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PubMedDate not supplied

Acute hemodynamic effects of tocainide in patients undergoing cardiac catheterization.

To characterize the acute hemodynamic effects of tocainide hydrochloride, a new antiarrhythmic agent, 11 patients undergoing diagnostic cardiac catheterization were given intravenous infusions of the drug for 15 minutes at rates of 0.50 (six patients) or 0.75 (five patients) mg/kg/min. The hemodynamic status of these subjects was determined before, during, and for 15 minutes after treatment, and blood levels of tocainide were followed during and after treatment. Tocainide blood levels at the end of the infusions were 14.9 +/- 1.6 microgram/ml (S.E.) and 15 minutes later were 6.0 +/- 0.7 microgram/ml. In these subjects treatment was not associated with significant changes in Ao or PCW, but it was associated with a statistically significant but small decrease in LV dp/dt. At the same time, LVED was not significantly elevated. Treatment was also accompanied by small increases in PA diastolic and mean pressures, but RA and RV were unchanged. Significant changes were not seen in HR, CO, CI, SV, SVR, or PVR. Thus, the intravenous infusion of 0.50 and 0.75 mg/kg/min of tocainide for 15 minutes produced small but statistically significant depression of left ventricular function without producing changes in CO or clinical evidence of congestive heart failure.

Adult↗
PubMed1978

Human Electropharmacology of Tocainide, a lidocaine congener.

The electropharmacology of tocainide, an orally active congener of lidocaine, was evaluated in 10 patients with coronary artery disease. Electrophysiologic measurements including sinus nodal recovery time, sinoatrial conduction time, intraatrial conduction time, atrial, atrioventricular (A-V) nodal and ventricular refractory periods and intraventricular conduction time were obtained before and after intravenous infusion of tocainide. At blood levels shown to be effective against ventricular arrhythmias, tocainide produced no statistically significant changes in the electrophysiologic measurements, although occasional marked individual effects were observed. No side effects were observed during these studies. No adverse effects on A-V conduction were observed in patients with an intraventricular conduction disturbance or a prolonged control H-V interval. Thus, plasma tocainide concentrations effective in the therapy of ventricular arrhythmias exert no adverse effects on cardiac electrophysiologic properties in patients with coronary artery disease.

Anilides↗
PubMed1978

Long-term tocainide therapy for ventricular arrhythmias.

Long-term tocainide therapy has been evaluated in 17 patients with ventricular arrhythmias. Ventricular tachycardia and/or fibrillation was recurrent and sustained in nine patients, and symptomatic but unsustained in three others. Five patients had frequent but only mildly symptomatic ventricular irritability. In all patients, arrhythmias could not be managed with quinidine, procainamide or propranolol. Tocainide doses ranged from 300 to 700 mg every 8 hours (mean steady-state plasma concentrations ranged from 5.75 to 12.18 microgram/ml). Tocainide therapy was unsuccessful in eight patients; three died during therapy and five had no antiarrhythmic response. The data suggest that evaluation of long-term drug efficacy, using the criterion of reduction of asymptomatic arrhythmias, is best documented by multiple sequential ambulatory electrocardiographic recordings, both on and off the drug. Tocainide controlled arrhythmias in nine patients (53%), with criteria of success being continued reduction of ectopic beats and/or control of symptomatic recurrences. Seven patients remain on therapy. Side effects generally have been minor and well-tolerated.

Adult↗
PubMed1979

Effects of tocainide on normal and myotonic mammalian skeletal muscle.

The effects of the lidocaine derivative 2-amino-2',6'-propionoxylidide hydrochloride (tocainide, W-36095) on the contraction force and on membrane resting and action potentials of rat diaphragm were tested in vitro. In a concentration of 5 x 10(-4) mol/l, tocainide reduced the amplitude of the twitch by about 25% within 15 min. This reduction was reversible on washout of the drug. Tocainide had little effect on the membrane resting potential, but considerably affected the action potential: rate of rise, maximum amplitude and rate of fall were reduced, the duration increased. The conduction velocity of the action potential was reduced by 20%. Experimental myotonia produced in excised diaphragms or in anesthetized whole animals by anthracene-9-carboxylic acid was completely abolished by low doses of tocainide.

Action Potentials↗
PubMed1995

Myocardial uptake kinetics of tocainide enantiomers in the isolated perfused rabbit heart.

The extent of myocardial accumulation of tocainide, administered as single enantiomers and as well as racemate, was determined in the isolated, spontaneous beating rabbit heart. The heart was retrogradely perfused at a constant rate and fractions of the perfusate were collected during and after infusion. Kinetic parameters for myocardial accumulation and disposition of tocainide were indirectly determined from drug concentration/time course in the outflow perfusate. No stereoselectivity in myocardial accumulation was observed. A two compartment model with mean half-lives for distribution and elimination of 0.60 and 3.78 min, respectively, was fitted to the accumulation and disposition data. At steady-state, tocainide enantiomers were accumulated about three times in the myocardium relative to the perfusion liquid.

Animals↗
PubMed1987

Paramyotonia congenita: successful treatment with tocainide. Clinical and electrophysiologic findings in seven patients.

Seven patients with paramyotonia congenita (PC) from two families were studied. Voluntary exercise of the hand muscles was performed at different hand temperatures, both before and after treatment with tocainide. All patients developed stiffness, prolonged weakness, and small compound muscle action potentials (CMAPs) following exercise; the temperature at which this occurred was individually different. Two patients with PC and associated episodes of generalized weakness underwent potassium loading. A prolonged exercise test was performed both immediately before and 90 minutes after K-loading. Exercise-induced weakness and CMAP-decline occurred only with high serum K levels. Thiazide treatment in these two patients was ineffective. All seven patients responded well to tocainide. Treatment response and side effects were dose-dependent. Good clinical improvement has been maintained in all patients for more than 6 months, with relatively small doses of tocainide (400-1200 mg/day).

Action Potentials↗
PubMed1985

Pharmacokinetics of tocainide in patients with severe renal failure.

The plasma levels of tocainide have been followed after oral administration of 600 mg p.o. to 20 patients with renal failure due to various causes, and to 8 healthy controls. The peak plasma concentrations in the patients with pyelonephritis (3.80 micrograms/ml) and interstitial nephritis (3.74 micrograms/ml) but not in those with glomerulonephritis (3.17 micrograms/ml) differed from that in healthy volunteers (3.24 micrograms/ml). The renal clearance of tocainide was well correlated with the endogenous creatinine clearance and was dependent on urine pH. No difference in renal clearance was observed between the patients groups. It is suggested that the changes in plasma levels are a consequence of decreased renal clearance. Creatinine clearance was shown to be a poor estimator of tocainide clearance, which suggests that extrarenal clearance plays an important role in the handling of the drug in the body. The findings are used to suggest a safe dosage regimen.

Acute Kidney Injury↗
PubMed1983

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis.

The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3 +/- 4.8 h (+/- SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5 +/- 4.6 h, which was calculated to correspond to removal of 25 +/- 14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10-55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2 +/- 4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.

Aged↗
PubMed1985

Canine digitalis arrhythmia as a model for detecting Na-channel blocking antiarrhythmic drugs: a comparative study using other canine arrhythmia models and the new antiarrhythmic drugs, propafenone, tocainide, and SUN 1165.

Antiarrhythmic effects of three new drugs, propafenone, tocainide, and SUN 1165, were examined using three canine ventricular arrhythmia models, i.e., digitalis, adrenaline and two-stage coronary ligation arrhythmias. The effects of procainamide, disopyramide, lidocaine, and phenytoin, class 1 antiarrhythmic drugs, on digitalis arrhythmia were also examined. The minimum effective plasma concentrations of all these drugs for each arrhythmia model were determined for a quantitative comparison. Propafenone and tocainide suppressed all the arrhythmias, while SUN 1165 suppressed digitalis and coronary ligation arrhythmias. The minimum effective plasma concentrations of propafenone for digitalis, adrenaline, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 1.8 +/- 0.7, 0.58 +/- 0.20, 3.5 +/- 0.3, and 3.6 +/- 0.9 micrograms/ml, respectively, and those of tocainide were 6.2 +/- 2.1, 23.7 +/- 9.0, 11.4 +/- 0.5, and 8.6 +/- 2.9 micrograms/ml, respectively (mean +/- standard deviation, n = 6-7). The minimum effective concentrations of SUN 1165 for digitalis, 24-h coronary ligation, and 48-h coronary ligation arrhythmias were 0.92 +/- 0.19, 2.5 +/- 0.4, and 1.2 +/- 0.4 micrograms/ml. The minimum effective concentrations for digitalis arrhythmias were 1.7 +/- 0.4 micrograms/ml for disopyramide, 10.1 +/- 2.4 micrograms/ml for procainamide, 3.5 +/- 1.6 micrograms/ml for lidocaine, and 11.3 +/- 3.0 micrograms/ml for phenytoin. Digitalis arrhythmia seems to be a useful model for detecting class 1 drugs, as it was suppressed by all the class 1 Na-channel blocking antiarrhythmic drugs, while class 2 beta adrenergic blockers and class 4 Ca-channel blockers had no effect. Also, not all the class 1 drugs suppressed coronary ligation and adrenaline arrhythmias.

Animals↗
PubMed1980

Treatment of ventricular arrhythmias with oral tocainide.

This is a report of a multicenter open study of the use of tocainide, a new lidocaine-like antiarrhythmic with a high oral bioavailability, in the treatment of life-threatening ventricular arrhythmias refractory to other therapy. The majority of patients have received 1,200 to 2,400 mg daily in divided doses and have been treated for over 6 months and some for longer than 3 years. Overall, 61% of the patients responded successfully to tocainide therapy. In the 252 patients with documented, severe, symptomatic arrhythmias, 71% responded, and the majority (87%) showed a total abolition of symptomatic events. Gastrointestinal and central nervous system events were the most common adverse experiences, and 11% had to discontinue therapy; however, the remaining 89% tolerated tocainide satisfactorily.

Adolescent↗
PubMed1985

A review of the uses and limitations of tocainide--a class IB antiarrhythmic agent.

In conclusion, it appears that tocainide will be an extremely important new antiarrhythmic agent in the armamentarium of the clinical cardiologist (Table V). Its similarity to lidocaine and the predictability of its efficacy in patients responsive to lidocaine is an important note. Its lack of interaction with beta blockers and digoxin is also a promising feature. While tocainide has proven to be effective in the prophylaxis and treatment of patients with both refractory and chronic ventricular arrhythmias, its efficacy is in the approximate range of other class I agents, such as quinidine, procainamide, and disopyramide. Its side effect profile appears to be similar in percentage to the adverse effects of quinidine, but often these side effects are milder, better tolerated, and respond to dosage alteration. Thus, tocainide will undoubtedly prove to be a useful new antiarrhythmic agent, particularly when compared to the currently available antiarrhythmic agents.

Animals↗
PubMed1987

Action of tocainide and mexiletine on the excitation threshold of myelinated nerves.

The antiarrhythmic drugs tocainide and mexiletine increase the excitation threshold and decrease the Na permeability (PNa) in nerves. Hodgkin-Huxley model calculations suggest that the PNa decrease is not sufficient to explain the threshold increase at low concentrations (less than 0.7 mM tocainide; less than 0.1 mM mexiletine). On the other hand, a drug action on the membrane surface potential would be consistent with results of recent experiments. To clarify this point electrophysiological experiments on single nerve fibres (Rana esculenta) were carried out. Changes of the threshold interval (difference between membrane and threshold potential; Vm-Vs) were measured and compared with the corresponding changes of Vm and Vs (Vs was measured by means of the transition voltage VTr). The quantitatively good agreement between changes of Vm-Vs and those of VTr suggests that at low concentrations tocainide and mexiletine decrease nerve excitability by acting mainly on the membrane surface charge. This possibility was supported by an independent electrophoresis experiment with myelin vesicles from the same nerve material.

Action Potentials↗
PubMed1987

The analgesic effect of tocainide in trigeminal neuralgia.

Tocainide is a derivative of lidocaine with anti-arrhythmic action and, unlike lidocaine, can be used for oral treatment. Tocainide was alternatively with carbamazepine given to 12 patients with trigeminal neuralgia in a double-blind cross-over study for 2 weeks. The analgesic effect was estimated each day by the patients using a 0-10-point scale summarizing the frequency and severity of the attacks. The similarity in analgesic effect of the two drugs was striking. A possible analgesic mechanism could be that tocainide blocks the sodium channels in the hyperexcitable nerve membranes in the pain-producing foci in trigeminal neuralgia.

Adult↗
PubMed1991

Comparative effects of procainamide, tocainide and lorcainide on Na(+)-K(+)-ATPase in guinea pig heart preparations.

1. The effects of three class 1 antiarrhythmic drugs procainamide (class 1A) tocainide (class 1B) and lorcainide (class 1C) on microsomal Na(+)-K(+)-ATPase activity were compared with those of ouabain in guinea pig heart preparations. 2. All three antiarrhythmic drugs exhibited concentration-dependent inhibitory actions on the enzyme activity in a fashion similar to that of ouabain. 3. The rank order of their potencies showed the following tendency: lorcainide much greater than tocainide greater than procainamide. However, while the actions of lorcainide were comparable to those of cardiotonic steroids, those of procainamide became significant only at concentrations above 80 microM. 4. The IC50 values were 1.8 +/- 0.5 microM for ouabain, 14.6 +/- 3.4 microM for lorcainide, 2.8 +/- 0.7 mM for tocainide and 6.7 +/- 1.1 mM for procainamide. 5. The results demonstrate that these antiarrhythmic agents inhibit the ouabain-sensitive myocardial Na(+)-K(+)-ATPase activity in vitro with comparatively varying potencies. 6. These interactions may be pertinent to the proarrhythmic or arrhythmogenic effects of the class 1 type of antiarrhythmic drugs.

Animals↗
PubMed1991

The effect of modifying potassium concentration on the inhibition of myocardial Na(+)-K(+)-ATPase by two class IB antiarrhythmic drugs: lidocaine and tocainide.

1. The inhibitory actions of two class IB antiarrhythmics, lidocaine and tocainide, on Mg(2+)-dependent ATP hydrolysis by myocardial Na(+)-K(+)-ATPase (EC 3.6.1.3), were tested in guinea-pig heart preparations incubated in media containing 2.5, 5.0 and 10 mM K+. 2. The IC50 values for lidocaine were 2.4 +/- 0.4 mM at 2.5, 4.1 +/- 0.8 mM at 5.0 and 5.3 +/- 0.5 mM at 10 mM K+. The corresponding IC20 values were 0.82 +/- 0.12 mM at 2.5, 1.3 +/- 0.2 mM at 5.0 and 1.7 +/- 0.4 mM at 10.0 mM K+ respectively. Tocainide exerted similar action with IC50 values of 3.1 +/- 0.9 mM at 2.5, 7.6 +/- 1.4 mM at 5.0 and 15.5 +/- 1.6 mM at 10.0 mM K+ and IC20 values of 0.71 +/- 0.19 at 2.5, 2.7 +/- 0.5 mM at 5.0 and 12.3 +/- 1.2 mM at 10.0 mM K+ respectively. 3. Thus, the inhibitory potencies of the drugs on myocardial Na(+)-K(+)-ATPase activity increased significantly with reduction in the K+ concentration. These results demonstrate therefore that the inhibitory actions of both lidocaine and tocainide depend on the K+ concentration of the incubation medium. 4. These findings may be indicative of the importance of K+ in some of the cardiac effects of the antiarrhythmic agents, particularly their tendency to induce or enhance already existing cardiac arrhythmias.

Animals↗
PubMed1991

Stereospecific high-performance liquid chromatographic determination of tocainide.

A sensitive high-performance liquid chromatographic assay was developed for the determination of tocainide enantiomers in plasma. Following extraction of tocainide from plasma, the enantiomers were derivatized with S-(+)-1-(1-naphthyl)ethylisocyanate. The resulting diastereomers were separated and quantified using normal-phase chromatography with fluorescence detection set at 220/345 nm (excitation/emission). The peaks, resolved with a resolution factor greater than 1.5, were free from interference. Linearity was established over the concentration range 0.25-10.0 mg/l for each enantiomer in plasma (r2 greater than 0.998). The inter-assay variability was less than 10% at all concentrations examined. The method can be used to determine the pharmacokinetics of tocainide enantiomers in man.

Adult↗
PubMed1984

Monitoring of S- and R-tocainide in human plasma after heptafluorobutyrylation, separation on Chirasil-Val and electron-capture detection.

The conditions for the heptafluorobutyrylation of tocainide have been studied. An almost instantaneous reaction was obtained with 0.01% of heptafluorobutyric anhydride in toluene at 40 degrees C. Higher anhydride concentration caused degradation of the initially formed derivative, mainly by the loss of water, as shown by mass spectral analysis. Tocainide was isolated from plasma by extraction into dichloromethane at alkaline pH. Gas chromatographic separation was performed with a fused-silica capillary column coated with a methyl silicone gum. The enantiomers were separated on a glass capillary column coated with Chirasil-Val. Upon analysing 0.1 ml of plasma eight times the precision was 4.7% at the 10 mumol/1 level for the S-form of tocainide.

Acylation↗
PubMed2002

Effect of acidity on the enantiomeric resolution of thyroxine and tocainide by HPLC on a (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid column.

Enantiomeric resolution of thyroxine and tocainide was achieved on a (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid column. The mobile phases were methanol/water (4:1, v/v) and methanol/water containing 5 mM sulfuric acid (4:1, v/v) for tocainide and thyroxine respectively. The flow rate was 0.5 ml/min. The effect of the acidity on the chiral resolution of these drugs was studied. Detection was at 220 nm for both drugs. The values of alpha and Rs were 2.08-3.11 and 1.00-2.60, respectively, for thyroxine while the values of alpha and Rs were 1.13-1.26 and 0.10-1.30, respectively, for tocainide.

Chromatography, High Pressure Liquid↗