Mexiletine Concentrations Research Articles

Salivary excretion of mexiletine after bolus intravenous administration in rats.

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg-1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg-1 h-1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P less than 0.001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0.56 +/- 0.10 for parotid saliva, 0.21 +/- 0.06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.

Comparative hemodynamic effects of mexiletine and quinidine in patients with severe left ventricular dysfunction

Mexiletine and quinidine are often administered to patients with severe congestive heart failure, but their hemodynamic effects have not been adequately studied in these individuals. In a randomized, crossover study, the hemodynamic responses to single oral doses of quinidine (600 mg) and mexiletine (400 mg) were compared in 20 patients with marked left ventricular dysfunction. Quinidine predominantly caused vasodilation, with mean arterial, left ventricular filling, and right atrial pressures all decreasing (−7 ± 2, −2.3 ± 1.0, and −1.1 ± 0.5 mm Hg, respectively) and the systemic vascular resistance also declining (−308 ± 84 dynes · sec · cm 5). In contrast, the systemic vascular resistance increased (314 ± 84 dynes · sec · cm −5) and the mean arterial, left ventricular filling, and right atrial pressures also increased (+2 ± 2, +6.1 ± 1.8, and +1.8 ± 0.6 mm Hg, respectively) after mexiletine. Cardiac performance declined with mexiletine (cardiac and stroke work indexes decreasing −0.3 ± 0.1 L/min/m 2 and −5 ± 1 gm · m/m 2, respectively), but there was no significant change in cardiac or stroke work indexes with quinidine (+0.1 L/min/m 2 and −0.3 ± 0.9 gm · m/m 2, respectively). The response to the two agents significantly differed for all parameters measured ( p < 0.005). These hemodynamic changes were accompanied by clinical effects. Mexiletine induced increased dyspnea in five patients and quinidine led to symptomatic hypotension in two patients. Plasma concentrations of mexiletine and serum concentrations of quinidine were within or below the therapeutic range in all patients. In conclusion, mexiletine and quinidine exert different hemodynamic effects when given to patients with severe congestive heart failure. Mexiletine is more likely than quinidine to cause exacerbation of heart failure, and quinidine is more likely to provoke hypotension.

Mechanism of Interaction between Theophylline and Mexiletine

The mechanism of an interaction between theophylline and mexiletine hydrochloride was investigated in 6 male inpatients coadministered both drugs and 16 inpatients (13 men, 3 women) administered theophylline only. Serum theophylline and mexiletine concentrations and urinary concentrations of theophylline and its metabolites were monitored. Theophylline clearance was 0.0278 +/- 0.0047 L/kg/h (mean +/- SD) in patients coadministered theophylline and mexiletine and 0.0441 +/- 0.0096 in patients administered theophylline only (p less than 0.05). The fractional urine contents of 1-methyluric acid and 3-methylxanthine were 18.7 +/- 2.5 and 12.6 +/- 2.1 percent in the former group and 26.5 +/- 6.0 and 17.1 +/- 2.0 percent in the latter group, respectively (p less than 0.05). The fractional urine content of 1,3-dimethyluric acid was 51.8 +/- 3.2 in the former and 44.7 +/- 4.1 percent in the latter, respectively (p less than 0.05). An inverse correlation was obtained between serum mexiletine concentrations and total fractional urine content of 1-methyluric acid and 3-methylxanthine (r = 0.704). These results suggest that the mechanism of an interaction between theophylline and mexiletine is an inhibition of demethylation of theophylline by mexiletine.

Sotalol and Mexiletine: Combination of Rate-Dependent Electrophysiological Effects

The rate-dependent electrophysiological effects of sotalol (30 microM), mexiletine (10 and 18 microM), and their coadministration were examined in isolated dog cardiac Purkinje fibers following abrupt changes in pacing cycle length. Combination of 30 microM sotalol with 10 microM mexiletine significantly lengthened premature action potential durations at diastolic intervals of less than 50 ms while the basic action potential duration evoked at a stimulus frequency of 2 Hz was not affected. This effect on the premature action potential duration was attenuated when the higher mexiletine concentration (18 microM) was coadministered with sotalol. The fast time constant for restitution of the action potential duration was significantly slowed by either combination. Coadministration of sotalol and mexiletine, like mexiletine alone, produced a rate-dependent depression of Vmax that displayed a second slow time component during recovery. This slow component for recovery of Vmax was not distinguished in the absence of drug or in the presence of sotalol alone. Sotalol-induced lengthening of the action potential duration observed at slow pacing frequencies was also attenuated by addition of mexiletine; and, under these conditions, Purkinje fiber early afterdepolarizations were prevented. In addition, the range of premature action potential durations was significantly decreased by mexiletine and by the combination, while sotalol alone increased this range slightly. These results indicate that coadministration of sotalol and mexiletine may provide beneficial electrophysiological effects expected to provide enhanced antiarrhythmic efficacy and fewer proarrhythmic complications in patients.

Low dose quinidine-mexiletine combination therapy versus quinidine monotherapy for treatment of ventricular arrhythmias

Low dose quinidine-mexiletine combination therapy was compared with quinidine monotherapy in 15 patients with frequent ventricular premature complexes and nonsustained ventricular tachycardia in a dose escalation crossover study. Oral combination therapy was initiated with quinidine gluconate (165 mg) plus mexiletine (150 mg) every 8 h. If ventricular premature complexes were not suppressed ≥80% and nonsustained ventricular tachycardia ≥90%, the dose was increased to a maximum of 330 mg of quinidine plus 200 mg of mexiletine. Quinidine monotherapy was initiated with 330 mg and escalated to a maximum of 660 mg every 8 h if criteria for effectiveness were not met.Combination quinidine-mexiletine therapy suppressed 80% of ventricular premature complexes in 13 of 14 patients and suppressed 100% of episodes of ventricular tachycardia in 6 of 8 patients (mean quinidine dose 200 ±70 mg; mean mexiletine dose 146 ± 24 mg every 8 h). The mean effective trough quinidine and mexiletine concentration was 1.0 ± 0.7 and 0.9 ± 0.4 μg/ml, respectively. Monotherapy was less effective; that is, ≥80% suppression of ventricular premature complexes was observed in 5 of 15 patients and 100% suppression of ventricular tachycardia in 2 of 9 patients. The mean quinidine monotherapy dose was 462 ± 155 mg every 8 h; the mean quinidine concentration was 1.8 ± 0.8 μg/ml.Adverse systemic effects occurred in 3 patients on quinidine-mexiletine therapy and in 11 on quinidine monotherapy. Neither treatment prolonged PR or QRS intervals, but monotherapy prolonged the QTc interval (p < 0.05); both treatments prolonged the coupling interval (p < 0.05). Low dose quinidine-mexiletine is more effective and better tolerated than are standard doses of quinidine.

急性心筋梗塞患者におけるＭｅｘｉｌｅｔｉｎｅの血しょう中蛋白質結合に及ぼすα１酸性糖蛋白の影響 Ｄｉｓｏｐｙｒａｍｉｄｅとの比較検討

The influence of alpha-i-acid glycoprotein (AAG.) concentration on plasma protein binding of mexiletine and of disopyramide were investigated in patients with acute myocardial infarction and other heart disorders. The following results were obtained:(1) There was a linear relationship between the dose and plasma total concentration of mexiletine. There was no significant correlationship between the dose and plasma total concentration of disopyramide.(2) There was no significant correlationship between the concentration of AAG and free fraction of mexiletine, and negative correlation was observed between the concentration of AAG and free fraction of disopyramide.(3) No significant differences were observed in patients with acute myocardial infarction and other heart disorders between total plasma concentration and free fraction of mexiletine.There was no significant difference in total plasma concentration of disopyramide between the patients with acute myocardial infarction and other heart disorders. The free fraction in patients with acute myocardial infarction was significantly lower than that in those with other heart disorders (P<0.01).(4) The influence of AAG concentration on free fraction percent of mexiletine was not appreciated. Therefore, we concluded that the monitoring of total plasma concentration of mexiletine was important.

血中メキシレチン濃度測定における蛍光偏光免疫測定法の評価

血中メキシレチン濃度測定における蛍光偏光免疫測定法の評価

Frequency-Dependent Effect of Quinidine, Mexiletine, and Their Combination on Postrepolarization Refractoriness In Vivo

Combination therapy with mexiletine and quinidine has been shown to enhance antiarrhythmic efficacy. To assess further the underlying electrophysiological mechanism, the effect of therapeutic concentrations of mexiletine and quinidine, and of their combination, on action potential duration (at the level of 90% repolarization, APD90), effective refractory (ERP), and the relationship between these two parameters (ERP-APD90) was determined in 21 in vivo canine hearts. The frequency dependence of these effects was assessed over a range of paced steady-state cycle lengths from 250-600 ms. A modified contact electrode technique allowed measurements of both APD90 and ERP simultaneously and at the same ventricular site. In the drug-free state, both APD90 and ERP shortened linearly with shorter cycle lengths, maintaining a constant relationship (ERP-APD90) difference = -9 +/- 2 ms) at all cycle lengths. Quinidine prolonged APD90 by a near constant amount of 11 +/- 1 ms over the entire range of cycle lengths, while mexiletine tended to shorten it. Both mexiletine and quinidine increased ERP and ERP-APD90 in a rate-dependent fashion, the effect increasing with shorter cycle lengths. When used in combination, mexiletine attenuated the lengthening effect of quinidine on APD90 but augmented the rate-dependent increase in ERP, thereby producing greater postrepolarization refractoriness than either drug alone. This effect may explain the clinically favorable antiarrhythmic efficacy of mexiletine and quinidine combination therapy.

The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas

The effects of intravenously administered subanesthetic concentrations of lidocaine, tocainide, and mexiletine on spontaneously active fibers (SAFs) originating in 7-day-old rat sciatic neuromas were studied. Control injections of normal saline caused no decrease in SAF or discharge rate. Lidocaine and tocainide given in incremental doses of 5, 10, 15, 20 and up to 25 mg/kg caused nearly all observed SAFs to stop firing. Mexiletine given in doses of 3, 5, 7, 10 and up to 15 mg/kg showed similar results at lower doses. All agents decreased the sensitivity of SAF to mechanical stimulation. No conduction blockade occurred at these doses of intravenously administered local anesthetics. The demonstrated reduction in firing rate of SAF may explain the pain relief observed in clinical trials of these orally available agents.

Mexiletine-quinidine in isolated hearts: an interaction involving the sodium channel

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.

血中メキシレチン濃度測定における蛍光偏光免疫測定法の評価

血中メキシレチン濃度測定における蛍光偏光免疫測定法の評価

A Comparison of the Cellular Electrophysiology of Mexiletine and Sotalol, Singly and Combined, in Canine Purkinje Fibers

To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1-100 microM), sotalol (3.1-400 microM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 microM of one drug combined with 3.1, 12.5, and 50 microM of the other. Mexiletine caused a concentration dependent depression of Vmax, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 microM, sotalol depressed Vmax slightly. Increasing the stimulation frequency did not result in further Vmax depression. The addition of sotalol did not alter the Vmax depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.

老年高血圧患者の心室性不整脈におけるｍｅｘｉｌｅｔｉｎｅの有効性，安全性および高速液体クロマトグラフィー法による血中ｍｅｘｉｌｅｔｉｎｅ濃度の検討

This study was designed to investigate the effectiveness, hemodynamic effects, and serummexiletine concentration in senile hypertensives with repetitive ventricular arrhythmias.Mexiletine, 100mg t. i. d. was administered in 10 senile hypertensives. Blood pressure, echocardiogram, 24-hr ambulatory ECG were obtained before and after medication. Serummexiletine concentration was measured by HPLC (High Performance Liquid Chromatography). Cardiac output, mean velocity of circumferential fiber shortening were calculatedfrom LVDd, LVDs, HR, ejection time by echocardiogram. The effcacy of mexiletine wasassessed by 24-hr ECG with comnuter analysis.No repetitive ventricular arrhythmias were found in all patients by administration ofmexiletine. Number of ventricular arrhythmias decreased from 925 to 120 per day. Althoughthey have low cardiac performance, no significant change was found in hemodynamics. Theaverage of serum mexiletine concentration was 0.75 μg/ml (equal to that of adult). Seriousuntoward effects were not found in all patients.In conclusion, orally administered mexiletine was very effective in the treatment ofrepetitive ventricular arrhythmias in senile hypertensives with conventional doses similarto that in middle-aged subjects and also, HPLC was thought to be superior to gas chromatography because of its rapidity, accuracy, and lower cost.

Persistence of the electrophysiologic effects of mexiletine in canine Purkinje fibers alters the response to subsequent hypoxia.

The persistence of cellular electropharmacologic effects of mexiletine on canine Purkinje fibers was studied utilizing standard microelectrode techniques and two different protocols. In the first, the tissue was exposed to hypoxic perfusion before and 30 min after perfusion with one of the following: mexiletine hydrochloride 6.25 microM solution, mexiletine hydrochloride 12.5 microM solution, or drug-free Tyrode's solution. With the higher concentration of mexiletine, depression of the maximal upstroke velocity (Vmax) persisted 30 min after drug washout and subsequent exposure to hypoxia did not result in the anticipated shortening of action potential duration but did prevent the restoration of normal Vmax. After perfusion with the lower concentration of mexiletine, Vmax was not depressed and hypoxic action potential duration shortening was not prevented. In the second protocol, Purkinje fibers were perfused with 12.5 microM mexiletine hydrochloride solution and then exposed to hypoxia after 15, 30, 45, or 60 min of perfusion with drug-free solution. Depression of maximal upstroke velocity and shortening of action potential duration persisted during washout, returning to control values by 45 min, although mexiletine was not detectable in the tissue bath after 10 min of washout. Hypoxia initiated at 15 or 30 min of washout failed to produce the anticipated shortening of action potential duration. At 45 and 60 min, action potential duration was shortened by hypoxia. We concluded that mexiletine depression of Vmax and shortening of action potential duration may persist in the absence of drug. Further shortening of action potential duration in response to hypoxia is prevented during this period. The persistence of Vmax depression is prolonged by hypoxia.

Mexiletine and Quinidine in Combination in an Ischemic Model: Supra-Additive Antiarrhythmic and Electrophysiologic Actions

Combination therapy with mexiletine and quinidine has been shown to be more effective than either agent alone in the treatment of ventricular tachycardia in humans. To assess the electrophysiologic correlates of this enhanced antiarrhythmic effect, concentration-response relationships of mexiletine and quinidine alone and in combination were evaluated in 117 isolated perfused rabbit hearts after circumflex occlusion-reperfusion. Normal and infarct zone recordings included monophasic action potential duration, ventricular effective refractory period, and conduction time during constant rate pacing. Ventricular fibrillation occurred in all 18 "vehicle only"-treated hearts during programmed electrical stimulation (S2). High-concentration mexiletine therapy was more effective in protecting against malignant ventricular arrhythmias than was quinidine. Both therapies produced concentration-dependent prolongation of ischemic zone conduction and refractoriness. When low concentrations of mexiletine and quinidine were combined (concentrations which when given alone had little or no electrophysiologic or antiarrhythmic activity) antiarrhythmic activity was seen which was greater than that seen with high-concentration single treatment. Low-concentration combination therapy was also associated with significantly greater prolongation of infarct zone conduction time and refractoriness. In conclusion, low-concentration combination treatment with mexiletine and quinidine prolonged infarct zone conduction time and refractoriness to a greater extent than was seen with single therapy at matched concentrations. These electrophysiologic effects were associated with enhanced antiarrhythmic activity.

Electropharmacologic Synergism With Mexiletine and Quinidine

We have previously shown that combination therapy with mexiletine and quinidine is more effective and causes fewer side effects than either agent alone in the treatment of patients with serious ventricular arrhythmias. To further assess this enhanced antiarrhythmic effect, the electrophysiologic actions of mexiletine and quinidine alone and in combination were evaluated in isolated perfused rabbit hearts. Dose-response curves were constructed for right ventricular effective refractory period, epicardial monophasic action potential duration, and conduction time (the time from pacing stimulus to the upstroke of the monophasic action potential signals) during constant rate pacing. No significant changes in these parameters were seen in 15 preparations treated with saline over a duration of 1 h (a time equal to the longest experiments). With gradually increasing concentrations of mexiletine (2.3-36 microM) prolongation of conduction time (12 +/- 5 msec, mean +/- SE, p less than 0.05) paralleled change in ventricular refractoriness (20 +/- 5 msec, mean +/- SE, p less than 0.05) but occurred in the absence of any significant change in monophasic action potential duration. With gradually increasing concentrations of quinidine (0.55-34 microM/L) prolongation of ventricular refractoriness (65 +/- 7 msec, mean +/- SE, p less than 0.01) and monophasic action potential duration (65 +/- 7 msec, mean +/- SE, p less than 0.01) occurred in parallel and at concentrations less than those required to prolong conduction time.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Pharmacokinetics of Mexiletine

The pharmacokinetics of mexiletine and the factors that have been shown to modify its disposition are reviewed. The clinical significance of the modifications observed is discussed. Mexiletine is well absorbed from the gut and the bioavailability is 80–88%, The volume of distribution is large (5–9 L/kg) and 70% of the drug is bound to serum proteins. The elimination half‐life varies between 6–12 hours. Concomitant administration of atropine, metoclopramide, gastric acids, narcotic analgesics and cimetidine modify the peak concentrations of mexiletine and the time required to attain these concentrations. Rifampicin, phenytoin, and cigarette smoking shorten the elimination half‐life and increase the clearance. The volume of distribution of mexiletine is increased to the acute phase of myocardial infarction, whereas its elimination half‐life is increased in both cardiac failure and cirrhosis. Factors modifying the elimination, unlike those affecting the absorption characteristics, of mexiletine are of clinical importance and may require a modification of the dosage regimen.

Effects of Simultaneous Administration of Mexiletine and Quinidine on the Electrophysiologic Parameters of Canine Purkinje Fibers

The electropharmacologic effects of an equimolar combination of mexiletine and quinidine on canine Purkinje action potential parameters were compared with the effects of either drug alone in concentrations ranging from 0.31 to 5.0 X 10(-5) M. Six separate experiments were performed with mexiletine alone, quinidine alone, and the combination. At low concentrations, all three shortened action potential duration (APD) and effective refractory period (ERP) to the same degree; however, the combination depressed Vmax to the same extent as did solutions containing twice the concentration of quinidine alone even though mexiletine alone, in these concentrations, had no effect on the maximum rate of depolarization of phase 0 of the action potential Vmax. In higher concentrations, the combination depressed Vmax and prolonged the ERP to values midway between that achieved by the two drugs separately. Although increasing concentrations of mexiletine alone progressively shortened APD, the combination prolonged this parameter to values similar to those seen with twice the concentration of quinidine alone. The electropharmacologic effects of mexiletine and quinidine in combination are not simply additive and cannot be entirely predicted on the basis of a knowledge of their effects in isolation.

Dose independent pharmacokinetics of mexiletine in healthy volunteers.

In 12 healthy volunteers who received orally 100, 200, 300, 400 and 600 mg mexiletine at weekly intervals, the maximum plasma concentration of mexiletine and AUC increased linearly with the dose of mexiletine. Between doses there were no significant differences in the values for clearance and volume of distribution of mexiletine but there were for plasma elimination half-life. These results indicate that the kinetics of mexiletine are linear.

Electrophysiological actions of mexiletine on rabbit sinoatrial node cells

The effects of mexiletine (1–100 μM) were examined on membrane potential and current of rabbit sinoatrial node cells by means of conventional microelectrode and double microelectrode voltage clamp techniques. Mexiletine decreased, in a dose-dependent manner, the maximum rate of depolarization of the action potential and the action potential amplitude, and increased the spontaneous cycle length. The slope of the diastolic depolarization (phase 4) was also reduced. In the voltage clamp experiment, mexiletine (40–100 μM) reduced the slow inward current (I si), the potassium outward current (I K) and the hyperpolarization-activated current (I h). The kinetic variable of I K was not altered by the drug. These results suggest that mexiletine does not have a specific effect on a single-current system, but that relatively high concentrations of mexiletine exert an inhibitory effect on the electrical activity of the sinoatrial node cells.