IC Agents Research Articles

Facilitating electrical cardioversion of persistant atrial fibrillation by antiarrhythmic drugs: update on clinical trial results.

Results from clinical trials suggest that antiarrhythmic drugs (AD) can facilitate electrical cardioversion (EC) for persistent atrial fibrillation (AF) (duration >48 hours, no spontaneous termination) by suppression of immediate reinitiation of AF following the procedure. Class IC agents may increase the atrial defibrillation threshold (DFT) by significantly reducing the availability of Na+-channel for depolarization. In contrast, class III agents may decrease the atrial DFT by markedly prolonging atrial refractoriness. Among all AD, ibutilide and amoidarone have been shown to be most effective in enhancing the acute outcome of EC. In patients who are over 65 years of age at high risks of stroke (e.g., atherosclerotic cardiovascular disease, diabetes, hypertension, previous thromboembolism, etc.), the rhythm control strategy offers no survival advantage over the rate control strategy and frequently subjects patients to serious adverse effects of AD therapy. It can not be overemphasized that adequate anticoagulation (INR 2.0-3.0) with warfarin is needed regardless of whichever strategy is chosen unless there are contraindications. On the other hand, in patients who are under 65 years of age without structural heart disease or other risk factors of stroke, rhythm control can be the treatment of choice. Specifically, if a patient has failed EC alone or if the patient has characteristics (e.g., duration of AF >6 months, left atrium >50 mm, etc.) that EC could fail, AD may be given before the procedure to facilitate EC. In the subgroup of patients who are symptomatic with hypertrophic cardiomyopathy and severe diastolic dysfunction requiring maintenance of sinus rhythm to have sufficient ventricular function for optimization of cardiac output, an aggressive approach for rhythm control with amiodarone along with adequate anticoagulation with warfarin should be encouraged.

Cardiac arrhythmias during pregnancy--what to do?

Atrial premature beats are frequently diagnosed during pregnancy, supraventricular tachycardia (atrial tachycardia, AV nodal reentrant tachycardia, circus movement tachycardia) less frequently. For acute therapy, electrical cardioversion with 50-100 J is indicated in all unstable patients. In stable supraventricular tachycardia, initial therapy includes vagal maneuvers to terminate breakthrough tachycardias. For short-term management, when vagal maneuvers fail, intravenous adenosine is the drug of first choice and may safely terminate the arrhythmia. For long-term therapy, beta-blocking agents with beta(1) selectivity are first-line drugs; class Ic agents or the class III drug sotalol represent effective and therapeutic alternatives. Ventricular premature beats are also frequently present during pregnancy and benign in most of the unstable patients; however, malignant ventricular tachyarrhythmias (sustained ventricular tachycardia, ventricular flutter, ventricular fibrillation) are less frequently observed. Electrical cardioversion is necessary in all patients with hemodynamically unstable situation and life-threatening ventricular tachyarrhythmias; in hemodynamically stable patients, initial therapy with ajmaline, procainamide or lidocaine is indicated. If prophylactic therapy is needed, beta-blocking agents with beta(1) selectivity are regarded as drugs of first choice. If this therapy proves ineffective, class Ic agents or sotalol can be considered. In patients with syncopal ventricular tachycardia, ventricular fibrillation, ventricular flutter or aborted sudden death, an implantable cardioverter-defibrillator is indicated. In patients with symptomatic bradycardia, a pacemaker can be implanted using echocardiography at any stage of pregnancy. The treatment of the pregnant patient with cardiac arrhythmias requires important modifications of the standard practice of arrhythmia management. The goal of therapy is to protect the patient and fetus through delivery, after which chronic or definitive therapy can be administered.

Outpatient prescribing of antiarrhythmic drugs from 1995 to 2000

There is growing evidence that some class III antiarrhythmic drugs, unlike class I agents, are not associated with an increased risk of death in patients with prior myocardial infarction and left ventricular dysfunction. 1‐14 For this reason, we evaluated the extent to which the current prescribing of antiarrhythmic medications complies with the evidence that supports the use of class III rather than class I agents. Using pharmaceutical marketing research data, we reviewed outpatient antiarrhythmic drug prescriptions in the United States from 1995 through the third quarter of 2000, to characterize the prescribing of these drugs and to examine drug use trends over this period. ••• Data on antiarrhythmic drug prescribing were derived from 2 audits owned by IMS Health (Plymouth Meeting, Pennsylvania): the National Prescription Audit (NPA) Plus and the National Disease and Therapeutic Index (NDTI). The NPA Plus audit measures the retail outflow of prescriptions in the United States. This includes prescriptions dispensed by retail pharmacies and mailorder pharmacies. The NDTI audit contains data on drug mentions associated with a diagnosis during a specific clinic visit. These data are collected by a continuing survey of 343,655 physicians in officebased practices in the United States. An NDTI panel of physicians, a subset of 343,655, is selected every 2 weeks to provide demographic information, diagnoses, and recommended drugs for each diagnosis on all patients encountered. This is then projected to the national level. The NPA Plus audit was queried for all class I and class III antiarrhythmic drugs for which an oral dosage form was marketed and sold in the United States between January 1995 and September 2000. The numbers presented for the year 2000 represent a 9-month period. Class I agents included the class IA agents quinidine, procainamide, and disopyramide, the class IB agents mexiletine and tocainide, and the class IC agents flecainide, propafenone, and moricizine. Class III agents included amiodarone and sotalol. We limited this analysis to class I and III antiarrhythmic drugs because it would be difficult to determine whether blockers (class II antiarrhythmic agents) and calcium channel blockers (class IV antiarrhythmic agents) were prescribed solely for an arrhythmic indication. The NDTI audit was queried for all oral class I and class III antiarrhythmic agents strati fied by physician specialty and diagnoses for which the agent(s) was used. Trends in antiarrhythmic drug prescriptions were evaluated based on physician specialty and the diagnosis for which each agent or class of agents was reported to be prescribed.

Oral loading with propafenone for conversion of recent-onset atrial fibrillation: a review on in-hospital treatment.

Atrial fibrillation (AF) is a very common arrhythmia. In order to treat acute AF rapidly, effective drug regimens are required. Propafenone is a class IC antiarrhythmic agent that is suitable for oral loading as it reaches peak plasma concentrations within 2 to 4 hours of administration. The use of propafenone loading in patients with AF must be based on appropriate patient selection in view of the negative inotropic effect and the potential proarrhythmic effects of the drug. A series of controlled trials in patients with recent-onset AF without heart failure who were hospitalised with enforced bed rest has shown that orally loaded propafenone (450 to 600 mg as single dose) exerts a relatively quick effect (within 3 to 4 hours) and a high rate of efficacy (72 to 78% within 8 hours). A potentially harmful effect of class IC agents is the risk of transforming AF into atrial flutter (3.5 to 5% of patients). However, atrial flutter with 1 : 1 atrioventricular response was observed in only two of 709 patients receiving propafenone (0.3% incidence). Nevertheless, the potential negative inotropic effect of propafenone demands careful patient selection, with systematic exclusion of patients with left ventricular dysfunction or congestive heart failure. Oral loading with propafenone can be considered as an episodic treatment in patients with AF recurrences, as has been proposed for other drugs in the past. However, the safety of oral loading with propafenone as an outpatient treatment in appropriately selected patients has to be assessed by appropriately designed prospective studies.

Atrial fibrillation in the elderly: facts and management.

Although atrial fibrillation is not widely known by the general public, in developed countries it is the most common arrhythmia. The incidence increases markedly with advancing age. Thus, with the growing proportion of elderly individuals, atrial fibrillation will come to represent a significant medical and socioeconomic problem. The consequences of atrial fibrillation have the greatest impact. The risk of thromboembolism is well known; other outcomes of atrial fibrillation are less well recognised, such as its relationship with dementia, depression and death. Such consequences are responsible for diminished quality of life and considerable economic cost. Atrial fibrillation is characterised by rapid and disorganised atrial activity, with a frequency between 300 and 600 beats/minute. The ventricles react irregularly, and may contract rapidly or slowly depending on the health of the conduction system. Clinical symptoms are varied, including palpitations, syncope, dizziness or embolic events. Atrial fibrillation may be paroxysmal, persistent or chronic, and a number of attacks are asymptomatic. Suspicion or confirmation of atrial fibrillation necessitates investigation and, as far as possible, appropriate treatment of underlying causes such as hypertension, diabetes mellitus, hypoxia, hyperthyroidism and congestive heart failure. In the evaluation of atrial fibrillation, cardiac exploration is invaluable, including electrocardiogram (ECG) and echocardiography, with the aim of detecting cardiac abnormalities and directing management. In elderly patients (arbitrarily defined as aged >75 years), the management of atrial fibrillation varies; it requires an individual approach, which largely depends on comorbid conditions, underlying cardiac disease, and patient and physician preferences. This management is essentially based on pharmacological treatment, but there are also nonpharmacological options. Two alternatives are possible: restoration and maintenance of sinus rhythm, or control of ventricular rate, leaving the atria in arrhythmia. Pharmacological options include antiarrhythmic drugs, such as class III agents, beta-blockers and class IC agents. These drugs have some adverse effects, and careful monitoring is necessary. The nonpharmacological approach to atrial fibrillation includes external or internal direct-current cardioversion and new methods, such as catheter ablation of specific foci, an evolving science that has been shown to be successful in a very select group of atrial fibrillation patients. Another serious challenge in the management of chronic atrial fibrillation in older individuals is the prevention of stroke, its primary outcome, by choosing an appropriate antithrombotic treatment (aspirin or warfarin). Several risk-stratification schemes have been validated and may be helpful to determine the best antithrombotic choice in individual patients.

The actions of ibutilide and class Ic drugs on the slow sodium channel: new insights regarding individual pharmacologic effects elucidated through combination therapies.

Ibutilide (I) has been reported to block I(k) and to delay inactivation of the slow Na(+) current (S-Na). There is debate about the clinical importance of the latter. Class Ic drugs block the fast Na(+) channel, but their effect on S-Na is uncertain. If Ic treatment before infusion lessened the QT increase with I, this result would suggest both an Ic effect on S-Na and significant S-Na actions of I. We infused I, 2 mg over 30 minutes, to 6 patients pretreated with propafenone (n = 5) or flecainide (n = 1) (group 1) and compared their increase with the QT increase seen with I alone in a combined group of 85 patients from our lab and the multicenter I database (group 2). The QTc increased in group 2, 65 ms, from 413 to 478 ms. This effect was attenuated by 47% in group 1 patients to 34 ms (P <.01). There appeared to be a dose-response relationship between Ic dose and its effects on QTc prolongation. The lowest dose of propafenone had minimal effect on the increase in QTc with I (72 ms), while higher doses of propafenone and high doses of flecainide attenuated the increase to 13 to 39 ms. Nonetheless, ibutilide efficacy was not changed, possibly suggesting differing importance of K(+) channel and slow sodium-channel effects in atrial versus ventricular tissues, and having implications for means to reduce some antiarrhythmic drug proarrhythmia without reducing efficacy. (1) Pretreatment with Ic agents can reduce the increase in QTc seen with I; (2) I's effect in humans appears to be at least partly mediated through the delay of S-Na inactivation; and (3) Ic agents probably inhibit S-Na.

Influence of propafenone on resetting and termination of canine atrial flutter.

Previous studies on atrial flutter (AF) presumed that resetting was due to the prematurity effect (PE) in which the stimulated antegrade wavefront travels in the tail of the AF preexisting wavefront. We studied the collision effect (CE) between the AF and the stimulated retrograde wavefronts, its contribution to resetting, and its relationship to AF termination and how they are affected by the Class IC agent propafenone (PPF). A canine model of AF was created using a Y-shaped lesion in the right atrium in 14 dogs (33 +/- 3 kg). Five atrial bipolar electrodes were positioned around the tricuspid valve. In a subsequent set of 11 dogs, we used 16 bipolar electrodes for recording. AF was induced by burst pacing. Single and multiple stimuli were applied to measure conduction time and reset-response curves (RRCs). This was repeated after the administration of PPF (1 mg/kg loading dose for 10 minutes, followed by 1.8 mg/kg/per hour infusion). Three distinct mechanisms were found to contribute to the RRC: the PE, the CE, and heterogeneity. PPF stabilized the RRC, increased significantly the cycle length (CL), the duration of the effective refractory period, as well as the duration of the excitable gap. However, PPF did not alter the duration of the fully excitable portion. We studied 36 annihilations without and 48 with PPF. Transient fibrillation was found in 75% of the episodes without, compared to 22% with PPF. Other types of termination such as conduction block, CL oscillations, and reversal of activation were found for 25% of the episodes without and 78% with PPF. In many cases, conduction block and CL oscillations were associated with a failure of propagation of the stimulated antegrade wavefront in the region of collision. Termination by reversal of activation suggests that propagation was two dimensional and could not be represented by a one dimensional movement. The average coupling interval (in percent of CL), that induced fibrillation was not significantly different from that at which conduction block occurred. This suggests that transient fibrillation is associated with a weak CE rather than with rapid pacing. The CE is amplified by multiple stimuli and PPF. The incidence of transient fibrillation in AF annihilation diminishes with PPF as the CE becomes more important. This suggests that the evaluation of PE and CE in AF may be an indication of the risk of atrial fibrillation.

Drug choices in the treatment of atrial fibrillation

When considering therapy for atrial fibrillation (AF), the dominant issues are rate control, anticoagulation, rhythm control, and treatment of any underlying disorder. Drug choices for rate control include β-blockers, verapamil and diltiazem, and digitalis as first-line agents, with consideration of other sympatholytics, amiodarone, or nonpharmacologic approaches in resistant cases. Anticoagulation may be accomplished with aspirin or warfarin, with the latter preferred in all older or high-risk patients. Antiarrhythmic drug therapy may be used (1) to produce cardioversion (most effective with ibutilide or class IC agents in recent onset AF); (2) to facilitate electrical conversion (class III agents); (3) to prevent early reversion after cardioversion; (4) to maintain sinus rhythm during chronic therapy; and/or (5) to facilitate conversion of fibrillation to flutter, which may then be amenable to termination or prevention with antitachypacing or ablative techniques. Antiarrhythmic drug selection for AF is guided by efficacy considerations (most drugs are similar), by convenience, cost, and discontinuation considerations; and, most importantly, by safety considerations. When possible, agents with serious organ toxicity potential and proarrhythmic risk should be avoided as first-line choices. In structurally normal hearts, class IC antiarrhythmic drugs are least proarrhythmic and least organ toxic (when considered together). In normal hearts, sotalol, dofetilide, and potentially azimilide also appear to have attractive profiles. Amiodarone has low proarrhythmic risk but can produce bradyarrhythmias and toxicity. In hypertrophied hearts, the risk of torsade de pointes with class III/IA agents is enhanced, whereas in ischemia or conditions with impaired cell contact, whether functionally (as by ischemia) or anatomically (as by fibrosis, infiltration, etc), proarrhythmic risk with class I antiarrhythmic drugs (sustained ventricular fibrillation/flutter) is greatly increased. The class I drugs should be avoided in these circumstances. Additional issues to consider are where to initiate therapy (in- or outpatient), what follow-up protocols to use, and whether to limit therapy to proprietary drugs or to allow generic formulation substitution. Each of these considerations is detailed in this article.

Spatial Correlation Analysis of the Pharmacological Conversion of Sustained Atrial Fibrillation in Conscious Goats by Cibenzoline

The nonlinear spatial redundancy and the linear spatial correlation function were used to investigate to what extent non-linearity was involved in the coupling of atrial regions and how organization in activation patterns of sustained atrial fibrillation (AF) had been modified by administration of the class IC agent cibenzoline in the experimental model of sustained AF in instrumented conscious goats. Electrograms were measured in five goats during sustained AF and when the fibrillation interval had been prolonged to about 25%, 50% and 85% (CIB25, CIB50, CIB85) with respect to control. The nonlinear association length and linear correlation length were estimated along the principal axes of two-dimensional correlation maps estimated from the spatial redundancy and the spatial correlation function, respectively. The estimated short axis association length in the right atrium increased already shortly after the start of infusion (CIB25, +61%), and remained significantly different from control during the experiment, including the effects of non-simultaneous interaction. At CIB85 the association length had almost become twice as long with respect to control (increase from 16 to 29 mm, 89%), while in the left atrium changes were less pronounced (increase from 9 to 12 mm, +32%). The linearized association length which was estimated using multivariate surrogate data increased more gradually and was less sensitive to changes in spatial organization. The results of the spatial correlation analysis suggest that the drug-induced nonlinearity in the spatio-temporal dynamics of sustained AF is related to activation patterns which are characterized by extended uniformly propagating fibrillation wavefronts (AF type I). We conclude that cibenzoline enhanced the spatial organization of sustained AF associated with a transition from type II to type I AF activation patterns. This may destabilize the perpetuation of AF since an increase in association length is equivalent to a reduction of atrial tissue mass available to support reentrant circuits. The results are consistent with the hypothesis that larger association lengths result from fewer and larger reentrant circuits. It is argued that effects of diminished curvature of fibrillation wavefronts are anti-arrhythmic under conditions of suppressed excitability imposed by cibenzoline. Termination of AF may be mediated by a mechanism resembling a bifurcation of the dynamics which sets in when the ends of fractionated wavefronts cannot sufficiently curve anymore to maintain a positive balance of newly generated wavelets needed to sustain AF.

Evolution, mechanisms, and classification of antiarrhythmic drugs: focus on class III actions

Since the use of cinchona bark to treat heart palpitations in the 1700s, antiarrhythmic drug therapy has developed with the discovery of new compounds and the identification of ionic, cellular, and tissue mechanisms of action. Classifications have been developed that organize the large amount of information available about antiarrhythmic drugs around groups of compounds with common mechanisms of action. Despite important and well-recognized limitations, antiarrhythmic drug classification is still widely used. In particularly broad use is the system developed by Singh and Vaughan Williams in the early 1970s and subsequently modified by Singh and Hauswirth and by Harrison. This classification divides drug actions into class I for sodium-channel blockade (with subclasses IA, IB and IC), class II for adrenergic antagonism, class III for action-potential prolongation, and class IV for calcium-channel blockade. The development of class I drugs was curtailed when studies showed that potent sodium-channel blockers (particularly IC agents) can increase mortality in patients with active coronary artery disease. The emphasis in drug development shifted to class III agents, but their use has been limited by the risk of ventricular tachyarrhythmia induction associated with QT prolongation. Current research focuses on the development of new class III drugs that may have improved safety by virtue of greater selectivity of action at faster rates (like those of arrhythmia) or for atrial tissue. Alternative approaches include the modification of existing molecules (like amiodarone) to maintain positive properties while removing undesirable ones, and treatments that target development of the arrhythmia substrate instead of the final electrical product.

Antiarrhythmic drug initiation in patients with atrial fibrillation

Antiarrhythmic drugs remain the mainstay of treatment of atrial fibrillation, but their potential proarrhythmic effects hamper their optimal use. Drug-induced tachyarrhythmias (ventricular tachycardia or atrial tachyarrhythmias with rapid ventricular response) are life-threatening and often cause syncope. Because these events tend to cluster shortly after drug initiation, it is common practice to routinely hospitalize patients for drug initiation under continuous electrocardiographic surveillance. The low incidence of serious proarrhythmia makes the cost-effectiveness of this practice controversial. Torsades de pointes, in particular, can be predicted by the presence of one or more of the following risk factors: female gender, structural heart disease, prolonged baseline QT interval, bradycardia, hypokalemia, previous proarrhythmic responses, and higher drug plasma levels. Proarrhythmia induced by class IC agents is seen almost exclusively in patients with structural heart disease and ventricular dysfunction. A variety of monitoring devices permit electrocardiographic monitoring of patients in the outpatient setting. Efficient clinical pathways for the safe initiation of antiarrhythmic drugs in patients with atrial fibrillation do not require universal hospital admission. In patients without structural heart disease, outpatient initiation of most antiarrhythmic drugs appears safe. In patients with significant structural heart disease, class IC drugs are contraindicated, and most other drugs should be initiated in the hospital under continuous monitoring. The incidence of severe proarrhythmia is very low when loading doses of amiodarone of 600 mg/d or less are given to outpatients with structural heart disease. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 1 (July/August), 1999: pp 75-90

Optimal management with Class I and Class III antiarrhythmic drugs should be done in the outpatient setting: protagonist.

It has been suggested that patients be admitted for the initiation of Class I and Class III antiarrhythmic drugs to avoid serious proarrhythmic consequences. The most clinically significant proarrhythmic response to Class IC agents is likely due to an interaction with acute ischemia, and hospitalization for initiation of drug therapy has little predictive or preventive value. Amiodarone has a low risk of proarrhythmia, and any proarrhythmic reactions are generally delayed. Class IA and Class III antiarrhythmic drugs cause acquired long QT syndrome arrhythmias, which can occur soon after initiation of therapy; however, only about half of the arrhythmic events occur within 3 days of initiation of therapy. It could be argued that all patients should be hospitalized to begin Class IA or Class III drugs; however, this approach has a low yield and is extremely expensive. An alternative is to use Class IA and Class III drugs for patients at low risk of torsades de pointes (e.g., males without heart failure, ventricular tachyarrhythmias, or active coronary disease), in whom hospitalization for drug initiation is not warranted. Higher risk patients are probably better treated with other agents, such as Class IC drugs or amiodarone for women without organic heart disease and amiodarone for patients with heart failure, a history of ventricular tachycardia, or active coronary disease. When a Class IA or Class III drug is required for patient with an increased risk of torsades de pointes, hospital admission for drug initiation may be indicated.

Treatment of cardiac arrhythmias during pregnancy: safety considerations.

Maternal and fetal arrhythmias occurring during pregnancy may jeopardise the life of the mother and the fetus. When arrhythmias are well tolerated and patients are minimally symptomatic, conservative therapy, such as observation and rest or vagal manoeuvres, should be employed. When arrhythmias cause debilitating symptoms or haemodynamic compromise, antiarrhythmic drug therapy is indicated. Although no antiarrhythmic drug is completely safe during pregnancy, most are well tolerated and can be given with relatively low risk. Physiological changes that occur during pregnancy mandate caution when administering antiarrhythmic drugs, with close monitoring of serum concentration and patient response. Drug therapy should be avoided during the first trimester of pregnancy if possible, and drugs with the longest record of safety should be used as first-line therapy. Several therapeutic options exist for most arrhythmias in the mother and fetus. Of the class IA agents, quinidine has the longest record of safety during pregnancy, and is generally well tolerated. Procainamide is also well tolerated, and should be a first line option for acute treatment of undiagnosed wide complex tachycardia. All IA agents should be administered in the hospital under cardiac monitoring due to the potential risk of ventricular arrhythmias (torsade de pointes). The IB agent, lidocaine (lignocaine), has local anaesthetic role but is also generally well tolerated as an antiarrhythmic agents. Phenytoin should be avoided due to the high risk of congenital malformations and limited role as an antiarrhythmic drug. Of the IC agents, flecainide has been shown to be very effective in treating fetal supraventricular tachycardia complicated by hydrops. Beta-Blockers are generally well tolerated and can be used with relative safety in pregnancy, although recent data suggest that they may cause intrauterine growth retardation if they are administered during the first trimester. Amiodarone, a class II agents with characteristics of the other antiarrhythmic drug classes, has been reported to cause congenital abnormalities; it should be avoided during the first trimester and used only to treat life-threatening arrhythmias that fail to respond to other therapies. Adenosine is generally safe to use in pregnancy, and is the drug of choice for acute termination of maternal supraventricular tachycardia. Digoxin has a long track record of treating both maternal and fetal arrhythmias, and is one of the safest antiarrhythmics to use during pregnancy. Direct current cardioversion to terminate maternal arrhythmias is well tolerated and effective, and should not be delayed if indicated. The use of an implantable cardioverter-defibrillator should be considered for women of childbearing potential with life-threatening ventricular arrhythmias.

Identification of the to×ic agent in metal-contaminated sediments from Manitouwadge Lake, Ontario, using to×icity–accumulation relationships in &lt;I&gt;Hyalella azteca&lt;/I&gt;

Identification of the to×ic agent in metal-contaminated sediments from Manitouwadge Lake, Ontario, using to×icity–accumulation relationships in &lt;I&gt;Hyalella azteca&lt;/I&gt;

The Rise Time of the Monophasic Action Potential

The kinetics of global use-dependent conduction slowing produced by sodium channel blockers in the human heart, estimated as a change in the QRS width, are known to be similar to those of use-dependent block of the maximum rate of depolarization in in vitro studies. However, the kinetics of the regional use-dependent decrease in conductivity have not been investigated. We examined whether the rise time of the monophasic action potential would be clinically useful as a marker of the local use-dependent decrease in conductivity by sodium channel blockers. In 12 patients without organic heart disease, monophasic action potentials (MAPs) were recorded at the right ventricular endocardium using a contact electrode before and after the administration of disopyramide (n = 6, 2 mg/kg, i.v.) or pilsicainide (class Ic agents, n = 4, 1 mg/kg, i.v., and n = 2, 150 mg, po) while the stimulus frequency was abruptly increased from 100/min to 150/min. The rise time, defined as the interval from the pacing pulse to the first peak deflection of the monophasic action potential, and the ORS width were measured simultaneously. In the absence of the sodium channel blockers, the abrupt increase in heart rate did not alter the QRS width or the rise time. In the presence of the agents, both variables were lengthened exponentially. The rate constants of onset changes in the QRS width and the rise time were 2.1 +/- 0.5 beats and 2.1 +/- 0.4 beats after the administration of disopyramide, and 7.5 +/- 3.0 beats and 8.2 +/- 4.0 beats after pilsicainide, respectively. The rate constant of the rise time was closely correlated with that of the QRS width. The present results are very closely comparable with the onset rate constants of use-dependent block of the maximum rate of depolarization in in vitro studies. These results suggest that (1) the rise time is a good indicator of local use-dependent decrease in conductivity by sodium channel blockers in human hearts and (2) the local use-dependent decrease in conductivity has kinetics similar to those of use-dependent sodium channel blocks.

The differentiation of propafenone from other class Ic agents, focusing on the effect on ventricular response rate attributable to its beta-blocking action.

Propafenone, encainide and flecainide have been categorized as class Ic antiarrhythmic drugs, since they produce similar clinical electrophysiological effects. However, propafenone has also modes of action that differ substantially from pure class Ic activity. The most distinctive electrophysiological difference from other class Ic antiarrhythmic drugs stems from its structural similarity with other beta-adrenoceptor antagonists. The potency of the beta-adrenoceptor blocking property of propafenone has been estimated to range from 1/20 to 1/50 that of propranolol on a molar basis. Because the plasma concentrations of propafenone during long-term treatment may be up to 50 or more times that of propranolol, the beta-adrenoceptor blocking effect may be clinically relevant. However, although the beta-adrenoceptor blocking effects are readily demonstrable in vitro, clinical data are more inconsistent, because the beta-adrenoceptor blocking action has been reported as being undetectable to significant. During atrial fibrillation, with or without accessory pathways, propafenone exerts effective and prompt control of the ventricular rate in patients who fail to convert to sinus rhythm. However, compared with other class Ic antiarrhythmic drugs, propafenone has not been proved generally better in controlling the ventricular rate.

Effects of oral propafenone on defibrillation and pacing thresholds in patients receiving implantable cardioverter-defibrillators

The effects of propafenone, a predominantly class IC antiarrhythmic drug, on defibrillation and pacing thresholds were evaluated in patients undergoing cardioverter-defibrillator implantation. 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. 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. 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. 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.

Prevention of class III-induced proarrhythmias by flecainide in an animal model of the acquired long QT syndrome.

The influence of the class Ic agent, flecainide, on the incidence of class III-induced torsades de pointes was examined in an animal model of the acquired long QT syndrome. Twenty-four chloralose-anaesthetized rabbits were pretreated at random with flecainide or vehicle and subsequently given a concomitant infusion of methoxamine and the class III antiarrhythmic agent almokalant. In seven out of eight vehicle-treated rabbits, almokalant induced torsades de pointes which was preceded by a significant lengthening of the JTU interval (used as an indirect measure of ventricular repolarization time) by 55 +/- 9.2 msec. Flecainide dose-dependently reduced the incidence of almokalant-induced torsades de pointes. Hence, in a group of rabbits given a low dose (0.14 mumol/kg + 1.4 mumol/kg/hr) of flecainide, four out of eight animals experienced torsades de pointes (P = 0.1538 versus vehicle) whereas no case (n = 8) was observed after a higher dose (4.8 mumol/kg + 4.8 mumol/kg/hr, P = 0.0007). In the former group almokalant induced a maximal increase in the JTU interval not differing from that seen in the vehicle-treated group (58 + 12.1 msec, P > 0.05). Pretreatment with the high dose of flecainide, however, caused a significant attenuation of the almokalant-induced lengthening of the JTU interval (18 +/- 6.5 msec. P < 0.05). It is concluded that flecainide reduces the risk of proarrhythmia in the setting of delayed repolarization partially by attenuating the primary electrophysiological effect of class III agents.

964-11 Circadian Variation of Ventricular Arrhythmias is of Importance for Effective Drug Therapy

With regard to the restrictive and safe use of class I-antiarrhythmics (AA) clinical criteria predicting drug efficacy and safety have become important. In 140 pts (102 men, 63 ± 7 years) with frequent and symptomatic, but not life-threatening arrhythmias (VA; &gt; 30/h) occurrence, reproducibility and therapeutic consequences of a circadian distribution (CD) of single/repetitive VA was studied. Pts underwent 3 24 h-Holter recordings at baseline, after 2 weeks of placebo and after 6 weeks of dose-titrated antiarrhythmic therapy. 67/140 pts (48%) had reproducible day-night CD (daytime VA increase: 50/67 pts, 75%). In Cox's regression analysis CD was characteristic of a lower VA rate (p &lt; 0.05), but more frequent tachycardia episodes (risk: 3.8 times, p &lt; 0.05) and a lower ejection fraction. AA response was better in pts with CD (3.3 times, p &lt; 005). Day-/night CD pattern was also predictive for a superior response of class IA or IC agents (Fig.). CD of VA is common in half of the pts with symptomatic VA. When class I agents are used. CD provides clinical evidence for selection of the most effective AA and dose and may help to improve overall antiarrhythmic benefit.

Non-Neuroleptic Pharmacotherapy of Schizophrenia

Patients with schizophrenia are typically treated with a neuroleptic and some form if psychosocial intervention. In spite if optimum treatment, up to one-third ifpatients continue to remain severely disabled due topersistent positiveornegativesymptoms. A varietyifdrugs have been triedas alternativesor additions to traditional neuroleptics in thesepatients. This paperis a review ifthese nonneuroleptic treatment alternatives and an attempt to establish someguidelines.for their use. The cur re nt approac h to treatm ent of patien ts wit h schizophreni a is a combinat ion of medi cation a nd psych osocial int ervention; this approach has yie lde d the best res ults ( I). The efficacy of medi cation is well documented (2) , ye t up to 30% of patients who have had opt im um tria ls of neu rol eptics continue to expe rience posit ive or negative sym pto ms, or di spl ay un con trolled behavior (2) . Pa t ie nts wh o do not respond ade quate ly to neuroleptics may be severe ly impai red du e to persisten t sym pto ms . They may also develop significa nt side effects like ta rdive dyskinesia . It is, th erefore, ext reme ly importa n t th a t alternat ive therapies be developed to br ing th ese sym pto ms under con trol. Seve ra l t rials invo lving non neurolept ic agents ha ve been carried out with va rying results. Can these resu lts be exte nde d to involve all neuroleptic resist ant patients? How does one decid e which pa tien t to match with whi ch drug? This paper is a n a t te m pt to t ry to answer these q uest ions and also to review th e th erap eutic modalities avail abl e for th e neu roleptic resis tant pa tient. Kane et al (3) defin ed neuroleptic resist ance as occurring in a patient who cont inued to expe rie nce significan t impairment fro m sympto ms of the illn ess in spite of trials of at least 3 different neuroleptics, from 2 di fferent chemica l cla sses, for six weeks each, in doses of up to 1,500 mgs of chlorpro maz ine eq uiva lent, over th e last 5 yea rs, a fte r organi c pathology had been rul ed ou t. This defini tion of resist ance appears to be com pre he nsive and is wid ely used . Sho uld blood levels be a part of th e definition of resistance? At this stage, testing for blood levels of neuroleptics is not routinely us ed in clinical se t t ings because both actual resul ts a nd test ing techniques Sajiv J ohn, M.D. is a PGY-3 resid ent in the Dep artmen t of Psychi a t ry a t th e Univers ity of C hicago. Atul Mahab leshwarka r, M.D . is an In struct or in the Depart ment of Psych iat ry a t Fin ch U nivers ity of Health Sciences in C hicago.