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PubMed1994

Ischemia enhances use-dependent sodium channel blockade by pilsicainide, a class IC antiarrhythmic agent.

OBJECTIVES: The aim of this study was to elucidate whether the electrophysiologic properties of pilsicainide, a novel class IC drug with slow kinetic properties, could be altered in the presence of acute myocardial ischemia. BACKGROUND: An increase in the rate of sudden death in patients taking flecainide and encainide has been reported by the Cardiac Arrhythmia Suppression Trial (CAST), implying a proarrhythmic effect that may be due to the interaction between ischemia and class IC antiarrhythmic drugs. METHODS: Thirty-five patients and 16 age-matched control patients performed a treadmill exercise test and were assigned to four study groups: group A = 16 control patients; group B = 15 patients with ischemic ST segment depression; group C = 11 patients receiving pilsicainide without ST segment depression; and group D = 9 patients receiving pilsicainide with ischemic ST segment depression. The QRS duration was measured at rest and at heart rates of 80, 100 and 120 beats/min. RESULTS: There were no changes in the QRS duration as heart rates increased to 120 beats/min in the control patients. Ischemia, however, independently caused a significant increase in QRS duration at a heart rate of 120 beats/min. Pilsicainide produced a rate-dependent prolongation of the QRS duration in patients without ST segment depression as the heart rate increased to 100 beats/min. The combination of ischemia and pilsicainide led to a much greater rate-dependent prolongation of the QRS duration. CONCLUSIONS: Combination of a class IC drug and acute ischemia could lead to additive rate-dependent ventricular conduction slowing. This may be one plausible mechanism for the induction of proarrhythmias noted in the CAST study.

Acute Disease↗
PubMed1996

Effects of oral propafenone on defibrillation and pacing thresholds in patients receiving implantable cardioverter-defibrillators. Propafenone Defibrillation Threshold Investigators.

OBJECTIVES: The effects of propafenone, a predominantly class IC antiarrhythmic drug, on defibrillation and pacing thresholds were evaluated in patients undergoing cardioverter-defibrillator implantation. BACKGROUND: Previous studies have shown that the class IC agents encainide and flecainide may increase the energy requirements for pacing and defibrillation. Animal studies with propafenone have shown inconsistent results regarding its effect on defibrillation energy requirements. This report investigated the effects of propafenone on defibrillation and pacing thresholds in humans. METHODS: After cardioverter-defibrillator implantation, 47 patients were enrolled in a double-blind, three-way parallel, randomized trial of 450 mg/day (Group 1) or 675 mg/day (Group 2) of oral propafenone or placebo (Group 3) for 3 to 7 days. Predischarge defibrillation and pacing thresholds after treatment were compared with baseline thresholds obtained at implantation. RESULTS: There was no statistically significant difference between implantation and predischarge defibrillation thresholds in the three groups (Group 1: [mean +/- SE] 11.0 +/- 1.3 vs. 12.1 +/- 1.5 J; Group 2: 11.5 +/- 1.1 vs. 13.6 +/- 1.3 J; Group 3: 12.5 +/- 1.2 vs. 13.3 +/- 1.6 J), and no significant difference between treatment groups was found with a 0.86 power to detect a 5-J difference between groups. Paired pulse width pacing thresholds at 2.8 V were compared in 14 patients. A small increase of 0.02 ms was noted at predischarge testing in patients treated with propafenone and placebo. CONCLUSIONS: Short-term oral propafenone (450 and 675 mg/day) does not significantly affect defibrillation or pacing thresholds. Concomitant use of propafenone in patients with implantable cardioverter-defibrillators with recurrent ventricular or atrial tachyarrhythmias should not interfere with proper device function.

Administration, Oral↗
PubMed1996

From first class to third class: recent upheaval in antiarrhythmic therapy--lessons from clinical trials.

In recent years, the results of large randomized and controlled trials of antiarrhythmic agents for primary and secondary prevention of ventricular tachycardia and ventricular fibrillation have changed perceptions of the actions of antiarrhythmic agents regarding both efficacy and risk. The premature termination of the CAST trials of primary prevention in postinfarct patients highlighted the proarrhythmic risk and inefficacy of the sodium channel blockers (class I action), encainide, flecainide, and moricizine, in patients at relatively low risk for death in the long term. The excess mortality with therapy was attributed to proarrhythmia due to facilitation of reentry, especially during acute ischemia. About the same time, European trials with amiodarone, a complex agent with antiadrenergic action and powerful action to prolong refractoriness (class III action), indicated enhanced survival after infarction with amiodarone but not with agents with class I action. Recent verbal reports of larger and placebo-controlled trials (EMIAT and CAM-IAT) confirm a significant reduction in arrhythmia mortality, possibly with a favorable trend in total mortality. While an older trial with dl-sotalol (class III and beta-blocking actions) showed a trend toward improved survival after infarction, a recent trial with d-sotalol in patients with recent infarction or remote infarction and heart failure was prematurely terminated because of excess mortality attributed to proarrhythmia (torsades de pointes), indicating the importance of beta-blocking properties of a class III agent. A secondary prevention trial (ESVEM) in patients surviving an episode of VT or VF showed significant superiority of dl-sotalol compared to an array of agents that block sodium channels with respect to both efficacy and tolerance. Occurrence rates of arrhythmias treated with drugs tested for efficacy either by suppression of inducible arrhythmias or by suppression of spontaneous ectopy were higher and equivalent for both testing methods. A secondary prevention trial of amiodarone and multiple agents that block sodium channels in survivors of cardiac arrest (CASCADE) showed a significant increased efficacy of amiodarone but poorer long-term tolerance compared with the other agents. Comparative analysis of the results of the various trials suggests that class III action coupled with antiadrenergic action is more efficacious in both primary and secondary prevention of life-threatening ventricular arrhythmias and that lethal proarrhythmias may be the predominant effect in attempts at primary prevention in low-risk populations due to class I or so-called pure class III action.

Adrenergic beta-Antagonists↗
PubMed1998

Safety of oral propafenone in the treatment of arrhythmias in infants and children (European retrospective multicenter study). Working Group on Pediatric Arrhythmias and Electrophysiology of the Association of European Pediatric Cardiologists.

This study was designed to assess adverse effects of oral propafenone in a large number of pediatric patients. Retrospective data from 27 European centers covering 772 patients treated with oral propafenone were analyzed. The following arrhythmias were treated: reentrant supraventricular tachycardia in 388 patients, atrial ectopic tachycardia in 66, junctional ectopic tachycardia in 39, atrial flutter in 21, ventricular premature complexes in 140, ventricular tachycardia in 78, and other arrhythmias in 39 patients. Two hundred forty-nine patients (32.3%) had structural heart disease. Significant electrophysiologic side effects and proarrhythmia were found in 15 of 772 patients (1.9%): sinus node dysfunction in 4, complete atrioventricular block in 2, aggravation of supraventricular tachycardia in 2, acceleration of ventricular rate during atrial flutter in 1, ventricular proarrhythmia in 5, and unexplained syncope in 1 patient. Cardiac arrest or sudden death occurred in 5 of 772 patients (0.6%): 2 patients had supraventricular tachycardia due to the Wolff-Parkinson-White syndrome and a normal heart; the remaining 3 patients had structural heart disease. Overall, adverse cardiac events were more common in the presence (12 of 249 patients, 4.8%) than in the absence (8 of 523 patients, 1.5%) of structural heart disease (p <0.01). There was no difference between patients treated for supraventricular and ventricular arrhythmias. Thus, propafenone is a relatively safe drug for the treatment of several pediatric tachyarrhythmias. Proarrhythmic effects seem to be less frequent than those reported for encainide or flecainide and occur predominantly in patients with structural heart disease.

Administration, Oral↗
PubMed1998

Effects of lidocaine and mexiletine on defibrillation energy requirements in animals treated with flecainide.

We previously reported that mexiletine alone did not increase the ventricular defibrillation threshold (DFT). However it has been stressed that the interaction of antiarrhythmic drugs may be one of the cause of sudden death in patients taking flecainide or encainide. In the present study, the effect of lidocaine and mexiletine combined with flecainide on DFT was investigated. Experiments were performed on 27 mongrel dogs. Flecainide 2 mg kg(-1) was administered i.v. as a loading dose and repeated for maintenance. Lidocaine (n = 10) or mexiletine (n = 10), was cumulatively administered 15 min later. Saline was administered in control group (n = 7). In these groups, fibrillation/defibrillation trials were repeated. The flecainide concentration ranged from 0.84 to 1.02 microg ml(-1). The lidocaine and mexiletine concentrations increased up to 12.54 and 7.47 microg ml(-1), respectively. DFT15, 15 min after the administration of flecainide, increased from 2.0 to 3.2 J in lidocaine group (mean +/- S.E.M.; P < 0.05), from 2.1 to 3.7 J in mexiletine group (mean +/- S.E.M.; P < 0.05). DFT increased with lidocaine concentrations of 3.42 microg ml(-1) or higher, and mexiletine of 3.60 microg ml(-1) or higher (P < 0.05). In conclusion, both lidocaine and mexiletine elevated the DFT in the dog treated with flecainide, especially with lidocaine in a therapeutic concentration.

Animals↗
PubMed1991

Role of combination drug therapy with a class IC antiarrhythmic agent and mexiletine for ventricular tachycardia.

The combination of mexiletine and a class IC antiarrhythmic agent (encainide, propafenone or flecainide) was evaluated by electrophysiologic testing in 14 patients with a history of sustained ventricular tachycardia whose tachycardia remained inducible during therapy with the class IC drug alone. During the control drug-free state, all patients had inducible ventricular tachycardia, with a mean cycle length of 260 ms (range 190 to 400). During monotherapy with the IC agent the tachycardia remained inducible in each patient, but there was a significant increase in the cycle length to 340 ms (240 to 500) (p less than 0.001). The effective refractory period of the ventricle was not altered. Treatment with mexiletine (oral in 13 and intravenous in 1) was begun and electrophysiologic testing was repeated. Ventricular tachycardia in one patient was rendered noninducible and one patient had arrhythmia aggravation. The tachycardia in the remaining 12 patients remained inducible but its average cycle length increased further to 392 ms (340 to 460) (p = NS). Nine patients had rate slowing and the average cycle length of the ventricular tachycardia in this group was significantly increased (302 to 388 ms, p less than 0.05). The average effective refractory period was significantly increased during combination therapy (267 ms) compared with no drug therapy (235 ms) and therapy with the class IC drug alone (247 ms) (p less than 0.05). After a mean follow-up interval of 22 months, seven patients continue on the combined treatment and have no ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction.

BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) tested the hypothesis that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarizations in survivors of myocardial infarction would decrease the number of deaths from ventricular arrhythmias and improve overall survival. The second CAST study (CAST-II) tested this hypothesis with a comparison of moricizine and placebo. METHODS: CAST-II was divided into two blinded, randomized phases: an early, 14-day exposure phase that evaluated the risk of starting treatment with moricizine after myocardial infarction (1325 patients), and a long-term phase that evaluated the effect of moricizine on survival after myocardial infarction in patients whose ventricular premature depolarizations were either adequately suppressed by moricizine (1155 patients) or only partially suppressed (219 patients). RESULTS: CAST-II was stopped early because the first 14-day period of treatment with moricizine after a myocardial infarction was associated with excess mortality (17 of 665 patients died or had cardiac arrests), as compared with no treatment or placebo (3 of 660 patients died or had cardiac arrests); and estimates of conditional power indicated that it was highly unlikely (less than 8 percent chance) that a survival benefit from moricizine could be observed if the trial were completed. At the completion of the long-term phase, there were 49 deaths or cardiac arrests due to arrhythmias in patients assigned to moricizine, and 42 in patients assigned to placebo (adjusted P = 0.40). CONCLUSIONS: As with the antiarrhythmic agents used in CAST-I (flecainide and encainide), the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful.

Arrhythmias, Cardiac↗
PubMed1984

Characterization of a human liver cytochrome P-450 involved in the oxidation of debrisoquine and other drugs by using antibodies raised to the analogous rat enzyme.

Debrisoquine 4-hydroxylase activity is a prototype for genetic polymorphism in oxidative drug metabolism in humans; approximately 10% of Caucasian populations exhibit the poor metabolizer phenotype, and the clearance of at least 14 other drugs has been shown to be deficient in patients exhibiting this phenotype. Antibodies prepared to a cytochrome P-450 shown to be responsible for debrisoquine 4-hydroxylation in rats were found to inhibit the oxidation of debrisoquine and sparteine, encainide, and propranolol, three other drugs suggested to be associated with this phenotype, in human liver microsomes. The antibodies did not inhibit the oxidation of seven other cytochrome P-450 substrates. The antibodies recognized a single polypeptide of Mr51,000 after combined sodium dodecyl sulfate/polyacrylamide electrophoresis and immunochemical staining of human liver microsomes. The intensity of this band was significantly correlated with debrisoquine 4-hydroxylase activity when liver microsomes from 44 organ donors were examined. Immunoprecipitation of in vitro translation products of total liver RNA revealed major electrophoretic bands corresponding to the cytochrome P-450 in rats and humans. The level of translatable mRNA coding for the debrisoquine-hydroxylating cytochrome P-450 was an order of magnitude less in human liver than in rat liver. The availability of these antibodies provides a biochemical basis for further basic and clinical studies on the role of a particular cytochrome P-450 polymorphism in humans.

Animals↗
PubMed1988

The new antiarrhythmic drugs. How to put them to the best use.

Treatment of cardiac arrhythmia should be specifically aimed at symptom control or reduction in the risk of sudden cardiac death. Until recently, a limited number of antiarrhythmic drugs were available to the practicing physician, but during the last four years, seven new ones were approved. However, these drugs are complex and have different mechanisms of action and potential for adverse effects, so the safety of therapy with them continues to be debated. Although there is little doubt that many of the new drugs (particularly flecainide [Tambocor] and encainide [Enkaid]) are highly effective in suppressing ventricular premature complexes, they should be used with caution, since they also carry a potential for worsening arrhythmia (proarrhythmic effect) and congestive heart failure. Since suppression of arrhythmia has not yet been proven to reduce mortality, care must be taken in evaluating the risk-benefit ratio when prescribing therapy, particularly for patients with less malignant arrhythmias. Careful evaluation of the effects of treatment in individual patients is indicated whenever antiarrhythmic drugs are used. Until important mortality trials have been completed (eg, the Cardiac Arrhythmia Suppression Trial), therapy should be conservative and reserved for patients with severely symptomatic or malignant arrhythmias.

Anti-Arrhythmia Agents↗
PubMed1983

Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification.

The kinetics of onset of rate-dependent depression of maximum rate of depolarisation (Vmax) of guinea-pig ventricular action potentials were studied for nine Class I anti-arrhythmic drugs using standard microelectrode techniques. The drugs were found to fall into three well-demarcated subgroups with "fast" (lignocaine, tocainide and mexiletine), "intermediate" (quinidine, disopyramide and procainamide) and "slow" (flecainide, encainide and lorcainide) kinetics. The "fast" drugs were found to share the ability to markedly prolong the effective refractory period (ERP) relative to the action potential duration (APD). The "slow" drugs had only minor effects on this parameter. The "intermediate" drugs produced small to moderate increases in ERP relative to APD but in addition significantly prolonged APD, which was shortened by the "fast" drugs. Thus, using the parameters of speed of onset of rate-dependent depression of Vmax and APD it was possible to subdivide the nine Class I drugs into three distinct subclasses.

Action Potentials↗
PubMed1988

Selective depression of conduction of premature action potentials in canine Purkinje fibres by class Ib antiarrhythmic drugs: comparison with Ia and Ic drugs.

Microelectrodes were used to record action potentials and to estimate their conduction velocity in canine Purkinje fibres 8-15 mm long mounted in a tissue bath. The effects of varying stimulation rates and protocols were studied in the presence of nine different class I antiarrhythmic drugs at each of two concentrations (high and low therapeutic range). In all cases, as stimulation rate increased (range of cycle lengths 1000 ms to 200 ms), conduction velocity in the presence of a drug fell progressively below that in control solution at the same rate. No major differences in rate dependent behaviour at steady state were observed between the subclasses Ia, Ib, and Ic. Differences were apparent, however, in the rate at which conduction velocity fell after a sudden decrease in cycle length. This was studied using two protocols. In the first of these, the conduction velocity was recorded of each action potential of a 20 beat train induced after a long rest period. In the presence of class Ib drugs (lignocaine, tocainide, and mexiletine) there was a rapid decline within 2-3 beats to a new equilibrium level of conduction velocity. Class Ia drugs (quinidine, disopyramide, and procainamide) required 12-16 beats to achieve equilibrium, and class Ic agents (flecainide, encainide, and lorcainide) produced slow falls in conduction velocity that did not reach equilibrium within the 20 beat trains. The second protocol involved interpolation of increasingly premature extrastimuli. Class Ib drugs progressively slowed conduction of premature beats as the diastolic interval was reduced below 300-400 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1989

Pharmacological characterisation of a re-entry model for atrial tachycardia in conscious dogs.

We studied the effects of intravenously administered autonomic agents, the calcium channel blocker diltiazem, and Class I and III anti-arrhythmic agents on a re-entry model for atrial tachycardia in seven conscious dogs. The model was created by a Y-shaped incision in the intercaval region and front free wall of the right atrium. Acetylcholine (30 micrograms.kg-1) transiently but significantly shortened the cycle length of atrial tachycardia (CL) by 9 (SD 5)% while atropine (0.2 mg.kg-1) alone did not change or terminate the rhythm. Isoprenaline (4 micrograms.kg-1) briefly reduced CL, by 13(6)% whereas propranolol (1 mg.kg-1) alone significantly prolonged the CL and terminated the arrhythmia in 50% of the trials. Diltiazem (200 micrograms.kg-1) did not significantly change the CL. Class Ia agents procainamide (30 mg.kg-1) and quinidine (3.5 approximately 20 mg.kg-1, effective doses) increased CL by 60(30) and 43(28)% respectively and terminated the arrhythmias. Class Ib agents, phenytoin (5 and 10 mg.kg-1, cumulative doses), lignocaine (3.2 approximately 7 mg.kg-1), and mexiletine (6 approximately 20 mg.kg-1), prolonged CL by 31(14), 40(15), and 72(13)%; however, consistent conversion of the rhythm occurred only with mexiletine. Ic agents flecainide (0.5 approximately 3 mg.kg-1) and encainide (0.6 approximately 6.4 mg.kg-1) lengthened the CL by 58(17) and 75(43)% and converted the rhythm in all cases. Class III agents clofilium (0.5 mg.kg-1), d-sotolol (3.2 approximately 20 mg.kg-1), and N-acetylprocainamide (15 approximately 120 mg.kg-1) prolonged the CL by 14(4), 16(5), and 19(7)% and terminated the arrhythmia in all trials. The magnitudes of CL prolongation by the Class III agents were significantly smaller than those by the Class Ia, Ib, or Ic agents. These results show that in this re-entrant model for atrial tachycardia endogenous adrenergic but not cholinergic systems play a major role in maintaining impulse propagation and that calcium channel mediated slow inward currents do not participate in the impulse generation processes. Further, using CL as an index, the model serves as a useful tool for differentiating Class III from Class I anti-arrhythmic activities.

Acetylcholine↗
PubMed1991

Catecholamine release and arrhythmias in acute myocardial ischaemia.

Increased sympathetic activity is assumed to contribute substantially to the occurrence of malignant arrhythmias in patients with coronary heart disease, since the rate of sudden cardiac death is significantly reduced by beta-adrenoceptor blockade, but not by antiarrhythmic agents such as flecainide or encainide. During acute myocardial ischaemia, adrenergic stimulation of the ischaemic myocardium is independent of plasma catecholamines. Rather, it is caused by the combination of excessively high local noradrenaline concentrations and an enhanced responsiveness of the myocyte to catecholamines. Myocardial ischaemia of 15 min duration results in a 100-fold increase in catecholamine concentrations within the extracellular space of the ischaemic zone, a two-fold increase in functionally coupled alpha-adrenoceptors, and a 30% increase in beta-adrenoceptors. Within the first 10 min of ischaemia, the myocardium is protected from excessive catecholamine release. Ischaemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release caused by central sympathetic activation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of ischaemia to more than 10 min, local nonexocytotic catecholamine release becomes predominant. This release is independent of central sympathetic nerve activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and it is not accompanied by the release of sympathetic cotransmitters such as neuropeptide Y. It has been demonstrated to be nonexocytotic and to be caused by a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is not modulated through presynaptic receptors. It is, however, suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic surgical or chemical sympathectomy effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release, such as uptake1 blocking agents or sodium-proton exchange inhibitors, effectively reduce the occurrence of ischaemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic release mechanisms in myocardial ischaemia.

Animals↗
PubMed1989

Propafenone--a new agent for the treatment of ventricular arrhythmias.

Over the last several years a number of new and potent antiarrhythmic agents have been developed. One of these promising new drugs, propafenone hydrochloride (Rhythmol), will soon be available for use in this country. Although similar in some aspects to flecainide and encainide, the drug possesses some unique characteristics. The purpose of this review is to summarize the pharmacologic and physiologic effects of propafenone and to outline its clinical use.

Arrhythmias, Cardiac↗
PubMed1991

Hemodynamic effects of antidysrhythmic drugs.

Antidysrhythmic medications, when administered in the clinical setting, demonstrate a variety of effects on cardiac electrophysiology, inotropy, and peripheral vascular smooth muscle. The resultant hemodynamic effects may be of profound importance to the clinical well-being of the patient being treated for dysrhythmias. The following review will discuss the hemodynamic effects of the Class I agent moricizine; Class IA agents: quinidine, procainamide hydrochloride, and tocainide hydrochloride; Class IC agents: flecainide acetate, encainide hydrochloride, and propafenone; Class II agents: propranolol hydrochloride, esmolol hydrochloride, and acebutolol; Class III agents: bretylium tosylate and amiodarone hydrochloride; as well as the Class IV agent verapamil. Adenosine, an unclassified antidysrhythmic indicated in the treatment of supraventricular tachycardia will also be discussed. Specific attention will be directed toward the use of these agents in patients with left ventricular dysfunction or history of congestive heart failure.

Anti-Arrhythmia Agents↗
PubMed1988

Cellular electrophysiological properties of a new aminosteroid antiarrhythmic agent, SC-35135.

SC-35135 is a structurally unique class I antiarrhythmic agent previously shown to suppress arrhythmias produced by a two-stage coronary artery ligation or by administration of ouabain, but to be arrhythmogenic at high doses. SC-35135 was evaluated in guinea pig papillary muscle using standard microelectrode techniques to record transmembrane action potentials. SC-35135 markedly blocked Vmax (maximum rate of membrane depolarization) as a function of pacing frequency in the concentration range of 3 x 10(-6) to 3 x 10(-5) M, and was without effect on action potential duration. The effective refractory period was significantly shortened only at the highest concentration tested (3 x 10(-5) M). Rate constants for the onset of Vmax block determined at two stimulation rates, 60 and 200 pulses/min, were 0.17 +/- 0.052 and 0.06 +/- 0.005 (action potentials)-1, respectively, in the presence of 10(-5) M SC-35135. The recovery from Vmax depression following a train of stimuli was very slow in the presence of SC-35135. The average time constant for the recovery from block of Vmax after addition of 10(-5) M SC-35135 was 10.2 +/- 0.94 s. SC-35135 caused both a concentration- and stimulation frequency-dependent hyperpolarizing shift in the half point of the relationship between Vmax and resting membrane potential. Slow response (Ca current-dependent) action potentials were not changed by SC-35135 at concentrations less than or equal to 3 x 10(-5) M, indicating a lack of class IV antiarrhythmic activity. The results of these experiments indicate that SC-35135 has electrophysiological properties similar to other previously studied aminosteroid antiarrhythmics such as amafolone and CCI 22277. Its onset and recovery kinetics also resemble the well known class IC antiarrhythmics flecainide, lorcainide, and encainide. The arrhythmogenic activity of SC-35135 has prevented further development of this compound.

Action Potentials↗
PubMed1993

Lidocaine shows greater selective depression of depolarized and acidotic myocardium than propafenone: possible implications for proarrhythmia.

We have previously shown reduced selectivity for depolarized and acidotic myocardium for encainide and flecainide compared to lidocaine and amiodarone. The present study aims to compare propafenone and two of its metabolites (5-OH-propafenone and N-despropyl-propafenone) to lidocaine in the same model. Standard microelectrode methods were used to record intracellular action potentials from strips of guinea pig right ventricular myocardium superfused with either standard physiological saline (pH 7.3; pO2 > 600 mm Hg; [K+] = 5.6 mM), or the same solution modified to produce either hyperkalemia (K+ = 11.2 mM), acidosis (pH = 6.3), or hypoxia (pO2 = 60 mm Hg). The effects on action potential parameters of three "therapeutic" concentrations of lidocaine, propafenone, and two of its metabolites were studied under all four conditions at four different drive rates from 200 to 25 beats/min. Hyperkalemia, in the absence of drugs, produced reductions in the resting potential (-86.7 +/- 2.5 to -71.8 +/- 3.7 mV) and the maximum rate of depolarization (Vmax, 300.0 +/- 46.5 to 205.6 +/- 37.6 V/s). All four drugs produced increased depression of Vmax in hyperkalemia and acidosis compared to control conditions, but it was a consistent finding that at concentrations that were approximately equipotent in control conditions, lidocaine produced greater increments in depression of Vmax in hyperkalemic and acidotic superfusate than did propafenone or either of its metabolites. Qualitatively similar results were obtained for both metabolites compared to lidocaine. Hypoxia produced no significant modulation of drug effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1994

Electrophysiologic effects of detajmium on isolated dog cardiac ventricular and Purkinje fibers.

We studied the electrophysiologic effects of the antiarrhythmic compound detajmium (Tachmalcor) on isolated dog and rabbit cardiac preparations, applying the conventional intracellular microelectrode techniques. In dog ventricular muscle fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium did not change resting potential (RP), action potential amplitude (APA), AP duration measured at 90% of repolarization (APD90), or effective refractory period (ERP) significantly, but reduced maximum rate of depolarization (Vmax) significantly from 236.7 +/- 28.9 to 177.3 +/- 22.5 V/s (n = 6, p < 0.01). In dog Purkinje fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium significantly decreased APA from 111.1 +/- 12.3 to 100.0 +/- 2.5 mV (n = 8, p < 0.003), APD90 from 359.0 +/- 17.5 to 262.1 +/- 12.3 ms (n = 8, p < 0.001) and Vmax from 687.5 +/- 57.2 to 523.7 +/- 58.2 V/s (n = 8, p < 0.001) without changing maximal diastolic potential or ERP/APD ratio significantly. The effect of detajmium on Vmax in both dog ventricular muscle and Purkinje fibers was frequency dependent. Fractional Vmax block was 0.185 +/- 0.008 1/AP. The recovery kinetics of Vmax (offset kinetics) was extremely slow (time constant = 348.16 +/- 57.43 s) considerably slower than most of those of other antiarrhythmic drugs yet reported. Detajmium in concentration < 32 microM did not influence the beta-adrenoceptors or slow response APs in dog ventricular tissue significantly. On the basis of its electrophysiologic effects, detajmium, like prajmaline, encainide, or flecainide, can be best classified as a class I/C antiarrhythmic drug according to the Vaughan Williams' classification scheme.

Action Potentials↗