Electrophysiological characterization of BRL-32872 in canine Purkinje fiber and ventricular muscle. Effect on early after-depolarizations and repolarization dispersion

Amongst the different pharmacological approaches to the treatment of cardiac arrhythmias, compounds with multiple electrophysiological activities appear to exhibit a reduced adverse effect profile. BRL-32872 (N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride) is a typical example of an antiarrhythmic agent with combined K(+) and Ca(2+) blocking actions. In this study, we investigated the effects of BRL-32872 on early after-depolarizations and on dispersion of repolarization. Action potentials were recorded either in canine cardiac Purkinje fibers alone or in preparations containing both ventricular muscle and the attached Purkinje fibers. In Purkinje fibers, BRL-32872 (0. 3-10 microM) induced a bell-shaped concentration-dependent increase in action potential duration. At 90% of repolarization, the action potential was prolonged at concentrations up to 1 microM and was shortened when the concentration of BRL-32872 was further increased. In all 17 experiments, BRL-32872 did not cause early after-depolarizations in Purkinje fibers. On the contrary, BRL-32872 (3 microM) systematically suppressed early after-depolarizations induced by clofilium (4-chloro-N, N-diethyl-N-heptylbenzenebutanaminium tosylate, 1 microM), a selective inhibitor of the delayed rectifier K(+) current. A similar effect was observed once with 1 microM BRL-32872, a concentration able to prolong Purkinje fiber action potentials. Simultaneous recording of action potentials in ventricular and Purkinje preparations showed that increasing concentrations of BRL-32872 (0. 3-10 microM) induced a limited increase in the difference of repolarization time between the two tissues. The selective K(+) channel inhibitor E-4031 (N-(4-(1-[2-(6-methyl-2-pyridyl) ethyl]-4-piperidyl)-carbonyl] phenyl) methanesulfonamide dihydrochloride dihydrate) exhibited a significant concentration-dependent increase in dispersion of repolarization. We conclude from the present results that the Ca(2+) blocking activity of BRL-32872 (i) prevents the occurrence of early after-depolarizations associated with action potential prolongation and (ii) limits an excessive increase in action potential duration heterogeneity. These electrophysiological features might represent the basis for antiarrhythmic compounds with reduced proarrhythmic profile.     

抗心律失常药物的不良反应

<正>心律失常是心内科常见病种,抗心律失常药物分类不同,作用机制有差异,不良反应也较多,这为临床医生合理使用抗心律失常药物增加了难度。了解抗心律失常药物的不良反应有助于临床合理、安全用药,现将国内常用抗心律失常药物的不良反应做一总结。 1 抗心律失常药物的致心律失常作用抗心律失常药物的致心律失常作用,是指服用治疗量或亚治疗量抗心律失常药物引起用药前没     

抗心律失常药物不良反应分析

目的：探讨抗心律失常药物所致不良反应(ADR)的发生情况,为临床安全、合理用药提供参考。方法130例抗心律失常药物所致不良反应报告,对患者的年龄、性别、基础疾病、用药途径、用药剂量、不良反应史、所用药物、不良反应的临床表现等进行统计分析。结果上报的抗心律失常药物所致不良反应发生在21~97岁;不良反应主要包括致心律失常作用及其他系统损害。结论医疗机构应重视抗心律失常药物引起的不良反应,加强抗心律失常药物的合理应用。     

The novel antiarrhythmic drug dronedarone: comparison with amiodarone

Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents I(Kr), I(Ks), I(KI), I(KACh), and I(sus), as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone.     

Therapeutic drug monitoring of antiarrhythmic drugs

Most antiarrhythmic drugs fulfil the formal requirements for rational use of therapeutic drug monitoring, as they show highly variable plasma concentration profiles at a given dose and a direct concentration-effect relationship. Therapeutic ranges for antiarrhythmic drugs are, however, often very poorly defined. Effective drug concentrations are based on small studies or studies not designed to establish a therapeutic range, with varying dosage regimens and unstandardised sampling procedures. There are large numbers of nonresponders and considerable overlap between therapeutic and toxic concentrations. Furthermore, no study has ever shown that therapeutic drug monitoring makes a significant difference in clinical outcome.Therapeutic concentration ranges for antiarrhythmic drugs as they exist today can give an overall impression about the drug concentrations required in the majority of patients. They may also be helpful for dosage adjustment in patients with renal or hepatic failure or in patients with possible toxicological or compliance problems. Their use in optimising individual antiarrhythmic therapy, however, is very limited.     

Therapeutic drug monitoring: antiarrhythmic drugs

Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the β-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.     

Therapeutic drug monitoring: antiarrhythmic drugs

Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the b-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.     

New approaches for identifying antiarrhythmic drug targets

Sudden cardiac death, secondary to ventricular fibrillation (VF), remains the leading cause of death in many developed countries. Substantial experimental and theoretical support exists for the idea that VF is caused by spiral wave re-entry. The initiation and subsequent break-up of spiral waves have been linked to electrical alternans, a phenomenon typically associated with a steeply sloped restitution relationship. Interventions that reduce the slope of the restitution relationship have been shown to prevent the induction of VF and to terminate existing VF in experimental models. These results suggest that electrical restitution may be a promising new target for antiarrhythmic therapies.     

Novel targets for cardiac antiarrhythmic drug development

Cardiac arrhythmias remain a major source of morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of cardiac arrhythmia treatment; however, drug therapy of cardiac arrhythmias has been plagued by incomplete efficacy and by potentially serious adverse reactions, of which the most worrisome has been a potential for malignant proarrhythmia and related effects to increase cardiac mortality. This article reviews the principal arrhythmia mechanisms and their ionic determinants, and discusses potential innovative approaches to new antiarrhythmic drug development, including the consideration of novel ionic targets, potential biophysical approaches and non-channel components involved in composing the arrhythmic substrate.     

Reliability of antiarrhythmic drug plasma concentration monitoring

Measurement of drug levels is becoming increasingly popular to optimise the dosage of various drugs. In the case of antiarrhythmic drugs, the narrow therapeutic margin of most of these agents and a direct relationship between their pharmacological effects and plasma concentrations would justify more widespread use of monitoring. Optimum plasma concentration ranges have been described for lignocaine (lidocaine), procainamide, quinidine and, more recently, also for disopyramide, mexiletine, tocainide and other new antiarrhythmics. A critical analysis of the original data shows, however, that therapeutic and toxic levels are not so well defined as often assumed: small numbers of patients, marked interindividual variability, sometimes inadequate documentation of arrhythmias and lack of standardised blood sampling characterise many of these studies. Uncertainty about the reliability of concentration-effect relationships also arises when active drug metabolites are identified or there are marked concentration-dependent changes of drug protein-binding. In addition, abolition of various types of arrhythmias might require different drug concentrations. Nevertheless, therapeutic monitoring can be of practical value in patients with life-threatening ventricular arrhythmias and can also greatly facilitate dosage adjustment in cases with renal hepatic or severe cardiac failure. For a correct interpretation of drug levels, the time of blood sampling, dosage regimen, duration of treatment, pharmacokinetic principles, and the clinical condition of the patient must be taken into account. Further studies are needed to define the optimum therapeutic range for several drugs and to evaluate the usefulness of plasma concentration measurements in routine antiarrhythmic treatment.     

Newer aspects of antiarrhythmic drug development: Introduction

Although cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re-evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.     

Potassium channels as targets for antiarrhythmic drug action

Recent cellular electrophysiologic studies have begun to clarify the basis of antiarrhythmic drug action. The Class I agents have been shown to block cardiac sodium channels in a use-dependent manner, and the kinetics and potency of sodium channel block correlated with molecular weight and lipid solubility of drug. The Class IA agents, like quinidine, which increase cardiac action potential duration and refractory period in addition to their effects on conduction, also appear to have potent blocking actions on the potassium channels responsible for repolarization in myocardial cells, whereas the Class IB agents, like lidocaine, shorten action potential duration and are relatively specific in their block of sodium channels. In contrast, Class III agents, which prolong the action potential without slowing conduction, appear to exert their primary blocking action on the potassium channel only. Conversion from Class I to Class III electrophysiologic profiles can be achieved by the substitution of electron-withdrawing groups (e.g., NO₂) in place of electron-donating groups (e.g., NH₂) on the aromatic portion of the basic local anesthetic pharmacophore. Class III agents appear to be most effective against ventricular fibrillation and ventricular tachycardia due to re-entry, but are generally without activity in the 24 hr Harris dog arrhythmia model. Further evaluation of the mechanism of antiarrhythmic drug action will require use of well-defined arrhythmia models in a combination with a detailed understanding of drug-channel interactions.     

A novel approach to identifying antiarrhythmic drug targets

Sudden cardiac death, secondary to ventricular fibrillation (VF), remains the leading cause of death in the USA. Recent experimental and theoretical studies suggest that VF could be caused by spiral wave re-entry. The initiation and subsequent break-up of spiral waves has been linked to electrical alternans, a phenomenon produced in cardiac tissue that has a steeply sloped restitution relation. Agents that reduce the slope of the restitution relation have been shown to suppress alternans and, presumably by that mechanism, terminate VF. These results suggest that electrical restitution could be a promising new target for antiarrhythmic therapies.     

Clinical implications of variable antiarrhythmic drug metabolism.

Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.     

Assessment of the risk-benefit ratio for antiarrhythmic drug use

Arrhythmia treatment has always been difficult, particularly as there are no good indicators of the optimal management strategy. The introduction of new antiarrhythmic agents has forced reappraisal of how these drugs are used. Dynamic electrocardiography and invasive electrophysiological studies are important tools for classifying and characterizing arrhythmias and for assessing the efficacy of therapy. There is still an enormous gulf between present day treatment and a scientific basis for drug selection, but risk-benefit analysis is possible, at least for patient populations and for some specific arrhythmias. Individual risk-benefit analysis, much needed by clinicians, is still a long way from reality. This article examines the concept of risk-benefit analysis and indicates those areas where progress can be made.     

Pharmacokinetic characterization of the antiarrhythmic drug diprafenone in man

The pharmacokinetics of the antiarrhythmic drug diprafenone have been investigated in 6 healthy volunteers following single intravenous (50 mg) and oral doses (50 and 150 mg). Diprafenone was mainly eliminated by metabolism in the liver. Following i.v. infusion of 50 mg diprafenone, the terminal half-life of elimination was 1.50 h, the volume of distribution at steady-state was 1.23 l.kg-1, and the free fraction in plasma was 1.68%. Mean total plasma clearance was 741 ml.min-1.70 kg-1, which approaches normal liver blood flow after correction for the blood/plasma concentration ratio. Thus, diprafenone can be classified as a high extraction drug. Following oral administration, a dose-dependent increase in bioavailability from 10.9 (50 mg dose) to 32.5% (150 mg dose) was observed. The data suggest that diprafenone is subject to saturable hepatic first-pass metabolism.