Disopyramide. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiac arrhythmias

Disopyramide is a widely used class IA antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. Over the past 10 years disopyramide has demonstrated its efficacy in ventricular and atrial arrhythmias. In therapeutic trials, usually involving small numbers of patients, the efficacy of disopyramide was comparable with that of mexiletine, perhexiline, tocainide, propafenone or prajmalium. Recent comparisons with quinidine have confirmed the similar efficacy and better tolerability of disopyramide. The suggestion from initial studies that disopyramide may be less effective than amiodarone or flecainide requires further investigation. In addition, studies have failed to demonstrate that the early administration of disopyramide after acute myocardial infarction decreases important arrhythmias or early mortality. Thus, disopyramide is now well established as an effective antiarrhythmic drug in ventricular and supraventricular arrhythmias although its role in therapy relative to that of recently introduced antiarrhythmic agents is not clear.     

Clinical pharmacokinetics of disopyramide

Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.     

Pharmacology and clinical use of mexiletine

Mexiletine is an antiarrhythmic agent with structural and electrophysiologic properties similar to those of lidocaine. Mexiletine decreases ventricular automaticity while shortening both action potential duration and effective refractory period. The drug may be administered orally or intravenously. Hepatic metabolism is the major route of elimination. The elimination half-life is approximately 10 hours, but longer in patients with acute myocardial infarction, chronic congestive heart failure or hepatic insufficiency. Mexiletine suppresses ventricular ectopy in the acute phase of myocardial infarction. The drug is effective for some patients in whom lidocaine has failed. It suppresses chronic ventricular ectopy and is well tolerated in approximately two-thirds of stable outpatients treated with this agent. In that population, mexiletine is comparable in efficacy to quinidine, procainamide and disopyramide. It is effective in 30-50% of patients with ventricular arrhythmias refractory to other antiarrhythmic drugs. In patients with refractory arrhythmias, the efficacy of mexiletine may be enhanced by combination with propranolol, quinidine or amiodarone. Adverse reactions limit use of mexiletine in approximately 20% of patients. Gastrointestinal and central nervous system side effects are the most common. Mexiletine does not depress myocardial function. Aggravation of arrhythmias is uncommonly observed. The usual intravenous dose of mexiletine is 150-250 mg over at least 10 minutes. Long-term oral dosages are usually 200-300 mg 3 or 4 times daily.     

SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.     

Rapid infusions of bidisomide or disopyramide in conscious dogs: effect of myocardial infarction on acute tolerability.

The acute tolerability of rapid infusions of bidisomide or disopyramide was evaluated in normal conscious dogs and in conscious dogs 48 h after the creation of myocardial infarctions (MIs). Both drugs were given in total doses of 15 mg/kg (1.5 x the canine antiarrhythmic dose for each drug). Bidisomide was well tolerated at infusion rates of 3, 5, 11, and 15 mg/kg/min by normal dogs. Disopyramide was well tolerated, except for anticholinergic effects, by normal dogs given infusions at rates of 1.5 and 3 mg/kg/min. Disopyramide caused a ventricular arrhythmia at 4.5 mg/kg/min in one dog, however. Bidisomide (15 mg/kg/min) was well tolerated and antiarrhythmic in dogs with infarctions. Disopyramide (3 and 4.5 mg/kg/min) was lethal in dogs that had myocardial infarctions. A 1 mg/kg/min infusion rate of disopyramide was antiarrhythmic and well tolerated, except for anticholinergic effects, in the post-MI dogs. Both drugs prolonged the ECG lead II P duration, PR interval (bidisomide more so than disopyramide), and QRS duration. Both bidisomide and disopyramide shifted the mean electrical axis of the QRS complex from a right axis deviation to the normal range in dogs with infarctions. The data indicated that the desired cardiac electropharmacologic effects of bidisomide can be achieved in a 1 min infusion. Normal dogs, and especially dogs with infarctions, revealed the potential hazards of rapidly infusing disopyramide.     

Moricizine: a new class I antiarrhythmic

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.     

Efficacy of intravenous disopyramide in acute cardiac arrhythmias

Summary The efficacy of intravenous disopyramide was studied during 200 episodes of supraventricular and ventricular arrhythmias in 160 patients, mainly presenting with acute myocardial infarction or cardiac failure. Disopyramide 50 mg was administered in a few seconds and any remaining dose within 2 to 5 min. The overall success rate was 80.5%. Intravenous disopyramide was more effective in patients with ventricular arrhythmias (85%) than in those with supraventricular arrhythmias (76%). Dose dependent prolongation of the PR interval, QRS time and the QT interval occurred in 16.32 and 20% of the cases, respectively. The adverse effects were aggravation of the arrhythmias, decrease of blood pressure and anticholinergic activity.     

Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

As a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals. In the dosage range 600 to 900 mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis. Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.     

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)     

Efficacy of and adverse effects of disopyramide

Summary The efficacy of disopyramide compared to placebo for exercise induced ventricular arrhythmias was tested in a double-blind randomized controlled clinical trial with cross-over design in 14 patients with coronary heart disease. Disopyramide was given as ordinary capsules (q.i.d.) or as a slow release preparation (b.i.d.) in a total dose of 600 mg per day. The placebo preparations were identical looking capsules and tablets. Each treatment period lasted one week. Efficacy was assessed by a standardized exercise test on a bicycle ergometer and a 6-h Holter monitoring at the end of each period.Plasma levels of disopyramide, measured in conjunction with exercise test, fell within therapeutic range, with a mean value of 7.9 and 8.9 µmol/l for capsules and slow release tablets, respectively.Disopyramide gave a marked and significant reduction of ventricular ectopic beats both at rest and during and after exercise. There was also a significant decrease in the number of ectopic beats recorded on tape during treatment periods compared to during placebo periods. There were no differences between the two preparations with respect to antiarrhythmic effect.Only mild side-effects, mainly mild anticholinergic symptoms, similar for both preparations were reported. No significant cardiovascular changes (heart rate and blood pressure response) were observed.     

Tocainide. A review of its pharmacological properties and therapeutic efficacy

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.     

Propafenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

Propafenone is a Class I antiarrhythmic agent with weak beta-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 micrograms/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (greater than 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias. Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs.     

Cibenzoline. A review of its pharmacological properties and therapeutic potential in arrhythmias.

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.     

Combination drug therapy for ventricular arrhythmias

The role of drug combinations for the treatment of patients with ventricular arrhythmias is reviewed. The use of single drugs to suppress ventricular arrhythmias is often unsatisfactory; a drug may be ineffective or cause intolerable adverse effects. Simultaneous use of antiarrhythmic agents with different but compatible electrophysiologic effects may control arrhythmias refractory to single-drug therapy. Patients may tolerate combination therapy fairly well because dosages in combination therapy are often lower than those employed when either drug is used alone. Although comparison of drug trials is hampered by nonuniformity among study protocols, the data suggest that drug combinations can be effective in treating some patients. Pairs of drugs showing the most promise have been a class IA drug (procainamide, quinidine, or disopyramide) with a class IB drug (usually mexiletine), and a class IA drug with a beta blocker. Amiodarone should be combined with a class I drug only as a last resort. There is little evidence to support the simultaneous use of two class IA drugs. Selection of a drug combination should be guided by consideration of the patient's medical history, concurrent disease states, and risk of sudden cardiac death. The efficacy of combination therapy should be evaluated by electrophysiologic testing or ambulatory electrocardiography. Combination antiarrhythmic therapy should be reserved for patients in whom single-drug therapy has been ineffective or poorly tolerated. More studies are needed to further define the efficacy, safety, and role of drug combinations in the treatment of ventricular arrhythmias.     

Moricizine. A review of its pharmacological properties, and therapeutic efficacy in cardiac arrhythmias

Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal re-entry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extra-cardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderality depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death.     

Assessment of drug effects on spontaneous and induced ventricular arrhythmias in a 24-h canine infarction model

The antiarrhythmic efficacy of encainide, sotalol, flecainide and disopyramide was evaluated in anesthetized dogs subjected to 2-stage total occlusion of the left anterior descending coronary artery. Utilization of this canine model, while anesthetized, permitted the assessment of drug effects not only on uni- and/or multi-focal ectopic ventricular arrhythmias, but also on dysrhythmias associated with aberrant conduction or reentrant excitation pathways. The former was assessed by quantification of ectopic-to-total beat ratios while the later was determined by subjecting the animal to provocative stimuli which produced repetitive ventricular responses. At the cumulative i.v. doses studied, encainide (0.5-4 mg/kg), flecainide (1-8 mg/kg) and disopyramide (0.3-10 mg/kg), but not sotalol (2-8 mg/kg), effectively suppressed ventricular ectopic activity in a dose-related manner. In contrast, sotalol was highly effective in preventing the induction of reentrant ventricular tachyarrhythmias. Disopyramide was only modestly active, while flecainide and encainide had the least favorable profiles of effect in suppressing re-entry arrhythmias in this model. Based on these observations, the anesthetized Harris dog appears to represent a useful two-faceted in vivo model for use in the evaluation of potential antiarrhythmic agents.     

Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.

The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.     

The absorption of oral mexiletine in coronary care patients

Summary 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 µg/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.     

New antiarrhythmic drugs

While controversy still exists as to the precise indications for the treatment of all forms of ventricular arrhythmia, advances in the number and, more importantly, type of antiarrhythmic drugs can provide the clinician with a rational basis for selecting antiarrhythmic drug therapy. A host of new agents with different pharmacokinetic and electrophysiological actions are now available, and can be compared or contrasted to conventional antiarrhythmic agents such as quinidine, procainamide, disopyramide, lignocaine (lidocaine) and bretylium. This review summarises the electrophysiological, haemodynamic, pharmacokinetic, and efficacy and safety data of mexiletine, tocainide, flecainide, encainide, propafenone, amiodarone, sotalol, pirmenol, cibenzoline (cifenline) and ethmozine (moracizine, moricizine), and aims to provide a basis on which clinicians can compare and contrast these agents and form an algorithm for selection of antiarrhythmic drug therapy in the treatment of patients with ventricular arrhythmias.     

Antiarrhythmic and hemodynamic effects of prifuroline

The antiarrhythmic activity of 4-(2-benzofuranyl)-2-(dimethylamino)-1-pyrroline (prifuroline) has been evaluated in rats, guinea-pigs and dogs. Prifuroline dose-dependently antagonizes the arrhythmogenic action of aconitine in rats, when administered either intravenously (5, 10 or 20 mg/kg) or intraduodenally (10, 20 or 50 mg/kg); it exhibits effectiveness by the digestive route at doses only twice as greater as the active i.v. doses: its intravenous anti-aconitine activity is comparable to that of disopyramide, and superior to that of quinidine; lidocaine is inactive in this test. Prifuroline also diminishes ventricular susceptibility to electrical stimulation in open-chest rats; its effect is comparable to that of disopyramide and amiodarone at the same dose levels; quinidine and lidocaine are less effective. Only prifuroline and propranolol were able to antagonize ouabain toxicity in guinea-pigs, quinidine showing only borderline activity, and disopyramide, lidocaine and verapamil being ineffective. In a model of arrhythmias induced by anoxic stress in rats, all the tested compounds were found active, with prifuroline and disopyramide providing complete protection at high dose levels. The arrhythmias induced in dogs by coronary artery ligation were markedly antagonized by prifuroline after doses of 5 and 10 mg/kg i.v. or 30 mg/kg intraduodenally; the duration of its antiarrhythmic activity in this model of arrhythmias in conscious dogs was much longer after intraduodenal than after i.v. administration. Prifuroline was also able to restore sinus rhythm in guinea-pigs after intracardiac conduction blockade with acetylcholine, although being devoid of anticholinergic activity. It also diminishes the maximal frequency of guinea-pig atria electrically stimulated in viro (EC25 = 5 X 10(-6) g/ml).(ABSTRACT TRUNCATED AT 250 WORDS)