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Efficacy of mexiletine for the treatment of ventricular arrhythmias in 16 dogs
Abstract
Mexiletine is a class IB antiarrhythmic drug with good oral absorption. It was administered to 16 dogs with ventricular arrhythmias. Four dogs were treated orally which resulted in complete resolution of the arrhythmias within two weeks. In 12 dogs with acute ventricular arrhythmias mexiletine was administered either by intramuscular or by intravenous route. Within 24 hours, 10 of these dogs responded either completely (n = 6) or partially with a reduction of the ventricular premature contractions by more than 50 per cent (n = 4). In three dogs mexiletine therapy was initiated after unsuccessful treatment with lidocain and/or procainamid. It resulted in complete resolution of the arrhythmias. Side effects were noted in one dog and consisted of muscle tremor and generalized weakness. Mexiletine is a safe antiarrhythmic drug for the treatment of ventricular arrhythmias in the dog. In accordance with the literature, the study reports good efficacy of the drug.
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In a preliminary study of mexiletine absorption in Coronary Care Unit patients with myocardial infarction, plasma mexiletine concentrations were significantly lower in those given narcotic analgesics. 166 patients then entered a comparative study of the effects of mexiletine and placebo on the incidence of ventricular arrhythmias after myocardial infarction (MI). Eighty-two patients were given mexiletine, 51 with MI. Mexiletine absorption was impaired in patients with MI and 66% failed to reach the minimum therapeutic plasma concentration of 1 g/ml in 3 h. On the second and third hospital days, 34% and 25% respectively had subtherapeutic levels. In patients without MI, low plasma mexiletine concentrations were associated with the use of narcotic analgesics. The incidence of serious ventricular arrhythmias (VF, VT, R on T ectopic beats) was significantly lower in patients given mexiletine, and after 3 h most arrhythmias in this group occurred in patients with subtherapeutic mexiletine concentrations. Therapeutic failure of oral antiarrhythmic drugs soon after MI may be due to impaired absorption.
The electrophysiological effects of intravenous mexiletine in a dose of 200 to 250 mg given over 5 minutes, followed by continuous infusion of 60 to 90 mg per hour, were studied in 5 patients with normal conduction and in 20 patients with a variety of disturbances of impulse formation and conduction, by means of His bundle electrography, atrial pacing, and the extrastimulus method. In all but 2 patients the plasma level was above the lower therapeutic limit. Mexiletine had no consistent effects on sinus frequency and atrial refractoriness. The sinoatrial recovery time changed inconsistently in both directions; however, of the 5 patients in whom an increase was evident, 3 had sinus node dysfunction. In most patients mexiletine increased the AV nodal conduction time at paced atrial rates and shifted the Wenckebach point to a lower atrial rate. The effective refractory period of the AV node was not consistently influenced, while the functional refractory period increased in 12 out of 14 patients. The HV intervals increased by a mean of 11 ms in 8 patients and were unchanged in 17. Both the relative and effective refractory period of the His-Purkinje system increased after mexiletine. Non-cardiac side effects occurred in 7 out of 25 patients, and cardiac side effects, including one serious, in 2. The results indicate that mexiletine shares some electrophysiological properties with procainamide and quinidine, when given to patients with conduction defects, and that the drug should not be used in patients with pre-existing impairment of impulse formation or conduction. It has additional effects on AV nodal conduction which may be of value in the treatment of re-entrant tachycardias involving the AV node.
Thirty mongrel dogs underwent proximal occlusion of the left anterior descending coronary artery to evaluate the comparative action of mexiletine and lidocaine on ventricular arrhythmias during myocardial reperfusion. Heart rate, arterial blood pressure, left ventricular end-diastolic pressure and dp/dt max were evaluated before and at the 20th and 25th min after coronary occlusion; at the 25th min coronary occlusion was removed. Dogs were randomly assigned to one of the following groups of 10: 1) control group; 2) dogs given i.v. mexiletine; 3) dogs given i.v. lidocaine. As expected, during ischemia, myocardial contractility decreased after mexiletine or lidocaine administration more than in the control group. Ventricular arrhythmias during myocardial reperfusion occurred in 9 dogs of the control group (ventricular tachycardia in 2 cases and ventricular fibrillation in 7 cases). Among dogs given mexiletine only 1 had ventricular fibrillation (p less than 0.001 vs control). Six of the 10 dogs given lidocaine had ventricular arrhythmias (ventricular tachycardia in 5 cases and ventricular fibrillation in 1 case) (p = ns vs control group; p less than 0.05 vs mexiletine group). Thus mexiletine and lidocaine had similar effects on cardiac function during myocardial ischemia and only mexiletine showed a protective effect against reperfusion ventricular arrhythmias.
Gastric distention-volvulus (GDV; at 50 mm of Hg gastric inflation pressure) was experimentally induced in 8 dogs anesthetized using pentobarbital. Hemodynamic indices including heart rate, mean arterial pressure, cardiac output, and coronary blood flow (4 dogs) were measured during a 20-minute period of GDV and for 10 minutes after decompression. Arterial and coronary venous oxygen tensions were also measured for calculation of myocardial oxygen extraction (7 dogs) and myocardial oxygen consumption (4 dogs). Dogs were monitored for 72 hours postoperatively for the occurrence of arrhythmias, then were euthanatized for gross and histologic examination of the heart. Experimental GDV resulted in significant (P less than 0.05) decreases in cardiac output (89%), mean arterial pressure (45%), and coronary blood flow (50%) compared with control values. Myocardial oxygen extraction increased (30%) and overall myocardial oxygen consumption decreased (50%), compared with control values. Evidence of subendocardial necrosis was seen in 6 dogs, 4 of which had developed ventricular arrhythmias 8 to 24 hours postoperatively.
The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.
Malignant ventricular arrhythmias often occur in patients with left ventricular (LV) dysfunction. Antiarrhythmic drugs may further impair LV function in these patients. Mexiletine, a lidocaine congener, is an effective antiarrhythmic drug, but when administered orally, its effect on LV and right ventricular (RV) function is unknown. To determine the hemodynamic effects of mexiletine, LV and RV ejection fraction (EF) were measured by radionuclide ventriculography in 10 patients with LV dysfunction (LVEF less than 50%). Symptom-limited exercise tests were also performed. Patients were studied before and during therapy with oral mexiletine. There was no significant change in LVEF (28% vs 27%) or RVEF (46% vs 41%). Also, heart rate at rest, exercise duration and peak heart rate during exercise were unchanged. Thus, in patients with LV dysfunction, oral mexiletine does not significantly affect LV or RV function.
Plasma collected from 6 experimentally induced and 29 clinical cases of gastric dilatation-volvulus was assayed for cardioactive substances utilizing isolated canine papillary muscles. The results were correlated with in vivo isovolumetric indices of myocardial contractility observed during experimental gastric dilatation-volvulus in the dog. Cardioactive substances were not detected during experimental gastric dilatation-volvulus. Two experimental dogs showed a cardiostimulatory response and 4 experimental dogs showed a cardiodepressant response following gastric decompression. Cardioactive substance bioassays correlated well with isovolumetric indices in experimental dogs. The variable response in cardioactive substance bioassay observed in experimental dogs was consistent with clinical gastric dilatation-volvulus bioassays which produced a widely variable response ranging from strongly cardiostimulatory to strongly cardiodepressant.
Lidocaine, procainamide, quinidine, or a combination of these drugs was used to treat a variety of cardiac arrhythmias in 70 dogs with gastric distention-volvulus. Antiarrhythmic drugs were administered by constant infusion, the double-infusion technique, or intramuscular injection. Most cardiac arrhythmias were ventricular in origin, although supraventricular arrhythmias including atrial fibrillation also were included. Normal sinus rhythm was reestablished in greater than 85% of the dogs treated. Restoration to normal rhythm was improved by combination drug therapy, normalization of acid-base balance, and appropriate electrolyte therapy.
In coronary care unite, intense activity is directed toward the recognition and suppression of those ventricular arrhythmias which are thought to herald ventricular fibrillation. Ventricular fibrillation is the most common cause of death in the early phase of myocardial infarction, as well as in chronic ischemic heart disease. In some cases it is preceded by ventricular tachycardia, but in others it occurs unexpectedly. Sustained ventricular tachycardia represents a significant problem in the initial care of patients with cardiac disease. Despite comparative safety and effectiveness, lidocaine appears to be less effective during the early phase of acute myocardial infarction.1*2 Although adequate serum levels may often not be achieved with standard doses, in some patients the ventricular arrhythmia appears to be truly “lidocaine resistant.“3*4 Alternative antiarrhythmic drugs, including procainamide, propranolol, and phenytoin, are variably effective. Intravenous disopyramide appears to be an effective antiarrhythmic drug in suppressing serious ventricular arrhythmias, including those not responsive to lidocaine.5 However, the patients with myocardial infarction who have low levels of systemic blood pressure are at increased risk of disopyramide-induced cardiac depression.6*7 Clearly, additional agents are desirable. Mexiletine is a new antiarrhythmic drug, available in oral and intravenous form, that is structurally and electrophysiologically similar to lidocaine. Experimental studies show that it is a quinidine-like drug from group II.8 Clinical studies have shown intravenous mexiletine to be safe and effective in suppressing ventricular arrhythmias that occurred in patients with acute and chronic heart disease as well as in patients with other acute clinical conditions.g-16 This report deals with the clinical evaluation of intravenous mexiletine in a study designed to assess its antiarrhythmic efficacy for emergency treatment of lidoCaine-resistant ventricular tachycardia. A total of 18 patients, 15 men and 3 women, with sustained lidocaine-resistant ventricular tachycardia were entered into the study. Their ages ranged from 40 to 60 years (mean 47 years). Clinical information on these patients is given in Table I. Acute myocardial infarction was present in eight patients; ventricular tachycardia