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PubMed1990

Preparative high-performance liquid chromatography and preparative thin-layer chromatography isolation of tocainide carbamoyl-O-beta-D-glucuronide: structural characterization by gas chromatography-mass spectrometry and fast atom bombardment-mass spectrometry.

Tocainide carbamoyl-O-beta-D-glucuronide, a major urinary metabolite of the antiarrhythmic drug tocainide [2-amino-N-(2',6'-xylyl)propanoxylidide], was isolated by preparative-TLC and preparative-HPLC. The isolated glucuronide was hydrolyzed in sodium hydroxide (pH greater than 12) to 3-(2',6'-xylyl)-5-methylhydantoin. This hydantoin product was also identified when tocainide was reacted with urea in urine. Structural characterization of the isolated tocainide glucuronide was carried out using GC-MS of the permethylated derivative. The molecular ion of the permethylated glucuronide was not observed, but ion fragments at m/z 232(244), 277(288), and 334(349) were found to correspond to the postulated novel carbamoyl ester structure of the permethylated (perdeuteromethylated) glucuronide. Structural evidence for the underivatized tocainide glucuronide was obtained using fast atom bombardment-MS. The [M + H]+ ion at m/z 413 was observed. Characteristic sodium ion adducts [M + Na]+ and [M-H + 2Na]+ were also observed at m/z 435 and 457, respectively.

Anti-Arrhythmia Agents↗
PubMed1991

Stereoselective interaction of tocainide and its chiral analogs with the sodium channels in human myoballs.

The effects of both enantiomers of tocainide and of some of its chiral analogs on the inactivation of the sodium current in human myoballs were investigated with the whole-cell recording technique. Structure and electron densities of the applied compounds were calculated and compared to the results. Both the R(-) and the S(+) enantiomers had little effect on fast inactivation determined with short prepulses according to Hodgkin and Huxley (1952; h infinity curve). When the inactivating prepulses used in this pulse protocol were prolonged to 1024 ms, both tocainide enantiomers increased inactivation severely, suggesting that the drug binds to the channel when it is in the state of intermediate inactivation (Fakler et al. 1990). Tetrodotoxin-resistant "juvenile" sodium channels were more affected than tetrodotoxin-sensitive "adult" channels. The R form was four times as effective as the S form. The compound obtained by substitution of the methyl group on the chiral centre of tocainide with a benzyl group, although in the less potent S form, affected inactivation of the juvenile sodium channels much more than the potent (R)-tocainide. Two additional substitutions, performed on the aromatic ring of tocainide, gave a compound that was most potent in shifting the inactivation curves, but without any selectivity for juvenile or adult channels.

Humans↗
PubMed1985

The value of tocainide in the treatment of tinnitus. A double-blind controlled study.

We assessed the value of tocainide in the treatment of tinnitus by performing a double-blind controlled trial in which each of 48 patients with annoying tinnitus received either tocainide HC1 900 mg/day or a placebo. Before the trial, the effect of intravenous lidocaine was evaluated in each patient so that both lidocaine and tocainide could be compared in altering tinnitus. We found that tocainide appeared to have no better effect than the placebo, whereas lidocaine suppressed tinnitus in 81% of the patients treated. The mechanisms of action of both drugs as well as their influence on tinnitus are discussed, as are the side effects of tocainide.

Adult↗
PubMed1980

Effects of tocainide and lidocaine on the transmembrane action potentials as related to external potassium and calcium concentrations in guinea-pig papillary muscles.

Effects of lidocaine and tocainide on transmembrane potentials were studied in isolated guinea-pig papillary muscles, superfused with modified Tyrode's solution containing either 5.4, 2.7, 10.0 or 8.1 mmol/l potassium concentration, [K]0. The last solution applied contained either 1.8 (normal [Ca]0) or 7.2 mmol/l [Ca]0 (high [Ca]0. The concentrations of lidocaine and tocainide used were 18.5, 36.9 and 73.9 mumol/l and 43.7, 87.5 and 174.9 mumol/l in 5.4 mmol/l [K]0 solution and 36.9 and 87.5 mumol/l in the other solutions, respectively. At the driving rate of 1 Hz in 5.4 mmol/l "K]0 solution, both drugs produced dose-dependently a reduction of maximum rate of rise of action potential (Vmax), together with a prolongation of the relative refractory period. Vmax decreased progressively as the driving rate was increased from 1 Hz (for lidocaine) and from 0.25 Hz (for tocainide) to 5 Hz. This action was accentuated dose-dependently. A slow component (time constant tau = 232 ms for lidocaine, 281--303 ms for tocainide) and slower component (tau = 2.1--3.8 s for tocainide) of the recovery (reactivation) of Vmax were observed in premature responses at 0.25 Hz and in the first response after interruption of the basic driving rate at 1 Hz. All these effects were accentuated with rising [K]0 and attenuated in the high [Ca]0 solution. Both drugs abbreviated the action potential duration at 50% (APD50) and 90% (APD90) levels at 5.4, 8.1 and 10.0 mmol/l [K]0 but not at 2.7 mmol/l [K]0 nor a high [Ca]0 at 1 Hz. These [K]0-dependent effects of lidocaine on Vmax were successfully simulated by the model proposed by Hondeghem and Katzung (1977), with a slight change in parameter values. The mode of interaction of lidocaine with sodium channels in the open, closed and rested states was deduced from these results.

Action Potentials↗
PubMedDate not supplied

Poisoning due to class 1B antiarrhythmic drugs. Lignocaine, mexiletine and tocainide.

Since most of the toxicity associated with class 1B antiarrhythmic drugs is dose-related, this review examines adverse effects seen in both therapeutic practice and accidental or premeditated overdose. Toxicity is very common with these agents and can be life-threatening. A high percentage of patients must discontinue therapy because of adverse effects. Mexiletine and tocainide are structural analogues of lignocaine (lidocaine) and toxicity is similar with all 3 drugs. With gradual intoxication (the most common form) central nervous system effects such as lightheadedness, dizziness, drowsiness and confusion are seen first. Seizures and respiratory arrest can occur. Cardiovascular toxicity is manifested by progressive heart block, reduced cardiac contraction, hypotension and asystole. Both mexiletine and tocainide may have proarrhythmic effects. Gastrointestinal toxicity is also common. Shock, hypotension, cardiac failure and beta-blocker therapy reduce lignocaine clearance and enhance the risk of intoxication during routine therapy. Both lignocaine and mexiletine elimination is impaired in severe liver disease while tocainide clearance is reduced in renal failure. Management of toxicity is largely supportive and symptomatic. Lignocaine infusion must be discontinued and decontamination of the gut in the case of oral preparations is recommended. Serious intoxication requires intensive care unit admission. Haemodialysis or haemoperfusion may be helpful in serious lignocaine and tocainide poisoning. In institutions where extracorporeal circulatory assistance is available, massive lignocaine poisoning has been successfully treated with this intervention. In the therapeutic setting serious toxicity can be prevented by close clinical surveillance and appropriate dose reduction in patients with reduced drug clearance. Because of the large interindividual variation in lignocaine pharmacokinetic parameters, therapeutic drug monitoring is recommended if results can be reported quickly. Mexiletine and tocainide have stereoselective metabolism and assays do not distinguish the more active isomers. Therapeutic drug monitoring is less useful in this situation.

Anti-Arrhythmia Agents↗
PubMed1997

Inhibition of frog skeletal muscle sodium channels by newly synthesized chiral derivatives of mexiletine and tocainide.

To search for potent use-dependent blockers of skeletal muscle sodium channels as potential antimyotonic agents, the actions of newly synthesized chiral analogs of mexiletine and tocainide were tested in vitro on sodium currents of single fibers of frog semitendinosus muscle by vaseline-gap voltage clamp method. The effect of each drug on the maximal peak Na+ transient (I(Na) max) was evaluated as both tonic and use-dependent block by using infrequent depolarizing stimulation and trains of pulses at 2-10 Hz frequency, respectively. The mexiletine analog 3-(2,6-dimethylphenoxy)-2-methylpropanamine (Me2), having an increased distance between the phenyl and the amino groups, was less potent than mexiletine in producing a tonic block but produced a remarkable use-dependent block. In fact, the half-maximal concentration (IC50) for tonic block of S(-)-Me2 was 108 microM vs. 54.5 microM of R(-)-mexiletine, but the IC50 was 6.2 times lowered by the 10 Hz stimulation with respect to the 2.4 fold decrease observed with mexiletine. The R(-)-mexiletine and the S(-)-Me2 were about twofold more potent than the corresponding enantiomers in producing a tonic block, but the stereoselectivity attenuated during use-dependent blockade. The more lipophilic 2-(4-chloro-2-methylphenoxy)-1-phenylethylamine (Me1), presently available as raceme, produced a potent and irreversible tonic block of the sodium currents with an IC50 of 29 microM, but had a less pronounced use-dependent inhibition, with a 1.9 fold decrease of the IC50 at 10 Hz. The R(-) isomer of 2',6'-valinoxylidide (To1), a tocainide derivative with an increased hindrance on the chiral carbon atom, was twofold (IC50 = 209 microM) and tenfold (IC50 = 27.4 microM) more potent than R(-)-tocainide in tonic and use-dependent block, respectively. Tocainide was almost devoid of stereoselectivity, whereas the eudismic ratio of To1 [(IC50 S(+)-To1/IC50 R(-)-To1] was 1.7. As for mexiletine and Me2, the stereoselectivity of To1 was the weaker the higher the frequency of stimulation. The cyclic pyrrolo-imidazolonic tocainide analog To2 produced a small tonic block at 500 microM, and 1 min stimulation at 10 Hz was needed to show up a 50% block of I(Na) max. All the compounds produced a left-shift of the steady-state inactivation curve correlated positively with the extent of use-dependent inhibition, with the exception of the cyclic To2 that acted as an open-channel blocker. The highly use-dependent blockers Me2 and To1 might be promising drugs to solve high frequency discharges of action potentials typical of myotonic muscles. Concomitantly the high potency of Me1 and the open-channel block exerted by To2 can represent important features to get selective blockers for skeletal muscle sodium channels.

Animals↗
PubMed1991

Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction.

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.

Animals↗
PubMed1984

The interaction of cycle length with the electrophysiological effect of lidocaine, tocainide and verapamil on canine Purkinje fibers.

Intracellular action potentials were recorded from normal canine Purkinje fibers using the standard microelectrode technique. The effects of lidocaine (2 and 5 mg/1), tocainide (10 and 20 mg/1) and verapamil (0.5 and 1.0 mg/1) on action potential characteristics as well as conduction times were measured at cycle lengths of 1000, 800, 600, 500, 400 and 300 ms. Lidocaine and tocainide shortened APD50 % and APD90 %, and verapamil shortened APD50 % and lengthened APD90 %. All of these effects were greatest at the longest cycle lengths. A similar interaction of changes in ERP with cycle length was observed for lidocaine and tocainide. Verapamil increased ERP but this effect was not significant. Tocainide and verapamil reduced dV/dtmax while lidocaine had no significant effect. All three drugs increased conduction time. This effect was accentuated at shorter cycle lengths. No direct relationship between dV/dtmax and conduction times were observed. These results indicate that many of the electrophysiological effects of lidocaine, tocainide and verapamil are modified by cycle length. We propose that future studies on the electrophysiology of antiarrhythmic drugs should include stimulation both at long and short cycle lengths.

Action Potentials↗
PubMed1989

Mexiletine and tocainide: a comparison of antiarrhythmic efficacy, adverse effects, and predictive value of lidocaine testing.

Thirty patients received one of the lidocaine analogues--mexiletine or tocainide--orally for treatment of symptomatic ventricular arrhythmias. Crossover to the other analogue was allowed if initial drug treatment was unsuccessful, and the controlled use of other marketed oral antiarrhythmic agents was permitted. After follow-up of 7 +/- 3 months (SD), mexiletine was successful in 5 of 13 patients initially and in 5 of 14 patients who failed to respond to tocainide. Tocainide was successful in 1 of 17 patients initially and in 2 of 7 who did not respond to mexiletine. Combination therapy was used in nearly half of all ultimately successful drug trials. A common cause of drug trial failure for both drugs was the occurrence of adverse effects that frequently appeared well after hospital discharge. Response to lidocaine was a sensitive but nonspecific predictor of clinical outcome with mexiletine or tocainide that helped to identify drug-resistant patients. Finally, although mexiletine provided effective antiarrhythmic therapy more often than tocainide, response to one lidocaine analogue did not predict response to the other.

Adult↗
PubMedDate not supplied

A specific effect of lidocaine and tocainide on ventricular conduction of mid-range extrasystoles.

Lidocaine and tocainide had no effect on ventricular conduction of extrasystoles with coupling intervals longer than 500 msec in isolated blood-perfused dog hearts, but caused interval-related increases in conduction time of extrasystoles in the range of 250--400 msec, here called mid-range extrasystoles (MRE). Quinidine, procainamide, disopyramide, and methyl lidocaine increased conduction times of extrasystoles at all coupling intervals, and no additional slowing of MRE was observed. The slowing of MRE specific to lidocaine and tocainide was confirmed in the intact dog heart. During acute myocardial ischemia in the intact dog heart, conduction was slowed and additional slowing of MRE was found. Lidocaine and tocainide caused further slowing of conduction of MRE. This unique effect of lidocaine and tocainide on the conduction of MRE may be important in the suppression of reentrant arrhythmias. However, lidocaine and tocainide were also found to be arrhythmogenic when extrasystoles were introduced, after acute coronary occlusion, in those animals in which such occlusion alone did not allow demonstration of arrhythmias due to extrasystoles.

Anilides↗
PubMed1986

Measurement of tocainide in serum by capillary gas chromatography.

A rapid and simple analytical method is described for the determination of tocainide in serum using flame ionization capillary gas chromatography. Following a single extraction with chloroform, tocainide is quantitated on an OV-17 bonded fused silica column, utilizing orphenadrine as internal standard. No interference was detected from endogenous substrates, tocainide metabolites, or other commonly used antiarrhythmic drugs. The lowest detectable tocainide concentration by this method is approximately 0.2 mg/L of serum, which is sufficiently sensitive for therapeutic monitoring. Utilizing temperature programming, this method for tocainide is applicable for several antiarrhythmic drugs.

Anti-Arrhythmia Agents↗
PubMed1983

Comparative study of tocainide and lidocaine in patients admitted for suspected acute myocardial infarction.

The antiarrhythmic effects of tocainide, administered as a bolus injection of 750 mg followed by oral therapy, and conventional lidocaine therapy were evaluated in 40 patients admitted for suspected acute myocardial infarction (AMI) and showing high-grade premature ventricular complexes (PVCs). The mean hourly PVC rate before therapy was 928 and its reduction was equally significant in the tocainide group, 73%, and in the lidocaine group, 68%. The number of 5-minute periods with multiform, paired and R/T PVCs or ventricular tachycardia was also significantly reduced, by 78% in the tocainide group and by 71% in the lidocaine group. Ten patients in the tocainide group reported moderate side-effects, compared to 13 in the lidocaine group, where the infusion had to be discontinued in 5 patients and the rate had to be reduced in 4. Tocainide, an amine analogue of lidocaine, is considered just as effective as lidocaine in patients with high-grade PVCs and suspected AMI.

Adult↗
PubMed1984

Prophylaxis against ventricular arrhythmias in suspected acute myocardial infarction: a comparison of tocainide and disopyramide.

Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study. Two hundred and eighty-three patients were excluded, mainly because of recent treatment with beta-adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty-eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1985

Pharmacokinetics and haemodynamic effects of tocainide in patients with acute myocardial infarction complicated by left ventricular failure.

The pharmacokinetics and haemodynamic effects of tocainide, an orally active structural analogue of lignocaine, were studied in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (mean age 65 years) with acute myocardial infarction complicated by mild left ventricular failure were studied, following a single dose of tocainide (250 mg) by intravenous infusion, over 30 min. Heart rate, systemic arterial pressure, pulmonary artery pressure and cardiac output were monitored. Plasma tocainide levels were estimated by gas chromatography. The mean plasma level of tocainide achieved was 2.95 micrograms/ml (15.37 mmol/l). The mean plasma half-life was 15.6 h. The mean cardiac index was reduced 5 min after completion of the infusion, from 2.24 1 min-1 m-2 (+/- 0.40) to 2.07 1 min-1 m-2 (+/- 0.29) (P less than 0.01). At 90 min the cardiac index had returned to pre-treatment levels. Small changes were seen in the heart rate, arterial blood pressure and the pulmonary artery pressure but these changes were not statistically significant. The pharmacokinetics of tocainide were not significantly altered in patients with acute myocardial infarction complicated by mild left ventricular failure.

Aged↗
PubMed1986

Short- and long-term therapy with tocainide for malignant ventricular tachyarrhythmias.

Tocainide was administered to 228 patients referred for treatment of recurrent ventricular tachyarrhythmias that were refractory to therapy with conventional antiarrhythmic drugs. After baseline studies, 1200 to 2400 mg tocainide/day was given for 4 days. Tocainide was effective in 49% of 180 patients evaluated with monitoring and exercise testing and in 35% of 48 patients undergoing electrophysiologic testing. No clinical parameter predicted the response to tocainide, although there was a correlation with the effect of lidocaine. Tocainide was selected for long-term treatment in 73 patients who were followed for an average of 26.4 months (range 1 to 92 months). The incidence of sudden death was 4.3% per year and two patients had nonfatal recurrence of arrhythmia. It is concluded that tocainide is effective and well tolerated during long-term use if therapy is evaluated carefully and is individualized.

Adolescent↗
PubMedDate not supplied

Tocainide: a new oral antiarrhythmic.

Tocainide is an orally active lidocaine analog indicated for the suppression of ventricular arrhythmias. It is electrophysiologically similar to lidocaine and produces minimal hemodynamic and electrocardiographic changes. Oral bioavailability is virtually complete, elimination half-life is 11-15 hours, and 40 percent of a dose is excreted unchanged in urine. Tocainide therapy is commonly associated with gastrointestinal and neurologic side effects that generally are well tolerated. Rash, aggravation of arrhythmias, and worsening of heart failure may also occur. While tocainide does not consistently suppress arrhythmias following myocardial infarction, it does control chronic ventricular arrhythmias, being particularly effective in patients responsive to lidocaine. Tocainide has not been shown to be more effective than quinidine or procainamide. Tocainide should be a useful agent in patients who are unable to tolerate other antiarrhythmics, who are responsive to lidocaine, or who have been troubled with Q-T prolongation with or without torsade de pointes.

Aged↗
PubMed1981

3-(2,6-Xylyl)-5-methylhydantoin--a metabolite or a metabonate of tocainide in rats.

1. G.1.c.-mass spectrometric analysis of urine extracts from rats dosed with tocainide (I) revealed the presence of cyclic compound identified as 3-(2,6-xylyl)-5-methylhydantoin (IV) derived from tocainide. 2. Evidence indicates that IV is derived from a conjugate of tocainide (tocainide carbonyl O-beta-D-glucuronide) (III) in humans. 3. Results of the present study indicate that in addition to being formed from a conjugate, IV is generated directly from tocainide in vivo in rats. Possible mechanisms for the formation of IV in rats in vivo are discussed.

Animals↗
PubMed1981

Effects of tocainide, an oral analogue of lidocaine, on thromboembolism after total hip replacement.

In an investigation of deep venous thrombosis and pulmonary embolism, where neither dextran nor other antithrombotic drug prophylaxis was employed, 30 patients subjected to total hip replacement under general anaesthesia were randomly allotted to one of two groups. One group (n=15) received tocainide, an oral analogue of lidocaine, as a means of preventing thromboembolism; the other group (n=15) served as a control. In patients given tocainide the frequency of deep venous thrombosis involving the femoral veins, as observed at phlebography, was 60% (9 of 15), and in the control group 73% (11 of 15). The frequency of pulmonary embolism, as determined by pulmonary perfusion lung scanning, was 20% (3 of 15) in the the tocainide group and 33% (5 of 15) in the control group. It was concluded that tocainide administration had no effect as an antithromboembolic agent. Phlebography revealed that the pattern of deep venous thrombosis after total hip replacement was characterized by a high frequency of isolated thigh vein thrombi in the operated leg, probably related to the surgical procedure. A finding of possible clinical significance was that patients given tocainide had a significantly lower intraoperative blood loss than control patients.

Aged↗