Liquid-chromatographic determination of tocainide in plasma, with N-acyl derivatives of tocainide as internal standards.
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Anti-Arrhythmia Agents↗
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Combination of tocainide and quinidine for better tolerance and additive effects in patients with coronary artery disease.
The efficacy and tolerance of tocainide used alone and in combination with quinidine were studied in 20 patients with coronary artery disease and frequent (greater than 30/h) ventricular premature complexes. Holter electrocardiographic monitoring was performed at baseline and during therapy with tocainide alone, quinidine alone and a combination of tocainide and quinidine. During single drug therapy, the dose of tocainide was 1,680 +/- 437 mg/day and that of quinidine was 1,340 +/- 235 mg/day. During combination therapy, with smaller doses of tocainide (1,350 +/- 394 mg/day) and quinidine (1,060 +/- 268 mg/day) in many patients, no patient had side effects. At baseline before therapy, the mean ventricular premature complexes/h were 629 +/- 567, couplets/h were 23.9 +/- 29.7 and nonsustained ventricular tachycardias/24 h were 60.5 +/- 152.2. Compared with baseline values (100%), the frequency of ventricular premature complexes was reduced to 33 +/- 44% with quinidine, 39 +/- 30% with tocainide and 10 +/- 16% with combination therapy (p less than 0.01 for combination versus quinidine or tocainide alone; p = NS for quinidine versus tocainide). Individually, an effective regimen (greater than 83% reduction of ventricular premature complexes and abolition of nonsustained ventricular tachycardia) was found in 3 (15%) of 20 patients receiving tocainide alone, in 6 (30%) receiving quinidine alone and in 16 (80%) receiving combination therapy (p less than 0.01 for tocainide versus combination, quinidine versus combination; p = NS for tocainide versus quinidine). Thus, the antiarrhythmic effects of quinidine and tocainide are additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Stereospecific interaction of tocainide with the cardiac sodium channel.
The antiarrhythmic action of type I antiarrhythmic drugs may be mediated via binding of the drugs to a receptor associated with the cardiac sodium channel. This suggested that the effects of type I drugs might be stereospecific. We measured the effect of the tocainide stereoisomers (which have stereospecific antiarrhythmic effects) on conduction time and on radioligand binding to the cardiac sodium channel. The concentration-dependent effects of the individual enantiomers of tocainide on interventricular conduction time measured during constant rate ventricular pacing at 350 msec were assessed in 47 isolated perfused rabbit heart preparations. Significant increases (p less than 0.05) in conduction time occurred for both R-(-)-tocainide (75 microM, 10 +/- 5 msec) and S-(+)-tocainide (150 microM, 4 +/- 1 msec). R-(-)-Tocainide was more potent than the S-(+)-tocainide in prolonging conduction time (p less than 0.05). This stereospecific prolongation of conduction time suggested a stereospecific interaction with the sodium channel. The affinities of the enantiomers for the channel were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate and freshly isolated cardiac myocytes. Both enantiomers inhibited [3H]batrachotoxin benzoate binding, but the IC50 (+/- SD) values were different: R-(-)-tocainide 184 +/- 8 microM; S-(+)-tocainide, 546 +/- 37 microM (p less than 0.003). Tocainide isomers are stereospecific in terms of prolonging conduction time and in binding to the sodium channel. The stereospecific electrophysiologic effects of tocainide may result from binding to a receptor associated with the cardiac sodium channel.
Animals↗
Prophylactic tocainide or lidocaine in acute myocardial infarction.
Twenty-nine patients with acute myocardial infarction (AMI) were studied in a randomized double-blind trial of intravenous lidocaine and tocainide, followed by either oral tocainide or placebo without regard to previous therapy, for the prophylaxis of arrhythmias associated with acute infarction. No patient had symptomatic ventricular tachycardia or fibrillation, although 1 patient taking lidocaine was withdrawn from therapy because of breakthrough arrhythmias. One patient in each group died from mechanical complications of AMI. Tocainide was administered to 16 patients and lidocaine to 13. Seven of the 13 patients receiving lidocaine had ventricular tachycardia or accelerated idioventricular rhythm, compared with 2 of 16 receiving tocainide (p less than 0.05). Adverse effects were noted in 11 of the 13 patients receiving lidocaine and 6 of the 16 patients receiving tocainide. The infusions used provided therapeutic levels of lidocaine or tocainide and the transition to oral tocainide was accomplished safely with maintenance of therapeutic antiarrhythmic levels. Thus, tocainide appears to be at least as efficacious and may be safer than lidocaine for the prophylaxis of ventricular arrhythmias associated with AMI. The transition to oral tocainide is well tolerated and can be accomplished with minimal difficulty.
Administration, Oral↗
A gas chromatographic assay for tocainide carbamoyl-O-beta-D-glucuronide:quantitation of the base hydrolyzed product, 3-(2',6'-xylyl)-5-methylhydantoin.
Quantitation of tocainide carbamoyl-O-B-D-glucuronide, a major metabolite of the antiarrhythmic agent, tocainide, was previously reported using sodium hydroxide hydrolysis (pH greater than 12) of the glucuronide followed by gas chromatographic analysis of the hydrolyzed product, 3-(2',6'-xylyl)-5-methylhydantoin. In this investigation, the hydantoin was found to undergo rapid degradation during base hydrolysis of the tocainide glucuronide. The hydantoin was synthesized and its hydrolysis in sodium hydroxide (pH greater than 12) was found to follow first-order kinetics with an estimated half-life of 24.6 minutes. This spontaneous and rapid degradation of the hydantoin during hydrolysis of the tocainide glucuronide may result in underestimation of the hydantoin. To correct for the degradation of the hydantoin, a gas chromatographic assay with a timed, base-hydrolysis calibration protocol was designed. To demonstrate the applicability of this assay, the elimination kinetics of tocainide and the tocainide carbamoyl glucuronide were studied in three healthy male volunteers after a single 200 mg oral dose of tocainide hydrochloride. From urine data, the elimination half-life of tocainide was approximately 15.5 hours. The urinary excretion half-life of the tocainide carbamoyl glucuronide was approximately 13.8 hours.
Adult↗
Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers.
The potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N-carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side-reactions during derivatization of the conjugate are discussed. The peak plasma levels of the enantiomers, observed at less than or equal to 2 h after dosing, were similar but plasma clearances and terminal half-lives were different after oral administration of (R)-tocainide (195.5 +/- 20.1 ml min-1 and 9.7 +/- 0.8 h) and (S)-tocainide (110.2 +/- 10.5 ml min-1 and 14.5 +/- 1.7 h). Over 0-96 h the averaged urinary recovery of (R)-tocainide was 36 per cent and of (S)-tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)-tocainide differed substantially from that of (S)-tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)- and (S)-conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min-1).
Adult↗
Tocainide and metoprolol: an efficacious therapeutic combination in the treatment of premature ventricular beats.
A double-blind crossover study was performed in 20 patients to verify the efficacy of tocainide plus metoprolol in patients with premature ventricular contractions (PVCs) class Lown greater than or equal to 2 (mean frequency greater than or equal to 30/h) judged as being "stable" by at least three basal 24-h Holter ECGs with PVC variation of less than +/- 25%. All 20 patients were submitted to a placebo period; and all were subsequently randomized to therapy with tocainide 1800 mg/day or metoprolol 200 mg/day for 15 days and then to tocainide 1800 mg + metoprolol 200 mg/day or tocainide 1200 mg + metoprolol 200 mg/day for 15 days, followed by a crossover of the two combination treatments. At steady state in every stage we controlled for plasma levels of the drugs, a 24-h Holter recording, and a 12-lead ECG. A modified Lown score was evaluated together with the Lown class. Tocainide (mean plasma level 3.3 +/- 0.7 micrograms/ml) was efficacious in 3 of 8 patients, the modified Lown score decreased from 63 +/- 32 (placebo period) to 42 +/- 27 (p less than 0.01) and Lown 4B arrhythmias were abolished in 3 of 4 patients. Metoprolol (mean plasma level 97.4 +/- 89.6 ng/ml) was efficacious in 2 of 10 patients; the modified Lown score and Lown classes did not change significantly. Administration of tocainide 1200 mg + metoprolol 200 mg obtained a positive response in 9 of 12 patients, the modified Lown score decreased significantly compared with placebo (from 53 +/- 31 to 32 +/- 30, p less than 0.01) and Lown 4B arrhythmias were abolished in 2 of 5 cases. Tocainide 1800 mg plus metoprolol 200 mg was scarcely tolerated owing to neurologic and gastroenteric side effects, and only three patients completed this stage with no better antiarrhythmic results compared to the lower dose. In conclusion, the combination of tocainide at 1200 mg and metoprolol 200 mg is well tolerated, efficacious in a high percentage of patients, and superior to single drug therapy in patients with stable PVCs.
Administration, Oral↗
Systemic tocainide relieves mechanical hypersensitivity and normalizes the responses of hyperexcitable dorsal horn wide-dynamic-range neurons after transient spinal cord ischemia in rats.
In the present study we examined the effect of systemic tocainide on sensory hypersensitivity in rats after spinal cord ischemia induced by a photochemical technique. After induction of spinal cord ischemia the rats exhibited a sensory disturbance which was mainly expressed as vocalization to innocuous cutaneous mechanical stimuli (allodynia) in the flank area during the following several days. Tocainide at 75 mg/kg i.p., but not 50 mg/kg i.p., significantly increased the vocalization threshold to mechanical pressure for 2 h. The effect of intraarterial (i.a.) tocainide on the responses of dorsal horn wide-dynamic-range (WDR) neurons to suprathreshold electrical stimulation of their receptive fields was also examined in normal rats and after transient spinal cord ischemia, at a time when the animals exhibited typical behavioral allodynia in the dermatomes innervated by the ischemic spinal segments. In normal rats, tocainide (50 mg/kg i.a.) strongly suppressed the responses of WDR neurons to C fiber input with lesser effect on A fiber input. In allodynic rats, tocainide suppressed the augmented A and C fiber mediated responses of WDR neurons to the extent that their responses were similar to those seen in normal rats without tocainide. There was no difference in the overall depression of A and C fiber mediated input by tocainide between normal and allodynic rats. The present results demonstrated the analgesic effect of systemic tocainide in relieving allodynia in rats and indicated that systemic local anesthetics, at doses that do not block nerve conduction, can be effective in suppressing dorsal horn WDR neuronal activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Double-blind randomized comparison of intravenous tocainide versus lidocaine in the treatment of chronic ventricular arrhythmias.
The efficacy and safety of intravenous tocainide were compared with intravenous lidocaine in patients with chronic ventricular arrhythmias in a double-blind, parallel study. Twenty-nine patients were randomized to a tocainide (n = 15) or lidocaine (n = 14) group. Antiarrhythmic efficacy was defined as a greater than or equal to 50% reduction in single ventricular premature complex (VPC) frequency, greater than or equal to 90% reduction in paired VPC frequency, and total abolition of ventricular tachycardia. Efficacy was observed in 40% (6 of 15) of patients in the tocainide group and in 36% (5 of 14) patients in the lidocaine group. A 75% or greater reduction in total VPCs occurred in 40% (6 of 15) of patients in the tocainide group and in 57% (8 of 14) of patients in the lidocaine group. Greater than 90% suppression of paired VPCs occurred in 9 of 13 (69%) patients taking tocainide and in 6 of 11 (54%) patients taking lidocaine. Total abolition of ventricular tachycardia was documented in 5 of 11 (45%) patients given tocainide and in two of six (33%) patients given lidocaine. A total of 17 adverse reactions affecting 86% (12 of 14) of patients taking lidocaine and 11 adverse reactions affecting 53% (8 of 15) of patients taking tocainide occurred. Four patients in each treatment group suffered dose-limiting adverse effects. This study suggests that the efficacy and safety of intravenous tocainide are similar to that of intravenous lidocaine in patients with chronic ventricular arrhythmias.
Anti-Arrhythmia Agents↗
Electrophysiological effects of tocainide on canine subendocardial Purkinje fibers surviving infarction.
The effects of 10 and 20 mg/l of tocainide on transmembrane action potential characteristics were examined in Purkinje fibers surviving infarction. Infarcted tissue was obtained from canine hearts 24 h after coronary artery ligation. The preparation was stimulated at basic cycle lengths (BCL) of 1000-300 ms. Tocainide reduced the overshoot and amplitude of Purkinje fibers surviving infarction. The maximum upstroke velocity (Vmax) was decreased by tocainide in a dose dependent manner. This effect was more prominent at the shorter BCL. Statistical analysis revealed a significant interaction of the BCL with the drug effect on overshoot, amplitude, Vmax and action potential durations (APD50% and APD90%). Tocainide reduced the effective refractory period (ERP) at the BCL of 1000 ms, but had no significant effect at the BCL of 300 ms. Membrane responsiveness and steady state characteristics of Vmax were shifted significantly to more negative membrane potentials by tocainide. Investigation of the recovery kinetics of Vmax in the presence of tocainide showed an exponential recovery of Vmax with a time constant of 514 ms. These results support the finding that the effect of tocainide on Vmax and conductions is enhanced at faster rates of stimulation. Thus tocainide may be able to depress conduction to produce bidirectional block in the termination of ventricular tachycardia caused by reentry, while having minimal effect on conduction at normal heart rates.
Action Potentials↗
Effects of tocainide enantiomers on experimental arrhythmias produced by programmed electrical stimulation.
The enantiomers of tocainide, a Class Ib antiarrhythmic agent, have recently been shown to exhibit differences in antiarrhythmic activity and pharmacokinetic characteristics. The present study examined the antiarrhythmic and electrophysiological effects of SR tocainide, S tocainide, and R tocainide on arrhythmias in a conscious canine arrhythmia model and compared the results with placebo. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious dogs, 7-30 days after coronary artery ligation. Each treatment was assessed for its ability to abolish sustained ventricular tachycardia, prevent nonsustained ventricular tachycardia, and protect against death (ventricular fibrillation), in groups of six dogs. In the placebo group, arrhythmias in four of six dogs remained unchanged, and two dogs died. SR tocainide prevented the arrhythmia in three of six dogs (mean effective dose, 21.3 mg/kg), one remained unchanged, and two died. S tocainide prevented the arrhythmia in four of six dogs (mean effective dose, 7.1 mg/kg), one remained unchanged, and one died (p less than 0.05 compared with placebo). R tocainide prevented the arrhythmia in five of six dogs (mean effective dose, 9.0 mg/kg), one remained unchanged, and none died (p less than 0.01 compared with placebo). PR intervals, QRS durations, and corrected QT intervals were unaffected by any treatment and there was no change in effective or functional refractory periods. These results indicate that the enantiomers of tocainide are more effective than the racemic mixture in abolishing ventricular arrhythmias and in preventing death in this model; no additive antiarrhythmic effect occurs with the racemic mixture, and adverse effects may be potentiated.
Animals↗
Efficacy and tolerance of tocainide during long-term treatment of malignant ventricular arrhythmias.
A group of 51 patients with malignant ventricular arrhythmias refractory to standard oral antiarrhythmic agents were treated with oral tocainide. Antiarrhythmic efficacy was defined as total abolition of occurrences of ventricular tachycardia (VT) or ventricular fibrillation (VF) as assessed by hospital admissions for arrhythmias and the occurrence of sudden cardiac death (SCD). Of the 51 patients, 32 (63%) initially tolerated tocainide and were discharged from the hospital. Of the 19 patients not initially responding to tocainide, 6 (12%) had arrhythmia recurrence and 13 (25%) developed intolerable central nervous system or gastrointestinal side effects. Of these 19 short-term nonresponders, 8 (42%) patients suffered SCD over an average follow-up of 24 months (annual SCD rate of 21%). Two patients suffered SCD during the first week of tocainide therapy. Discounting the 2 patients with SCD on tocainide therapy, 6 of 17 (35%) patients initially withdrawn from tocainide suffered SCD (annual SCD rate of 18%). Twenty-four of the 32 short-term responders did not have arrhythmia recurrence over a mean follow-up of 38 months resulting in an overall long-term efficacy of 47% (24/51). Over an average follow-up of 38 months for these 24 short-term responders, 12 patients expired from nonarrhythmic causes, 3 patients were withdrawn for non-drug-related causes, and 9 patients remain on tocainide therapy. Of the 8 long-term nonresponders, 3 patients had arrhythmia recurrence and died suddenly while 5 patients developed intolerable side effects. The annual SCD rate in short-term responders was 3%. Eighteen of the 51 patients (35%) were withdrawn from the study because of adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Death, Sudden↗
Randomized double-blind study of intravenous tocainide versus lidocaine for suppression of ventricular arrhythmias after cardiac surgery.
To compare the therapeutic efficacy and safety of intravenous tocainide with that of intravenous lidocaine in patients with ventricular arrhythmias after cardiac surgery, 25 patients were randomized to either agent in a double-blind manner. Tocainide was given in 16 patients as a 250 mg bolus followed by a loading infusion of 500 mg over 15 minutes and a maintenance infusion of 33.3 mg/min. Lidocaine was administered in 9 patients as a 100 mg bolus followed by a loading infusion of 60 mg over 15 minutes and a maintenance infusion of 1.4 mg/min. Therapy was continued for 24 hours in initially responding patients. With analysis of 24-h taped electrocardiograms it was found that single premature ventricular complexes (PVCs) were suppressed by tocainide by more than 80% in 94% of patients and by lidocaine in 75% of patients (p = NS). Couplets and ventricular tachycardia events were eliminated in all patients by either drug. Multiform PVCs were abolished in 94% of the patients after tocainide and in 75% after lidocaine (p = NS). Average overall success over the 24 hours with more than 80% suppression of single PVCs and simultaneous elimination of higher forms of arrhythmia was 71% with tocainide and 59% with lidocaine (p = NS). Adverse effects were negligible, with only one patient in the lidocaine group developing diaphoresis without necessitating termination of therapy. Treatment rapidly produced and then maintained blood levels of 4-10 mg/l for tocainide and 1-4 mg/l for lidocaine. We conclude that intravenous tocainide is well tolerated and has comparable efficacy to lidocaine in the acute therapy of postcardiac surgery ventricular arrhythmias.
Adult↗
The effect of histamine-2 receptor antagonists on tocainide pharmacokinetics.
The effects of cimetidine and ranitidine on tocainide pharmacokinetics were assessed in seven healthy subjects, using a randomized, double-blind, placebo-controlled, cross-over study design. After a 400-mg oral dose of tocainide, the area under the concentration-time curve decreased from (mean +/- SD) 31.64 +/- 14.16 micrograms.hr/mL during placebo, to 23.10 +/- 7.33 micrograms.hr/mL during cimetidine (P less than .05). Similarly, the peak tocainide concentrations were 2.81 +/- 0.89 micrograms/mL and 1.70 +/- 0.44 micrograms/mL with placebo and cimetidine, respectively (P less than .05). There was no change in the above parameters between ranitidine and placebo. The terminal half-life and renal clearance of tocainide were not altered by either H2-receptor antagonists, compared with placebo. However, the total amount of tocainide excreted unchanged in the urine, decreased from 159.8 +/- 14.7 mg with placebo to 136.8 +/- 26.8 mg with cimetidine (P less than .05), whereas there was no change with ranitidine. These data indicate that cimetidine, but not ranitidine, causes a decrease in the bioavailability of tocainide and that neither agent alters the apparent elimination rate of tocainide.
Adult↗
Comparative efficacy and safety of oral tocainide and quinidine for benign and potentially lethal ventricular arrhythmias.
The antiarrhythmic efficacy and safety of oral tocainide hydrochloride and quinidine sulfate were compared in a double-blind, 3-center, parallel trial involving 133 patients with benign and potentially lethal ventricular arrhythmias. Baseline demographic, etiologic, functional and ventricular arrhythmia data were not significantly different between the 2 groups. Two weeks of an initial placebo period were followed by 8 weeks of active drug treatment, concluding with 4 weeks of washout. Frequent 24-hour ambulatory electrocardiographic monitoring was used to judge efficacy. Ten of 27 patients (37%) receiving tocainide and 12 of 24 patients (50%) receiving quinidine had a 75% reduction with drug treatment compared with the initial placebo period (p greater than 0.25). Total abolition of ventricular tachycardia occurred in 6 of 16 patients (37%) receiving tocainide and 6 of 13 patients (43%) receiving quinidine (p greater than 0.25). Conditions that required discontinuation of therapy occurred in 18 of 67 patients (27%) receiving tocainide and 16 of 66 (24%) receiving quinidine (difference not significant). More patients had dizziness during tocainide treatment and diarrhea during quinidine treatment. Quinidine caused a prolongation in the QT interval (0.03 second); tocainide caused a slight reduction (0.01 second). No important changes in vital signs or laboratory measurements were observed in left ventricular ejection fraction when measured. Thus, tocainide, the new oral analog of lidocaine, appears to be as safe as quinidine but is slightly less effective in suppressing ventricular arrhythmias.
Administration, Oral↗
Selective effects of tocainide in canine acute myocardial infarction.
We examined the in vivo electrophysiologic effects of tocainide in canine acute myocardial infarction. We compared the effects of tocainide in infarcted and non-infarcted zones. The left anterior descending coronary artery of 8 dogs was ligated and bipolar ventricular electrograms were recorded from a needle electrode placed transmurally in the infarcted zone and from electrodes in the non-infarcted zone. Conduction intervals were measured from the onset of the limb lead QRS to the major deflection of the recorded electrograms in the infarcted and non-infarcted zones. Effective refractory periods were also determined. Measurements were made before, during and after intravenous infusion of tocainide in therapeutic doses 2 hours after infarct. Tocainide prolonged conduction intervals by 26-31% in the infarcted zone at peak (P less than 0.001), but by only 6% in the non-infarcted zone. Similarly, tocainide prolonged the effective refractory period by 27% (P less than 0.001) on the infarcted, but by 8% the non-infarcted zone. Tocainide had very slight effects on QRS duration. The present study shows that tocainide had selective effects in the infarcted zone on both conduction and effective refractory period. These selective effects may explain its antiarrhythmic effects in acute myocardial infarction.
Animals↗
Modification of the frequency- and voltage-dependent effects of quinidine when administered in combination with tocainide in canine Purkinje fibers.
Frequency- and voltage-dependent modification of drug-induced inhibition of maximal upstroke velocity of the action potential (Vmax) by the combined administration of two class I antiarrhythmic drugs was studied in canine Purkinje fibers, taking depression of upstroke velocity as an indicator of sodium channel blockade. The kinetics of onset of drug-induced Vmax depression and the time course of Vmax recovery were studied after exposure to therapeutic concentrations of tocainide (50 microM) and quinidine (5 microM) both singly and in combination. The rate constant for onset of block during a drive train at a cycle length of 600 msec was 0.95 +/- 0.32 pulses in the presence of tocainide and 5.61 +/- 0.50 pulses in the presence of quinidine. The magnitude of block was three times greater with quinidine than with tocainide. The magnitude of block produced by the combination was no greater than that produced by quinidine alone and may be partly due to abbreviation of action potential duration by tocainide. Onset of block in the presence of the combination was best fitted by a double exponential with rate constants of 0.88 +/- 0.19 and 6.47 +/- 1.36 pulses. Vmax recovery after termination of a rapid train of impulses was delayed by both drugs. Poststimulation recovery from either tocainide- or quinidine-induced block was characterized by a single time constant (1.04 +/- 0.49 and 4.81 +/- 0.76 sec, respectively), while that of the combination was characterized by two time constants (0.43 +/- 0.22 and 5.94 +/- 0.56 sec), presumably corresponding to dissociation of each drug from the sodium channel receptor. The mixture of the two drugs produced a large depression of Vmax of early diastolic premature responses without producing much further depression of Vmax than that produced by quinidine alone at longer coupling intervals. The time constant of recovery from tocainide-induced block was greatly dependent upon membrane potential. After steady-state changes in frequency, the combination produced a greater depression of Vmax at rapid heart rates compared with that produced by quinidine alone, but abbreviated action potential duration more at slower heart rates. Addition of tocainide to fibers equilibrated with quinidine shifted the Vmax-membrane potential relationship to more hyperpolarized potentials, resulting in greater depression of Vmax at more depolarized membrane potentials with little or no additional depression of Vmax at more negative membrane potentials. The results provide a rationale for a possible enhanced antiarrhythmic efficacy of a combination of two class I drugs that have different kinetics of interaction with the sodium channel.
Action Potentials↗
Electrophysiological and antiarrhythmic actions of tocainide in isolated heart preparations of the guinea pig.
Comparison of the action of tocainide in guinea pig atrial and ventricular myocardium has led to the following results: Tocainide effects a similar increase in threshold of alternating current induced arrhythmias in spontaneously beating right atria as well as stimulated left atria and papillary muscles. APD30 and APD90 (action potential duration at 30 and 90% repolarization) are decreased by tocainide in papillary muscles, especially at a low stimulation rate, but increased in left atria. On the other hand, maximum upstroke velocity of the action potential (Vmax) is decreased at a high stimulation rate (use-dependence) in both tissues. These effects are completely reversed by washing with drug-free solution within 15 min in papillary muscles and 60 min in left atria, respectively. Resting state block of Na-channels by tocainide occurs in left atria to a small degree (10-20%), but is negligible in ventricular myocardium. Recovery of Vmax following stimulus-induced inactivation is delayed by tocainide in papillary muscles and left atria. Functional refractory period is increased in left atria and in papillary muscles by tocainide. In the concentration range above 75 mumol/l the concentration response curve reaches a plateau in papillary muscles but shows a further steep increase in left atria. Quantitative analysis of the dynamic Na-channel blockade by tocainide in atrial myocardium using the modulated receptor hypothesis suggests that the drug shows a high affinity to activated and a low affinity to inactivated Na-channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗