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PubMed1987

Tocainide-induced reversible agranulocytosis and anemia.

Tocainide is an effective oral antiarrhythmic agent. We report a 77-year-old man who developed agranulocytosis and anemia while receiving tocainide therapy. These hematologic abnormalities were detected on routine evaluation six weeks after beginning tocainide therapy. The absolute granulocyte count decreased to 50/mm3 (0.05 X 10(9)/L). The anemia was mild; hemoglobin count, 10.9 g/dL (109 g/L). These abnormalities were associated with local and stromal adipocytic bone marrow damage, and decreased production of red blood cells and granulocytes. The platelet count was not affected. The patient had no evidence of infection. Hematologic values were restored to normal two weeks after discontinuation of tocainide therapy, indicating that bone marrow toxicity of tocainide is reversible.

Aged↗
PubMed1987

Fatal intoxication by tocainide.

A 26-year-old woman committed suicide by ingestion of a large quantity of tocainide, a recently developed oral antiarrhythmic agent with chemical similarities to lidocaine. Blood and bodily fluid analysis by thin-layer chromatography, high pressure liquid chromatography, and mass spectroscopy confirmed the presence of tocainide, with a serum level of 68 mg/L, nearly 7 times the upper recommended therapeutic level for this drug. Tocainide was also detected at significant levels in vitreous fluid and bile. Although the mechanism of death from tocainide intoxication in animal studies is related to central nervous system toxicity, the presentation of ventricular tachyarrhythmias with coma in this patient suggests that tocainide at high levels may have primary myocardiotoxicity in humans.

Adult↗
PubMed1985

Effect of tocainide on the concentrations of norepinephrine dopamine, serotonin and histamine in rat brain and its binding affinity to neuroceptors.

Tocainide (W-36095, Xylotocan) is a derivative of lidocaine which is applied clinically as a cardiac antiarrhythmic. In addition, it diminishes the severity of symptoms in neurological disorders such as myotonia and paramyotonia and in patients with torticollis spasmodicus it brings about a distinct reduction in the tension of the neck muscles. It was investigated whether in reducing the tonus in torticollis spasmodicus tocainide could be acting on the central nervous system. The binding affinity of the substance to the dopamine, serotonin, opiate, GABA and benzodiazepine receptors was measured without finding any significant affinities. In addition, the effect of tocainide on the concentration of the neurotransmitters norepinephrine (noradrenaline), dopamine, serotonin and histamine were investigated in rat brain, and it was found that tocainide induces a significant increase in dopamine and serotonin concentrations. This lead to the conclusion that, in addition to its antiarrhythmic effects, tocainide acts on the central nervous system.

Animals↗
PubMed1985

The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness, vertigo, and nystagmus.

The effects of TTS-scopolamine, dimenhydrinate, lidocaine, and tocainide on motion sickness and vertigo and on caloric and postrotatory nystagmus were evaluated in healthy volunteers. TTS-scopolamine was administered transdermally (delivering approximately 10 micrograms X h-1 scopolamine base) and 100 mg dimenhydrinate orally. Lidocaine and tocainide were administered intravenously (average plasma concentration of lidocaine 6 mol X L-1 and of tocainide 20 mol X L-1). TTS-scopolamine and dimenhydrinate significantly reduced vertigo induced by calorization of the ears, nausea provoked with Coriolis maneuvre, and nystagmus in caloric and rotatory tests. During treatment with lidocaine and tocainide no alleviation of vertigo and nausea was observed. Caloric nystagmus was reduced but rotation induced nystagmus was virtually unchanged. Presumably the motion sickness drugs act at the brain stem where TTS-scopolamine and dimenhydrinate have their target cells in the vestibular nuclei. Furthermore, the alleviation of motion sickness was linked to a decline of nystagmus. Lidocaine and tocainide, the action of which in vertigo and nausea in patients is proposed to be on the vestibular end organs and the supratentorial brain structures, consistently failed to alleviate motion sickness.

Administration, Topical↗
PubMed1984

Stereospecific salivary excretion of tocainide enantiomers in man.

Saliva and plasma samples collected from four healthy volunteers who had received racemic tocainide by intravenous infusion for 20 minutes were analysed by a stereospecific and sensitive gas chromatographic method. The enantiomeric composition of mixed saliva obtained for a period of 48 hrs have been determined and compared with the corresponding plasma profiles. The concentration of each enantiomer in saliva tended to be greater than those in the corresponding plasma sample, such that the mean saliva to plasma ratio for S(+) tocainide was 2.07 +/- 0.50 (SEM) and for the R(-) isomer 3.683 +/- 0.76 (SEM). Marked intersubject variability was found in the saliva/plasma ratio of both isomers, however, the correlation of saliva/plasma concentrations in each volunteer was good and ranged from r = 0.910 to 0.987 for S(+) tocainide and r = 0.884 to 0.986 for R(-) tocainide. There was a 6-fold difference between saliva and plasma concentration of R(-) isomer in one subject whose saliva pH ranged from 6.9 to 7.1. The difference was only 3.5 fold in another subject whose saliva pH was consistently higher (7.4 to 7.5). Therefore, the saliva/plasma ratio appeared to depend on pH, increasing with decreasing pH. However, the correlation between the saliva/plasma ratio observed and the ratio predicted was poor. Mechanisms other than passive diffusion are likely to be involved in the transfer of tocainide enantiomers from plasma to saliva and are more pronounced with the levo isomer.

Adult↗
PubMed1980

Dose-dependent pharmacokinetics of tocainide in the rat.

The pharmacokinetics of tocainide, an experimental antiarrthymic agents, were studied in rats. The concentration of intact drug in plasma and urine samples was determined by an electron capture detector gas chromatographic method. Plasma level and urinary excretion studies revealed the existence of nonlinear kinetics of disposition at and above a 20 mg/kg dose of tocainide. The area under the plasma concentration-time curve increased in a nonlinear fashion with an increase in the dose. Below a 20 mg/kg dose about 19% of the dose was excreted as intact drug in urine while at and above this dose level at least a 100% increase in excretion of intact drug was observed. The extent of inhibition of tocainide metabolism by SKF 525A is more pronounced at a 15 mg/kg dose of tocainide than at 20 mg/kg which suggests that the observed nonlinearity at 20 mg/kg is due to saturation of the metabolism of tocaininde. Study of the effect of route of administration reveals that tocainide is completely absorbed up to a dose of 15 mg/kg, following p.o. or i.p. administration.

Anilides↗
PubMed1995

[Inhibitory effect of tocainide on calcium current and potassium current in guinea pig ventricular myocytes].

In whole cell voltage clamp experiment with isolated guinea pig ventricular myocytes, tocainide was shown to exhibit a concentration-dependent inhibition of calcium current (ICa) and delayed rectifier potassium current (IK). Tocainide with a therapeutic concentration of 50 mumol.L-1 significantly inhibited the ICa and Itail (deactivating tail current of IK) by 16% and 3% respectively. Inhibition of ICa by tocainide was also shown to be dependent upon stimulating frequencies, with a greater blockade occurring at 2.0 Hz (57%) than at 0.2 Hz (17%). Tocainide was found to inhibit the IK,ATP by 74% at 200 mumol.L-1 but not at 50 mumol.L-1. These inhibitory effects on ICa and IK can probably explain the therapeutic effect of tocainide on supraventricular tachycardia, and the shortening of plateau phase of action potential.

Animals↗
PubMed1982

Species differences in the urinary excretion of the novel primary amine conjugate: tocainide carbamoyl O-beta-D-glucuronide.

The metabolism of the antiarrhythmic drug tocainide (I) has been shown previously to occur via a novel pathway involving the addition of carbon dioxide to the primary amine nitrogen of I followed by conjugation with glucuronic acid. The product of this reaction, tocainide carbamoyl O-beta-D-glucuronide (II), the principal metabolite of I in humans, has been found to cyclize under strongly basic conditions to form 3-(2,6-xylyl)-5-methylhydantoin (III). Thus, evidence for the existence of II can be obtained by two different procedures: conversion of II to III in the presence of strong base and by hydrolysis of II with beta-glucuronidase. The principal purpose of the present investigation was to identify suitable species for studies of the mechanism involved in the formation of II, as well as to find an animal model suitable for toxicological evaluation of tocainide and structurally related compounds. Eight animal species were examined to identify those capable of metabolizing I into II. The fraction of an intraperitoneal dose excreted in urine as II was estimated by measurement of tocainide released by beta-glucuronidase mediated hydrolysis of urine and by the quantitation of III formed after alkalinization of urine samples. Urinary recovery of unchanged drug ranged from 9.5% of the dose in the gerbil to 48.7% in the cat. The percent of the dose excreted in urine as acid hydrolyzable conjugates ranged from less than 1% in the gerbil to a mean of 13% in the rabbit. Guinea pigs, dogs, cats, rabbits, and pigtail monkeys excreted amounts of II ranging from 0.2 to 2.4% of the dose. Thus, none of the species appeared to be a suitable model for the study of the mechanism of formation of II because of the quantitative insignificance of this pathway.

Animals↗
PubMed1991

The different use dependences of tocainide and benzocaine are correlated with different effects on sodium channel inactivation.

To study the mechanism of use dependence, we investigated the influence of 0.5 mM tocainide on the amplitude of sodium currents elicited by membrane depolarizations with standard test pulses in voltage-clamped human myoballs. For comparison, the experiments were also conducted with 1 mM benzocaine, a drug with almost no use dependence. These concentrations were so chosen that without stimulation and at a holding potential of -135 mV, either drug blocked about 50% of the channels (tonic block). With repetitive stimulation at 1 Hz, tocainide blocked about 75% of the channels that had remained open in the rested state (phasic block), while benzocaine had little such effect. The potential dependence of steady-state inactivation (h infinity curves) of the sodium channels in these myoballs depended on the duration of the prepotential indicating that they possess at least two states of inactivation: fast and intermediate. The two drugs differed in their effects on these two states. Benzocaine always produced a left-shift of the h infinity curve, no matter whether the duration of the conditioning pulse was short (8 ms) or long (512 ms) indicating that it can bind when the channel is in the state of fast inactivation. Tocainide shifted the h infinity curve only with long prepulses, i.e. when the sodium channels were in the state of intermediate inactivation. The recovery from inactivation, a process governed by two time constants in the absence of drugs, was also differently influenced by the two drugs. In the presence of tocainide, the channels mainly recovered with the slow time constant and this time constant was significantly increased, whereas benzocaine did not substantially modify this biphasic process.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzocaine↗
PubMed1983

Pharmacokinetics of tocainide in patients with combined hepatic and renal dysfunction.

The disposition of tocainide following an i.v. infusion of tocainide HCl 100 mg was studied in 6 patients with decompensated cirrhosis (ascites) and renal dysfunction. In one patient with active hepatic necrosis the terminal plasma half-life was 57.4, and in the others the half life ranged from 16.0 to 29.0 h. The increase in half-life was correlated with biochemical evidence of renal dysfunction, but not with individual tests of hepatic function. Non-renal clearance of tocainide was similar to values reported previously in healthy subjects and patients with acute myocardial infarction. The apparent volume of distribution of tocainide was increased and the pattern of distribution was abnormal in some patients, as plasma concentrations increased after an initial fall and the elevated concentrations then persisted for several hours. This abnormality appeared to be most marked in patients with the greatest degree of liver dysfunction.

Adult↗
PubMed1980

Effects of tocainide on ectopic impulse formation in isolated cardiac tissue.

The effect of tocainide on enhanced automaticity if Purkinje fibers was studied under the influence of epinephrine (0.2 microgram/ml) by means of intracellular recordings with microglass electrodes. In the presence of tocainide 5 microgram/ml and 10 microgram/ml cycle length of enhanced automaticity was increased in the range of 10.6% and 34.9% and in the range of 26.3% and 108.7% respectively. Repetitive impulse formation in ventricular myocardium was generated by creating a potential difference in a papillary muscle mounted in a partition chamber. One chamber was connected to ground, the potential of the other chamber could be changed in the range of 0 to 500 mV. By progressively increasing the voltage difference across the papillary muscle repetitive rhythmic impulse formation was induced. The threshold voltage gradient increased in the presence of tocainide (100 microgram/ml) from--285 to--335 mV. The results suggest that tocainide is suitable to suppress arrhythmias due to enhanced automaticity of Purkinje fibers.

Action Potentials↗
PubMed1980

Hemodynamic and antiarrhythmic effects of tocainide in patients with acute myocardial infarction.

In order to evaluate the hemodynamic and antiarrhythmic efficacy of tocainide, studies were performed in patients suffering acute myocardial infarction. Intravenous tocainide was administered over a 15-minute period in order to determine its acute effects and subsequently, in a randomized double-blind study with placebo control, to determine its effects over a 24-hour period in acute myocardial infarction. Tocainide resulted in a significant decrease of frequent and complex ventricular arrhythmias acutely and had only minimal effects of hemodynamics in most patients. In the long-term studies, tocainide produced no adverse hemodynamic effects when compared with placebos.

Anilides↗
PubMed1980

Prophylaxis of ventricular tachyarrhythmias with intravenous and oral tocainide in patients with and recovering from acute myocardial infarction.

In a double-blind placebo controlled study, tocainide, 750 mg i.v. during a 15-minute period directly followed by 800 mg orally and later 400 mg t.i.d., was administered to patients wiht acute myocardial infarction (AMI). Treatment was started as soon as possible following onset of symptoms; the follow-up period was 6 months. The patient groups consisted of 56 tocainide and 56 placebo patients. There was no significant effect on the incidence of ventricular fibrillation or symptomatic ventricular tachycardia. The mortality rates were similar and low in both groups. Tocainide suppressed ventricular arrhythmias, including ventricular tachycardia, both in the acute stage of AMI and during convalescence. Tocainide also suppressed exercies-induced ventricular arrhythmias. Side effects were in general mild or moderate.

Administration, Oral↗
PubMed1980

Tocainide for refractory ventricular arrhythmias of myocardial infarction.

Oral tocainide was used as a long-term antiarrhythmic in patients with symptomatic high-grade ventricular ectopic activity refractory to conventional antiarrhythmic agents. Eleven of the 22 patients had a previous myocardial infarction (three patients had a ventricular aneurysm). Unacceptable side effects precluded long-term use of tocainide in two patients. Long-term tocainide was effect in six of the remaining patients for periods of 9 days to 42.5 months (mean 15.2 months). Eight of these nine patients responded to intravenous lidocaine prior to tocainide therapy.

Adult↗
PubMed1980

A prospective randomized trial of tocainide in patients following myocardial infarction.

One hundred forty-six patients with recent acute myocardial infarction were grouped at random into those treated with tocainide, an oral analogue of lignocaine, or placebo and followed up for 6 months. In addition to standard investigations, a 24-hour ambulatory taped ECG recording was obtained prior to randomization and thereafter at 2, 8, 16, and 24 hours after discharge. The ECGs were analyzed by means of an automated, computerized reporting system. Forty-two patients had significant ventricular arrhythmias, 10 of whom had effective plasma levels of tocainide compared with 27 patients on placebo (P < 0.005). In the placebo patients with increasing mobilization there was a consistent rise in the number of ventricular ectopic beats per day. There was no such increase in the tocainide patients (P < 0.01). Side effects were few and the incidence of central nervous system side effects was similar in both the tocainide and placebo groups. There was no conclusive evidence of myocardial depression, heart rate and blood pressure being unchanged over the 6-month period. Although ventricular arrhythmias were suppressed, the number of patients in the study was too small to draw conclusions regarding the mortality rate.

Anilides↗
PubMed1980

Open clinical studies at a referral center: chronic maintenance tocainide therapy in patients with recurrent sustained ventricular tachycardia refractory to conventional antiarrhythmic agents.

Chronic maintenance tocainide therapy was effective in controlling symptomatic, recurrent ventricular tachycardia in 11 of 15 patients. Patients were selected for tocainide therapy on the basis of refractoriness to conventional antiarrhythmic agents and responsiveness to the intravenous administration of lidocaine. Side effects were frequent but could usually be managed by taking the drug with meals or by more frequent administration of smaller doses. Survival, frequency of symptomatic tachycardia, frequency of asymptomatic ventricular tachycardia, and tolerance of the therapeutically effective dosage were the criteria used to assess therapeutic effectiveness. Factors common to the response group included primary and secondary Q-T prolongation before therapy, a paradoxical increase in ventricular ectopic activity with quinidine-like medications, and shortening of the Q-T interval with maintenance tocainide therapy. These factors may prove to be useful in identifying the patients who are most likely to benefit from chronic maintenance tocainide therapy.

Adolescent↗
PubMed1980

Hemodynamic and electrophysiologic interactions between antiarrhythmic drugs and beta blockers, with special reference to tocainide.

The administration of beta-receptor blocking drugs and antiarrhythmic drugs in close proximity may result in hemodynamic, electrophysiologic, or pharmacokinetic interactions. We examined the hemodynamic and electrophysiologic effects of 0.20 mg/kg intravenous metoprolol followed by a 15-minute infusion of 0.75 mg/kg/min tocainide. In the six patients sutided, metoprolol produced a fall in cardiac rate and output which was not further altered by tocainide. Both drugs decreased peak left ventricular (LV) dP/dt, ejection fraction, and mean Vcf. There was no change in LV end-diastolic pressure or echo dimension and in clinical ill effects. In eight patients without sinus A-V nodal disease electrophysiologic studies showed mild depression of A-V conduction by metoprolol. Tocainide depressed sinus node function and shortened the functional refractory period of the His-Purkinje system. There were no clinical sequelae. However, three patients with preexisting electrophysiologic abnormalities developed asystole. There was no evidence of pharmacokinetic interaction. It is concluded that metoprolol and tocainide can be given concurrently with reasonable safety to cardiac patients without electrophysiologic abnormalities.

Adrenergic beta-Antagonists↗
PubMed1980

Tocainide therapy for refractory ventricular arrhythmias.

Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.

Adult↗