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PubMed1992

Effect of antiarrhythmic drugs on choline uptake in cardiac cells in culture.

OBJECTIVE: The aim was to examine the effect on choline uptake of various antiarrhythmic drugs: lignocaine, tocainide, encainide, flecainide, propafenone, procainamide, N-acetylprocainamide, bretylium, and amiodarone. METHODS: Cardiac ventricular myocytes from 7 d old chick embryos were exposed in culture to these drugs, at concentrations ranging from 10(-6) to 10(-4) M, for 24 h. Myocyte choline uptake was assessed by the addition of methyl [3H] choline to media. After 120 min, media were removed, the cells were harvested, and intracellular [3H] actively was counted. RESULTS: Lignocaine and tocainide produced a significant (p less than 0.05) dose dependent increase in intracellular [methyl 3H] choline. Encainide produced a small increase and flecainide a small decrease in choline, neither of which was dose dependent. Propafenone significantly (p less than 0.05) altered choline uptake: at 10(-6) M and 10(-5) M choline uptake was increased and at 10(-4) M it was decreased. Amiodarone produced a marked and significant (p less than 0.05) dose dependent reduction in choline uptake. Bretylium, procainamide, and N-acetylprocainamide did not alter myocyte choline. CONCLUSIONS: Choline incorporation into cardiac myocyte is altered by some antiarrhythmic drugs, suggesting this may be part of their antiarrhythmic properties.

Amiodarone↗
PubMed1991

Effects of hyperkalemia, acidosis, and hypoxia on the depression of maximum rate of depolarization by class I antiarrhythmic drugs in guinea pig myocardium: differential actions of class Ib and Ic agents.

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 greater than 650 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 concentration of lidocaine, flecainide, and encainide were studied under all four conditions at four different drive rates (interstimulus interval = 2,400, 1,200, 600, and 300 ms). Hyperkalemia in the absence of drugs produced reductions in resting potential (-87.9 +/- 3.8 to -74.6 +/- 3.3 mV), maximum rate of depolarization (316 +/- 68 to 240 +/- 12 V/s), and action potential duration (178 +/- 21 to 165 +/- 27 ms). All three drugs produced increased depression of Vmax in hyperkalemia compared to control conditions but, at all three concentrations and all four rates, this enhancement of effect was greater for lidocaine than for either of the other two agents (which did not differ significantly from each other; p less than 0.001). Similar though less marked effects were produced by acidosis (3.5 mV depolarization and 19% reduction in Vmax), and once again the depression of Vmax by lidocaine was enhanced more by this intervention than were the actions of encainide or flecainide (p less than 0.01). Hypoxia had no effect on action potential parameters other than duration and no significant modulation of drug actions was seen for this intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1995

Antifibrillary action of class I-IV antiarrhythmic agents in the model of ventricular fibrillation threshold of anesthetized guinea pigs.

We compared the effects of class I-IV antiarrhythmic agents on the ventricular fibrillation threshold (VFT) induced by electrical stimulation directly on the myocardium in anesthetized, open-chest guinea pigs. VFT was assessed by determining the intensity (mA) of electrical current required to induce ventricular fibrillation (VF) and is expressed as a percentage change of the baseline premedication value. The following antiarrhythmic agents or their solvent were administered intravenously (i.v.) to pentobarbital-anesthetized animals (n = 6-12 per group): class I antiarrhythmic agent encainide (1.5 mg/kg); class II antiarrhythmic agents atenolol (2.5 mg/kg), metoprolol (2.5 mg/kg), and nebivolol (2.5 mg/kg); class III antiarrhythmic agents dofetilide (0.08 mg/kg), terikalant (0.04 mg/kg), and DL-sotalolol (10 mg/kg); and class IV antiarrhythmic agent verapamil (0.16 mg/kg). The antiarrhythmic compounds or their solvents resulted in the following changes in the VFT at 15 min after treatment: saline control, 1 +/- 14% (mean +/- SEM) from its baseline value; 10% hydroxypropyl-beta-cyclodextrine (CD), 4 +/- 13%; encainide, 183 +/- 46% (p < 0.05 vs. saline); atenolol, 66 +/- 23% (p > 0.05 vs. saline); metoprolol, 89 +/- 25% (p > 0.05 vs. saline); nebivolol, 224 +/- 58% (p < 0.05 vs. 10% CD); DL-sotalol, 485 +/- 119% (p < 0.05 vs. saline); dofetilide, 357 +/- 69% (p < 0.05 vs. saline); terikalant, 487 +/- 183% (p < 0.05 vs. saline), and verapamil, -17 +/- 21% (p > 0.05 vs. saline). At the doses used, all compounds significantly reduced heart rate (HR).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1984

Metabolites of cardiac antiarrhythmic drugs: their clinical role.

Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influence the rate of production of active metabolites and consequently influence the clinical efficacy of these drugs. Another consideration that deserves attention is the question of drug interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone↗
PubMed1995

Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I.

OBJECTIVE: To determine whether an interaction between encainide or flecainide and intercurrent ischaemia could account for the observed increase in cardiac and sudden deaths in the study group in the Cardiac Arrhythmia Suppression Trial (CAST) I. DESIGN: CAST I was a randomised, double blind, placebo controlled study in which patients received the drug which suppressed at least 6 premature ventricular contractions per minute by 80% or episodes of non-sustained ventricular tachycardia by 90%. Arrhythmic sudden death or aborted sudden death were the study end points. Measured secondary end points included recurrent myocardial infarction, new or increasing angina pectoris, congestive heart failure, and syncope. The CAST I database was analysed to determine which of three end points occurred first--cardiac death or cardiac arrest, angina pectoris, or non-fatal recurrent infarction. They were regarded as mutually exclusive end points. The triad of cardiac or sudden arrhythmic death plus congestive heart failure and syncope was similarly analysed. RESULTS: It was assumed that recurrent non-fatal infarction and new or increasing angina pectoris were ischaemic in origin. The sum of these non-fatal ischaemic end points and sudden death were nearly identical in the placebo group (N = 129) and the treatment group (N = 131). The one year event rate in each group was 21%. However, the treatment group had a much greater fatality rate (55 v 17; P < 0.0001) than the placebo group. The same relation was found when the data were examined on the basis of drug exposure rather than intention to treat. The temporal and circadian events were similar in each group and were consistent with an ischaemic pattern. No such patterns emerged from analysis of the presumed non-ischaemic end points of congestive heart failure and syncope. CONCLUSIONS: These data suggest that the interaction between active ischaemia and treatment with encainide or flecainide may have been responsible for the increased mortality seen in the treatment group in CAST I. This conversion of a non-fatal to a fatal event emphasises the need for future antiarrhythmic drugs to be screened in ischaemic models.

Angina Pectoris↗
PubMed1989

Relation of baseline characteristics to suppression of ventricular arrhythmias during placebo and active antiarrhythmic therapy in patients after myocardial infarction.

In the Cardiac Arrhythmia Pilot Study (CAPS), patients early (6-60 days) after acute myocardial infarction (MI) with ventricular premature complexes (VPCs) of over 10 per hour were randomized to receive, unaware, therapy with one of four antiarrhythmic drugs (n = 402) or placebo (n = 100). Treatment success was defined as 70% or more decrease in VPC rate and 90% or more decrease in VPC runs. If the first active drug was ineffective, a second drug was given. If placebo was ineffective, a second placebo was given. To determine whether or not baseline clinical characteristics predict the response to antiarrhythmic therapy, 10 baseline variables were selected for investigation: age, prior MI, time from CAPS MI to randomization, ejection fraction, baseline VPC frequency, presence of runs (greater than or equal to 3 consecutive VPCs, greater than or equal to 100 beats/min), beta-blocker therapy, digitalis therapy, MI transmurality, and MI location. At the end of the first drug treatment, apparent treatment success in patients receiving placebo was associated on univariate analysis with absence of prior MI, with trends for younger age and Q wave MI, whereas in patients receiving active therapies, higher ejection fraction and younger age were associated with better suppression. In the encainide and flecainide treatments, where the greatest response was observed, absence of prior MI, higher ejection fraction, and younger age were associated with more successful treatment. In a multivariate analysis with these variables, ejection fraction and age remained significant for all active therapies, absence of prior MI and ejection fraction remained significant in the encainide and flecainide treatments, and absence of prior MI in the placebo treatment. Few variables except ejection fraction were associated with VPC suppression during the 1-year follow-up, and only lower ejection fraction and older age related to loss of long-term suppression. Thus, there are only a few independent baseline clinical variables (notably, ejection fraction) that substantially affect antiarrhythmic drug efficacy in suppressing VPCs in patients early after MI. Some variables, however, may be associated with spontaneous arrhythmia variability, leading to an apparent (placebo) response. These findings will be helpful in designing and interpreting treatment studies in patients after MI.

Anilides↗
PubMed1992

Suppression of longitudinal versus transverse conduction by sodium channel block. Effects of sodium bolus.

BACKGROUND: Arrhythmias resulting from treatment with sodium channel-blocking antiarrhythmic drugs have been successfully treated with sodium infusion, although the mechanism underlying this effect is uncertain. METHODS AND RESULTS: In this study, we used a multielectrode array to examine the effects of O-desmethyl encainide (ODE), a potent sodium channel-blocking metabolite of encainide, on conduction in canine ventricle. ODE depressed both longitudinal and transverse conduction velocities in a plasma concentration-related fashion (r = -0.74, -0.60; p less than 0.001). At ODE concentrations less than or equal to 300 ng/ml (n = 34), conduction velocity was depressed to the same extent in the longitudinal (-21.9 +/- 8.4%, SD) and transverse orientations (-22.0 +/- 8.8%). However, at concentrations greater than 300 ng/ml (n = 17), conduction was significantly more impaired longitudinally than transversely (-44.5 +/- 11.7% versus -34.4 +/- 13.7%, p less than 0.02). In 12 animals with high concentrations (mean, 432 +/- 32 ng/ml), a 5-meq/kg bolus of sodium chloride over 1 minute immediately increased conduction velocity; this effect was significantly greater and longer lasting in the longitudinal orientation. In two animals, conduction block in the longitudinal orientation was documented at high plasma ODE and was immediately reversed by sodium bolus. CONCLUSIONS: We conclude that the major effect of sodium in animals with excess sodium channel block is improvement of longitudinal propagation; this effect may underlie the antiarrhythmic action of sodium in the analogous clinical setting.

Animals↗
PubMedDate not supplied

Clinical pharmacokinetics of the newer antiarrhythmic agents.

This article reviews clinical pharmacokinetic data on 8 new antiarrhythmic agents. Some of these drugs have been studied extensively while others are relatively new, with incomplete data due to limited evaluation. Amiodarone is a class III antiarrhythmic drug which is effective in treating many atrial and ventricular arrhythmias that are refractory to other drugs. Amiodarone accumulates extensively in tissues and its disposition characteristics are best described by models with 3 and 4 compartments. Its apparent volume of distribution is very large (1300 to 11,000L) and its elimination half-life very long (53 days). A delay of up to 28 days from of treatment to onset of antiarrhythmic effect may be observed, and the antiarrhythmic effect may persist for weeks to months following cessation of therapy. Clinically significant drug interactions have been observed with amiodarone and warfarin, digoxin, quinidine and procainamide. Encainide is a class Ic antiarrhythmic drug. Although it has a short elimination half-life (1 to 3h), 2 major metabolites with antiarrhythmic effects accumulate in the plasma of patients during long term therapy. Plasma concentrations of O-demethyl encainide appear to correlate with the antiarrhythmic effect. Flecainide, another class Ic antiarrhythmic agent, has an elimination half-life of 14 hours which makes it suitable for twice daily dosing. Flecainide elimination is prolonged in patients with low output heart failure. Significant drug interactions with digoxin and cimetidine have been reported. Lorcainide is also a class Ic antiarrhythmic drug, the bioavailability of which is nonlinear. Clearance of the drug is reduced during long term therapy. A major active metabolite, norlorcainide, accumulates in the plasma of patients during long term therapy and its concentration exceeds that of lorcainide by a factor of 2. The elimination half-lives of lorcainide (9h) and norlorcainide (28h) allow for once or twice daily dosing. Mexiletine, a class Ib antiarrhythmic drug, is structurally similar to lignocaine (lidocaine). A sustained release formulation provides effective plasma concentrations when administered twice daily. The apparent volume of distribution of mexiletine is 5.0 to 6.6 L/kg, and the elimination half-life varies from 6 to 12 hours in normal subjects and from 11 to 17 hours in cardiac patients. Mexilitine is extensively metabolised but the metabolites are not pharmacologically active. Renal elimination of mexiletine is pH dependent. Drugs which induce hepatic metabolism significantly alter the pharmacokinetics of mexiletine.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone↗
PubMed1992

Treatment of ventricular arrhythmias after CAST.

OBJECTIVE: The primary objective of this article is to review the management of ventricular arrythmias in the light of the unfavourable results reported in the Cardiac Arrhythmia Suppression Trial (CAST). STUDY SELECTION, DATA EXTRACTION AND SYNTHESIS: CAST tested the hypothesis that suppression of ventricular arrhythmias recorded on a Holter monitor in patients with myocardial infarction would lead to a decrease in subsequent mortality, presumably by preventing sudden death. In the trial, patients with a myocardial infarction which occurred six days to two years previously and with asymptomatic ventricular premature beats which could be suppressed by one of the antiarrhythmic agents flecainide, encainide or moricizine, were randomised to treatment with one of these agents or placebo. Over a mean follow-up period of 10 months, mortality was significantly higher in those patients receiving flecainide or encainide than in those receiving placebo. On the recommendation of the Data and Safety Monitoring Board the trial in these groups was terminated. More recently CAST II in which moricizine was compared to placebo was also terminated, again because of a higher mortality in the patients receiving active treatment. It is likely that much of the excess mortality can be attributed to proarrhythmic effects of the agents. CONCLUSION: Current management of ventricular arrhythmias are considered in the light of these findings. CAST suggests that specific treatment should be dictated by the presence of associated symptoms and as much by associated structural heart disease as the arrhythmia per se. In particular, specific treatment of ventricular premature beats alone should be avoided. In those with potentially lethal ventricular arrhythmias, referral for appropriate investigation and consideration of non-pharmacological measures is necessary.

Anti-Arrhythmia Agents↗
PubMed1991

A critical appraisal of the cardiac arrhythmia suppression trial (CAST).

The presence of ventricular ectopic activity in the post-myocardial infarction patient, especially associated with left ventricular dysfunction, has been associated with a high incidence of sudden cardiac death. To test the PVC hypothesis, that PVC suppression in asymptomatic patients with ventricular arrhythmias post-myocardial infarction might reduce sudden death rate, the cardiac arrhythmia suppression trial (CAST) was performed. In patients treated with encainide or flecainide, total mortality at 10 months was 7.7% compared to only 3% overall mortality on placebo. The increase in mortality and sudden cardiac death with these two drugs raised the question of whether PVC suppression in this group of patients should be attempted. In addition, the extrapolation of the results of this study to other patient groups has resulted in a change of our antiarrhythmic prescription habits. Criticism of the CAST study has included a low placebo mortality, which may have been secondary to entry of low-risk groups of patients, deaths in the open label titration groups not being included, and recent advances in thrombolysis and revascularization. In addition, this low placebo mortality may have been explained by the concept that drug-responsive arrhythmias may have more benign prognosis. The above results suggest that, except for the use of beta blockers, benefits of other anti-arrhythmic drug treatment in the post-infarction patient with asymptomatic benign and potentially lethal ventricular arrhythmias is questionable. Flecainide and encainide should be avoided in this group of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1992

[Combination anti-arrhythmic drug therapy].

Antiarrhythmic treatment with single agents is often ineffective and can be limited by dose-dependent side-effects. Therefore, combinations of antiarrhythmic drugs in smaller and well-tolerated doses are advocated in cases refractory to single antiarrhythmic drugs. Basically, substances belonging to the same electrophysiologic class should not be combined. A combination of beta-adrenoreceptor blockers with class I antiarrhythmic drugs may be effective, mainly in cases in which the arrhythmia is dependent on adrenergic stimulation. As shown in our study, the combination of class III and I B-substances can be useful in some cases, from the electrophysiological and clinical points of view. Among the successful combinations of this type are amiodarone and mexiletine, sotalol and mexiletine, and sotalol and tocainide. In patients refractory to amiodarone alone or to a combination with mexiletine, the combined treatment with amiodarone and class-I-C drugs such as flecainide and encainide prolongs the cycle length of ventricular tachycardia, but does not suppress induction of ventricular tachycardia during programmed stimulation. Combination therapy with amiodarone and encainide is associated with a remarkable incidence of proarrhythmic effects. Nevertheless, a combination of antiarrhythmic drugs improves efficacy of therapy in selected patients. However, a close monitoring is mandatory because of the risk of proarrhythmia.

Amiodarone↗
PubMed1995

Proarrhythmia of a class Ic drug: suppression by combination with a drug prolonging repolarization in the dog late after infarction.

Encainide treatment in patients after myocardial infarction is associated with increased risk of sudden cardiac death. This may relate to drug-induced changes in the electrophysiologic milieu, thus predisposing the patient to sustained ventricular tachyarrhythmias. The goals of this study were to first develop a model of class Ic-induced ventricular tachycardia (VT) and then to design treatments to oppose this prodysrhythmic activity. Dogs with time-dependent loss of inducible sustained VT in the antiarrhythmic drug-free state were studied late after infarction. These dogs received a series of three loading and maintenance infusions of O-demethyl encainide (ODME) to achieve concentrations of 60 +/- 31, 136 +/- 46 and 339 +/- 171 ng/ml. Drug maintenance continued until programmed stimulation induced monomorphic sustained VT. When ODME infusion allowed this induction, barium chloride infusions were added. ODME treatment allowed induction of monomorphic sustained VT in 9 of 10 dogs studied. Prodysrhythmic monomorphic VT was significantly related (P < .01) to prolongation of conduction velocity in the peri-infarct zone. ODME modestly increased ventricular refractoriness at some but not all peri-infarct sites. Infusion of barium chloride in the above nine dogs caused their hearts to return to the noninducible state. Prolongation of refractoriness in the peri-infarct zone was correlated to this suppression of prodysrhythmia. Prolongation of conduction velocity in the absence of substantial prolongation of refractoriness may underlie ODME-facilitated induction of monomorphic VT. Prolongation of refractoriness in the peri-infarct zone by combination treatment with barium chloride reversed prodysrhythmic VT in all of the dogs.

Animals↗
PubMed1996

The Cardiac Arrhythmia Suppression Trial: Implications for nursing practice.

BACKGROUND: Care of patients with ventricular arrhythmia after myocardial infarction requires careful nursing management, including assisting with arrhythmia monitoring and testing. Because ventricular premature depolarization is a known risk factor for sudden cardiac death, it was hypothesized that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarization would improve survival in these patients. OBJECTIVE: To review the Cardiac Arrhythmia Suppression Trial findings and provide implications for nursing practice for patients after myocardial infarction. METHODS: The Cardiac Arrhythmia Suppression Trial was a multicenter, randomized, placebo-controlled trial designed to determine whether the suppression of ventricular premature depolarizations in postmyocardial infarction patients would improve survival. Three class I antiarrhythmic drugs were used: encainide, flecainide, or moricizine. Patients for whom the drug suppressed their arrhythmia 80% or more were randomly assigned to that drug and dose or its matching placebo and were followed every 4 months (main study). Patients with 1% to 79% suppression were randomly assigned to the drug or its placebo that best treated their arrhythmia and followed every 4 months. RESULTS: Suppression of asymptomatic or mildly symptomatic ventricular premature depolarization in patients using encainide, flecainide, or moricizine failed to improve patient survival and was even harmful in some cases. CONCLUSIONS: Our results showed that in the absence of effective antiarrhythmic drug therapy, supportive nursing care and arrhythmia monitoring is important until appropriate therapy for the management of these arrhythmias in patients who have had a myocardial infarction can be found. Clinical trials are essential to provide an evaluation of therapies and direction for further studies, as well as a basis for practicing clinicians.

Aged↗
PubMed1993

Data monitoring in the cardiac arrhythmia suppression trial.

OBJECTIVE: This report discusses practical aspects of data monitoring in a clinical trial which stopped ahead of schedule due to adverse findings. DESIGN: A review of the considerations and decisions made by the data-monitoring committee of the Cardiac Arrhythmia Suppression Trial (CAST), a randomized, double-blind clinical trial. PATIENTS: CAST consisted of men and women with a recent myocardial infarction, asymptomatic or minimally symptomatic ventricular arrhythmias, and reduced left ventricular ejection fraction. INTERVENTIONS: In CAST, 3 antiarrhythmic agents, encainide, flecainide, and moricizine, were compared against placebo. MAIN OUTCOME MEASURES: The main outcome measures in CAST were arrhythmic death and total mortality. RESULTS: CAST found the 3 agents to be harmful. Encainide and flecainide were stopped first. Subsequently, moricizine was discontinued ahead of schedule. CONCLUSIONS: The complexity of the study design and a midcourse protocol modification raise several data-monitoring issues not previously discussed. These include how to handle apparently dramatic yet unexpected results, the need for flexibility in modifying study design and goals, and the conflict between existing study data and both conventional wisdom and medical practice.

Anti-Arrhythmia Agents↗
PubMed1990

A comparison of antiarrhythmic drugs for the suppression of ventricular ectopic depolarizations: a meta-analysis.

This article reports the results of a meta-analysis of the effectiveness of antiarrhythmic drugs for the suppression of ventricular ectopic depolarizations. We analyzed 97 published articles that referred to a total of 27 drugs and contained data from 2989 patient-treatment trials; our goal was to determine the number of patients responding to therapy, defined as greater than or equal to 80% suppression of ventricular ectopic depolarizations. By means of logistic regression we tested the effect of 10 clinical and experimental variables on the likelihood of response to therapy. The likelihood of a drug response was significantly affected by the following six variables: increased by the use of dose titration (t = 3.59, p less than 0.0001), increased by the use of a higher daily dose (t = 3.21, p less than 0.0001), decreased by older age (t-2.67, p = 0.004), decreased by the use of blinding (t = -2.28, p = 0.011), increased by treating more male patients (t = 1.72, p = 0.043), and decreased by the presence of cardiovascular disease (t = -1.52, p = 0.064). Incorporating these six variables into our logistic regression model, we adjusted the response rate in each published study and calculated the mean response and standard error for each drug. Of the drugs tested in at least 100 patients, the most effective were amiodarone (estimated response rate 90%), encainide (80%), flecainide (79%), and propafenone (74%). Class IC drugs were significantly more effective than class IB and II drugs (p less than 0.05). With the exception of lorcainide and moricizine, class IC drugs were also more effective than class IA drugs (p less than 0.05). Amiodarone was significantly more effective than all drugs except encainide and flecainide (p less than 0.05). We found no significant differences among the response rates to class IA, IB, and II drugs. Whereas several patient and study characteristics affect the likelihood of response to antiarrhythmic drugs, class IC drugs and amiodarone are significantly more effective than other drugs in suppressing ventricular ectopic depolarizations.

Anti-Arrhythmia Agents↗
PubMed1990

Advantages of beta blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction.

Patients who have sustained greater than or equal to 1 myocardial infarcts are at high risk for sudden death or reinfarction; the risk is highest for those with lowest ventricular ejection fraction, continuing myocardial ischemia and asymptomatic high-density and complex premature ventricular contractions. At present, beta blockers when given prophylactically are the only agents that reduce the incidence of sudden death and reinfarction in survivors of myocardial infarction (MI) in the first 2 years. The beneficial effect was shown to correlate with a reduction in heart rate, the effect being absent or deleterious with beta blockers with marked sympathomimetic activity. The effects of beta blockers on ventricular fibrillation appeared to be dissociated from those on premature ventricular contractions. Trials with calcium antagonists indicate that these drugs had no effect or increased the mortality rate. The divergent effect of beta blockers and calcium antagonists is unexplained but may be due in part to a lack of bradycardiac effect of calcium antagonists; there were no differences in effect among different calcium antagonists. Data from trials involving class I antiarrhythmic agents indicate that agents acting by depression of cardiac conduction are either devoid of effect or produce a modest increase in mortality. Results of the Cardiac Arrhythmia Suppression Trial, employing the newer class I agents flecainide and encainide, were used to determine whether the suppression of premature ventricular contractions in the survivors of acute MI reduces mortality. Flecainide and encainide suppressed premature ventricular contractions greater than 80%, but resulted in an increased mortality rate undoubtedly due to a marked proarrhythmic effect. Whether these data can be extrapolated to all class I agents is uncertain. Preliminary data with class III antiarrhythmic agents suggest that these agents, especially amiodarone, similarly to beta blockers, have the potential to reduce mortality in survivors of MI. Evolving data suggest that in the secondary prevention of morbid events in the survivors of acute MI, the focus must shift away from antiarrhythmic agents that delay conduction and toward beta blockers and antifibrillatory actions resulting from a prolongation of refractoriness.

Adrenergic beta-Antagonists↗
PubMed2006

Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin.

Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (dV/dt(max)) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents (I(Na)) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of I(Na). All of these treatments rescued I(Na) to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of I(Na). To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice.

Action Potentials↗
PubMed1991

Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.

BACKGROUND: The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds). METHODS AND RESULTS: With a computer representation of a cable with Beeler-Reuter membrane properties, we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug, the window was delayed an additional 341 msec, and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window, we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs. CONCLUSIONS: The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently, the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.

Anti-Arrhythmia Agents↗