, which developed after the onset of ocular signs and symptoms, included arthralgias, myalgias, weight loss, and markedly elevated antinuclear antibody (ANA) titers and antihistone titers. The clinical picture and laboratory abnormalities improved after discontinuation of the drug. Although systemic findings secondary to drug-induced lupus have been well described in the medical literature, this case represents the first detailed ophthalmologic documentation of scleritis as the presenting manifestation of procainamide-induced lupus.
A patient developed acute renal failure while receiving oral procainamide (PA). This lead to severe PA and N-acetyl procainamide (NAPA) toxicity. Rebound of NAPA plasma levels postdialysis prolonged the toxicity, which was treated with hemodialysis, hemoperfusion, and combined hemodialysis-hemoperfusion. Because of the potential for PA and NAPA toxicity in patients with renal insufficiency, especially in patients with changing renal function due to acute renal failure, it is recommended that the use of PA be curtailed in this population and that another substitute antiarrhythmic agent be used.
Brugada syndrome is a clinical and electrocardiographic entity characterized by ST segment elevation in the right precordial ECG leads and sudden death or syncope secondary to malignant ventricular arrhythmia, and has a high recurrence rate. We report a patient with this syndrome who had received an automatic implantable defibrillator, who presented with multiple appropriate discharges because of recurrent episodes of ventricular fibrillation. All episodes were started by a premature ventricular beat of the same morphology and coupling interval. Endovenous procainamide administration, paradoxically, was effective in preventing new episodes. The beneficial antiarrhythmic effect of procainamide in this patient is discussed.
In this study the membrane fluidity of fibroblasts under different pharmacological treatment was investigated. Two drugs, hydralazine and procainamide, were used to treat the immortalized mouse NIH 3T3 and hamster B14 fibroblasts. Membrane lipid dynamics was measured by fluorescence spectroscopy and electron spin resonance techniques. Two kinds of fluorescent probes (TMA-DPH and 12-(9-anthroyloxy)-stearic acid (12-AS)) and two spin labels (5-doxylstearic acid (5-DS) and 12-doxylstearic acid (12-DS)) were used to monitor fluidity in the upper polar and in the hydrophobic core regions of the lipid bilayer. The drugs influenced the membrane hydrophobic core, of which hydralazine induced fluidization and procainamide increased the rigidity. The membrane fluidity at the surface of the lipid bilayer was not modified by the drugs which indicates that both drugs intercalated mainly into the inner core of the cell membrane.
A sensitive and accurate spectrodensitometric method was developed for the determination of procainamide and its major metabolite, N-acetylprocainamide, in plasma. The method involves extraction into organic solvent at alkine pH, separation by thin-layer chromatography and direct measurement of the absorbance of the compounds on the plate at 275 nm. Quantities as low as 10 ng could be measured and a linear relationship was obtained between peak areas and amounts of the compounds in the spots from 10 to 200 ng. The recovery of both drugs from plasma was from 95.4 to 104.8%. The method is sensitive and specific, and procainamide was well separated from N-acetylprocainamide at all investigated concentrations. The method is recommended for clinical assays and pharmacokinetics studies.
Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.
Procainamide, an antiarrhythmic drug, and its biologically active metabolite, N-acetylprocainamide, were quantitated in serum by a commercially supplied enzyme immunoassay procedure. Replicate analyses of controls resulted in within-assay and between-assay coefficient of variation (CV) of less than 10%. Regression analyses of serum samples analyzed by immunochemical (y) and chromatographic or spectrofluorometric methods (x) gave equations with a slope of 0.99 to 1.11, y-intercept of -0.52 to -0.02, and correlation coefficient greater than 0.92. Clinical evaluation of the results indicates the respective enzyme immunoassay to be specific and sensitive for procainamide and N-acetylprocainamide. Immunochemical selectivity of the respective assay was quantitated by challenging the assay with other drugs. When the antibody reagent was crossreactive toward the other drugs, selectivity was determined to be inversely related to the concentration of the other drug.
Sixteen apparently intact procainamide tablets, in varied stages of drug depletion, were found distributed throughout the gastrointestinal tract of a man who died of arteriosclerotic heart disease with pulmonary complications. The tablets were found to contain procainamide by a thin layer chromatography system with cataloged compound identification characteristics. The drug was confirmed by ultraviolet spectrophotometry and gas chromatography/mass spectrometry. The concentration of the drug in the liver was in a therapeutic range and the drug was not attributed as contributing to the cause of death.
To gain insight into the immunopathogenesis of drug-induced autoimmune disorders, lymphocyte and immunoglobulin distributions and cytokine levels were monitored in the peripheral blood and pleural fluid of a patient with procainamide-induced lupus and pleural effusion. Approximately 80% of the B cells in both compartments were CD5+ compared to 10% to 25% in normal adults. CD4/CD8 ratio and percentage CD4 were normal in peripheral blood. Serum levels of IgG (particularly IgG2), IL-6, and soluble IL-2R were slightly elevated, and those of IgA were significantly elevated compared to normal controls. Analysis of the pleural effusion revealed an increased CD4/CD8 ratio because of an increased percentage of CD4+CD29+ helper memory T cells, lack of expression of the resting B-cell marker CD21, immune complex deposition and complement consumption, increased relative levels of ANA, abnormally high levels of IL-6 and soluble IL-2R, and detectable levels of IL-1b, IFN-g and TNF-a. These observations provide evidence for the involvement of CD5+ B cells and differential helper T-cell activity in procainamide-induced lupus and for an association between local lymphocyte activation and organ pathology.
With increased use of sustained-release forms of procainamide in treating common cardiac arrhythmias, more and more cases of severe neutropenia and occasional deaths have been reported. It is unclear whether all sustained-release procainamide preparations are implicated. I recommend that a complete blood count be done every two weeks for the first three months of treatment with these drugs. Any patient who has an unexplained fever or a toxic reaction while taking one of these preparations should have a complete blood count done.
The lupus anticoagulant, with or without other symptoms or signs of lupus, has been described in patients taking procainamide. Screening all such patients for the presence of these anticoagulants may be warranted (despite the rarity of episodes of bleeding) in view of the potentially increased risk of thrombotic events in patients who may already be predisposed. A prospective study to determine the incidence of lupus anticoagulant in procainamide-treated patients and the true frequency of thrombosis in these patients would be helpful in determining appropriate management.
Seventeen patients treated with procainamide for cardiac ventricular arrhythmias were followed for up to 40 weeks. Immunological data as a clue to developing the systemic lupus erythematosus (SLE)-like syndrome was emphasized. Ten patients developed antinuclear antibodies (IgG or IgM), but no increase in the plasma concentration of the complement split product C3d or immune complexes, measured by two different methods, was demonstrated. This finding is in contrast to the high levels of both C3d and immune complexes in SLE. The discrepancy may be caused by a lack of immune complex mediated complement activation by the procainamide induced antibodies, or may be due to a difference in severity of disease. The acetylator phenotype of the patients was determined but due to the low frequency of fast acetylators no comparison of the immunological response of the two phenotypes could be done.
1 Data from a comprehensive drug surveillance programme are analysed to provide details of procainamide use and toxicity in medical wards of teaching hospitals in five countries. 2 Out of a total of 488 recipients 9.2% had one or more adverse effect attributed to the drug; common effects being arrhythmias, gastro-intestinal upsets and drug fever. Although occasionally of major severity, no patient died as a consequence of procainamide toxicity. 3 Toxicity was directly related to total daily dose and duration of hospitalization but was not related to age, weight of the patient or presenting urea or albumin concentrations.
1 The pharmacokinetics of two different sustained-release oral procainamide preparations were studied in ten hospital patients with normal blood ureas and no clinical evidence of heart failure. Each patient received either one or other preparation at 12 hourly intervals for four doses. Frequent blood sampling enabled close monitoring of blood levels. 2 Results showed that both preparations were essentially similar in their pharmacokinetics. Both effectively double the half-life of conventional oral procainamide to 6.5 h and are suitable as prophylactic preparations. One patient developed toxic levels, thought to be related to her metabolic status of being a very slow acetylator. To avoid toxicity pre-therapy assessment of a patient's cardiac and renal function and acetylator status is advised.
The chemical reaction between procainamide hydrochloride and glucose following admixture to glucose infusion has been investigated. Substantial amounts (10-15% after 10 h at room temperature) of the procainamide is lost with the formation of a mixture of the corresponding alpha- and beta-glucosylamines. The chemical identity of the latter compounds was confirmed by 13C and 1H nuclear magnetic resonance spectroscopy.