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PubMed1992

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.

Anti-Arrhythmia Agents↗

PubMed1987

Differing electrophysiological effects of class IA, IB and IC antiarrhythmic drugs on guinea-pig sinoatrial node.

Standard microelectrode techniques were used to study the effects of class IA (quinidine, disopyramide, procainamide), IB (lignocaine, mexiletine, tocainide) and IC (flecainide, encainide, lorcainide) antiarrhythmic drugs on action potentials in spontaneously beating sino-atrial node cells from guinea-pigs. The IA drugs all produced significant slowing of spontaneous rate in therapeutic concentrations. The IB agents did so only in concentrations well above therapeutic levels and the IC drugs were of intermediate potency. All nine drugs markedly slowed the repolarization rate and this was the major mechanism of sinus slowing for the IA and IC compounds. The IB drugs shared this effect but prolongation of phase 4 by reduction of the slope of diastolic depolarization was also a prominent feature of their action.

Action Potentials↗

PubMed1989

Pharmacological characterization of conduction over a Mahaim fiber: evidence for adenosine sensitive conduction.

The presence of a nodoventricular pathway (Mahaim fiber) has been invoked to explain certain distinctive electrocardiographic and electrophysiological observations. The presence of an atrioventricular or atriofascicular fiber with decremental conduction properties has been documented in many of these patients. We report the case of a patient with a Mahaim fiber and the response to conduction over this pathway after adenosine, procainamide, encainide, verapamil, edrophonium, phenylephrine and isoproterenol. Conduction over the Mahaim fiber was blocked by adenosine, but not verapamil. The time course of adenosine induced block over the Mahaim fiber differed from adenosine induced AV nodal block. Mahaim fibers are decrementally conducting pathways that are adenosine sensitive. These findings support the concept that conduction in accessory pathways manifesting decremental properties is not mediated by the calcium channel.

Adenosine↗

PubMedDate not supplied

Moricizine: a novel antiarrhythmic agent.

Moricizine is a phenothiazine derivative with Vaughan Williams class 1 antiarrhythmic properties. It undergoes extensive first-pass metabolism, has a bioavailability of 34-38 percent, and is 95 percent bound to plasma proteins. Moricizine is extensively metabolized and may have pharmacologically active metabolites. A recent clinical study has shown that moricizine is slightly less effective than encainide or flecainide in suppressing ventricular premature depolarizations. Compared with disopyramide and quinidine, moricizine was equally or more effective in suppressing ventricular premature depolarizations, couplets, and nonsustained ventricular tachycardia. Further studies are needed comparing moricizine with other class 1 agents in the treatment of life-threatening arrhythmias; available data suggest that moricizine is comparable with these agents in the treatment of ventricular tachycardias and fibrillation. Moricizine appears to have a low incidence of serious adverse effects compared with other antiarrhythmics. This combination of apparently similar efficacy with a decreased incidence of adverse effects makes moricizine a worthwhile addition to currently available antiarrhythmic agents.

Anti-Arrhythmia Agents↗

PubMed1995

Probable propafenone-induced transient global amnesia.

OBJECTIVE: To describe a probable case of transient global amnesia caused by propafenone. This adverse effect has not been previously described for this agent. CASE SUMMARY: A 61-year old man with a history of sick sinus syndrome with persistent atrial fibrillation and infrequent premature ventricular contractions was admitted to the hospital for symptoms of amnesia and disorientation to time, place, and date. He began taking propafenone only 6 days prior to admission because of uncontrolled atrial fibrillation and symptoms of fatigue. His atrial fibrillation subsequently had converted to normal sinus rhythm while he received propafenone without adverse effects prior to this episode. His symptoms of amnesia resolved approximately 6-7 hours after discontinuing the propafenone therapy. DISCUSSION: Propafenone is a class 1C antiarrhythmic agent that blocks fast sodium channels in heart muscle and Purkinje fibers similar to the action of encainide and flecainide. It also produces weak beta- and calcium-channel blockade. It has a significant adverse effect profile, with 30-45% of patients reporting cardiac adverse effects and 15-20% experiencing noncardiac events. Central nervous system effects that parallel amnesia have been reported in 10-15% of the patients, including dizziness, ataxia, drowsiness, fatigue, confusion, and paranoia. Propafenone's distribution, clearance, and structural similarity to propranolol contribute to its central nervous system effects. CONCLUSIONS: The rapid resolution of this patient's symptoms after discontinuing propafenone therapy and the absence of recurrence lend credence to the probability of this effect. Comparable adverse effects, such as disorientation and temporary amnesia, have been reported in patients in the analogous agent, propranolol. Consequently, this is a likely, although rare, possible adverse effect with propafenone for which patients should be monitored.

Amnesia↗

PubMed2000

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance.

This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Amiodarone treatment in patients with ventricular arrhythmias.

Amiodarone has been used in the therapy of supraventricular and ventricular tachycardia, and has often been categorised as a class III rather than a class I agent. However, in patients with ventricular arrhythmias, amiodarone 800mg daily for 14 days prolonged the right ventricular effective refractory period by a mean of 18.8 msec (p less than 0.05), and HV interval by a mean of 5.2 msec (p less than 0.05), these changes being similar to those noted with drugs such as quinidine, procainamide, disopyramide and encainide. The antiarrhythmic efficacy of amiodarone was evaluated in 196 patients with recurrent sustained ventricular tachycardia, recurrent ventricular fibrillation or recurrent nonsustained ventricular tachycardia. Coronary artery disease, dilated (congestive) cardiomyopathy, or other forms of heart disease were present in most patients. After 1 month of therapy, 177 patients continued to receive amiodarone and, during the remainder of the follow-up period, 139 patients had no recurrence of spontaneous ventricular tachycardia or ventricular fibrillation. Sudden cardiac death occurred in 15 patients after a mean treatment period of 10.4 months. Overall, amiodarone was an effective form of therapy in patients with ventricular tachycardia and ventricular fibrillation.

Adolescent↗

PubMed1988

New antiarrhythmic drugs.

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

Anti-Arrhythmia Agents↗

PubMed1990

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

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

Animals↗

PubMed1993

Propafenone. A reappraisal of its pharmacology, pharmacokinetics and therapeutic use in cardiac arrhythmias.

Propafenone is an orally active sodium channel blocking agent with beta-adrenoceptor antagonist and weak calcium antagonist activity. The pharmacokinetic profile of propafenone is complex, characterised as typically nonlinear, saturable, stereoselective and dependent on both dose and debrisoquin metaboliser phenotype; individualised dosage titration is required. Both placebo- and drug-controlled studies have confirmed the efficacy of propafenone in the treatment of premature ventricular complexes, ventricular couplets and nonsustained ventricular tachycardia; in a large meta-analysis, propafenone together with amiodarone, flecainide and encainide were significantly more effective in the control of ventricular ectopy than other antiarrhythmic agents. However, the use of propafenone in these indications, like that of other antiarrhythmic agents, is likely to be limited to patients with a favourable risk-to-benefit ratio. Propafenone has also demonstrated efficacy in the treatment of malignant ventricular arrhythmias (ventricular fibrillation and sustained ventricular tachycardia); preliminary mortality data obtained with propafenone have been encouraging in this patient group. In addition, propafenone has a favourable noncardiac tolerability profile and beta-adrenoceptor antagonist activity, which may offer advantages in some specific patient groups. The area of research concerning propafenone which has shown the greatest expansion over the past 5 years is in the treatment of supraventricular arrhythmias. Propafenone has marked efficacy in patients with Wolff-Parkinson-White syndrome and has been recommended as a first-line prophylactic agent in those with rapid anterograde conduction. Propafenone is also effective in the conversion of atrial fibrillation to sinus rhythm, although comparative studies are required to determine advantages over more established agents. Propafenone use has been successfully extended to children with limited data demonstrating consistent efficacy in the control of junctional ectopic tachycardia. As with all antiarrhythmic agents, propafenone has the potential to induce arrhythmias. Comparative studies are required to assess in more detail the cardiac tolerability profile of propafenone against other class Ic agents. In conclusion, propafenone offers a broad spectrum of activity in the treatment of cardiac arrhythmias, although its use in patients with potentially malignant arrhythmias will remain limited for the present. Due to its unique pharmacodynamic profile, propafenone deserves consideration as an individual agent.

Animals↗

PubMed1987

Polymorphism of human cytochrome P-450.

The cytochrome P-450 forms involved in debrisoquine 4-hydroxylation (P-450DB), phenacetin O-deethylation (P-450PA), S-mephenytoin 4-hydroxylation (P-450MP), and nifedipine 1,4-oxidation (P-450NF) have been purified to electrophoretic homogeneity from human liver microsomes. All of these reactions show in vivo polymorphism in humans. Evidence for the roles of the purified proteins in these processes comes from in vitro reconstitution and immunoinhibition studies. The rat orthologs of these enzymes are as follows--P-450DB: P-450UT-H; P-450PA: P-450ISF-G; P-450MP: P-450UT-I; P-450NF: P-450PCN-E. Only in the case of P-450UT-H is the primary rat ortholog the same cytochrome P-450 which catalyses the catalytic reaction under consideration. Reconstitution and immunochemical studies establish that the following reactions are catalysed by the individual P-450s--P-450DB: debrisoquine 4-hydroxylation, sparteine delta 5-oxidation, bufuralol 1'-hydroxylation, encainide O-demethylation, and propanolol 4-hydroxylation; P-450PA: phenacetin O-deethylation; P-450MP: S-mephenytoin 4-hydroxylation and tolbutamide methyl hydroxylation; P-450NF: oxidation of nifedipine and 16 other substituted dihydropyridines, estradiol 2- and 4-hydroxylation, aldrin epoxidation, benzphetamine N-demethylation and 6 beta-hydroxylation of testosterone, androstenedione and cortisol. A cDNA clone has been isolated that corresponds to rat P-450UT-H, as shown by a number of criteria. Studies with this probe establish that the sex and strain variation in debrisoquine 4-hydroxylase and related activities is related to differences in the levels of a 2.0 kb length mRNA present.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+ -K+ ATPase.

The notion that the inhibition of the Mg2+ -dependent ATP-hydrolytic function of the myocardial Na+ -K+ ATPase by class I antiarrhythmic agents occurs as a result of their binding to the same receptor sites as the digitalis glycosides was tested by performing competitive binding assays of [3H]ouabain (OUA) with eight drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide, quinidine, and tocainide in guinea pig heart microsomal preparations. In the first set of experiments, 10-200 microM concentrations of the drugs were preincubated with the enzyme and displacement assays performed with 250 nM OUA. The drugs showed receptor occupancy of 19-32% at 50 microM, 25-44% at 100 microM, and 37-56% at 200 microM. Then, 10-500 nM concentrations of OUA were preincubated with the enzyme, and competitive assays were performed using 200 microM concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM, 44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration-dependent fashion. The results show that antiarrhythmic drugs interact with the same or similar receptor sites as ouabain on the Na+ -K+ ATPase, pointing to a possible contribution of these interactions to the mechanism for their inhibitory actions on the enzyme, and perhaps their arrhythmogenic effects.

Animals↗

PubMed1999

Antiarrhythmic drugs and ventricular defibrillation energy requirements.

PURPOSE: To understand the potential interaction between antiarrhythmic therapy and the implantable cardioverter-defibrillator (ICD) in patients who receive pharmacologic therapy as an adjunct to ICD therapy. DATA SOURCES: MEDLINE searching was employed and the information was indexed from approximately 3600 journals published world-wide from 1966 to 1998. STUDY SELECTION AND DATA EXTRACTION: Data were collected from 66 of approximately 455 originally identified articles and abstracts using explicit methodological criteria. RESULTS: The ICD therapy has been widely used for therapy of life-threatening ventricular arrhythmias (VT/VF) and prevention of recurrence of sudden cardiac death. Studies reported that 40%-70% or 10%-40% of ICD patients required concomitant antiarrhythmic medication to reduce the frequency of sustained arrhythmic episodes and to minimize the frequency of device discharges. Most studies on antiarrhythmic drug-ICD interactions have been performed in experimental animals. Antiarrhythmic drugs can influence the effectiveness of ICD to terminate arrhythmias through their effects on defibrillation threshold (DFT). Studies have demonstrated a rise in DFTs with class Ib agent lidocaine and class Ic agents encainide and flecainide. Class Ia agents, as well as amiodarone, bretylium and propafenone may have more variable effects on DFT probably because of the difference between acute and chronic drug dosing, dose-related changes, active metabolites, and reproducibility in determining DFT. Class III agents, with the exception of amiodarone, consistently decrease DFT. These drugs can be used as front-line agents in ICD patients. CONCLUSIONS: Antiarrhythmic drugs can increase, decrease, or have no effect on DFT. Class III agents except amiodarone can be safely administered in conjunction with ICD patients as long as the interaction between these therapeutic modalities is appreciated.

Animals↗

PubMed1992

The relevance of cellular to clinical electrophysiology in classifying antiarrhythmic actions.

The division of class I antiarrhythmic agents (sodium-channel blockers) into Ia, Ib, and Ic subgroups was based on clinical observations. Lidocaine, mexiletine, and tocainide (Ib) did not alter the QRS or H-V interval in sinus rhythm, but prolonged effective refractory period (ERP) in spite of some shortening of the J-T interval. Encainide, flecainide, and lorcainide (Ic) widened the QRS and prolonged H-V in sinus rhythm and at low concentration, but had little effect on the ERP or J-T. These clinical findings could be explained by fast onset/offset kinetics of Ib drugs, that when used in high concentrations, blocked most sodium channels during the action potential plateau; therefore, at the beginning of diastole, insufficient drug-free channels were available to support conduction, and the ERP was prolonged. Rapid dissociation of the drugs after repolarization insured that by the end of diastole most channels were again drug free, so that the QRS and H-V were normal. The Ic compounds were more potent, but of slow onset, so that a steady-state block of Na channels was not achieved until after many beats. Offset was also slow, so that a proportion of channels was persistently unavailable, Na current was reduced, and conduction slowed, causing widening of the QRS and lengthening of H-V. Because the remaining drug-free channels were normal, they recovered rapidly from inactivation, and the ERP was not prolonged. By clinical criteria, moricizine also must be classed as Ic, and its offset/onset kinetics are much slower than those of Ib drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1992

Differential analysis of frequency-dependent effects of antiarrhythmic drugs: importance of the saturation behavior of frequency-dependent sodium-channel blockade.

Frequency-dependent effects of class I antiarrhythmic drugs on Vmax reported in the literature are analyzed with respect to periodical drug binding to sodium channels. The analysis reveals that class I action can be differentiated according to the onset kinetics as well as to the saturation behavior of frequency-dependent sodium-channel blockade at increasing frequencies. As will be shown, class I drugs even of the same subclass (Ic) may differ markedly from each other with respect to the saturation behavior of frequency-dependent block. These findings may be of interest in view of the Cardiac Arrhythmia Suppression Trial (CAST) because the results found with flecainide and encainide in this study are usually extrapolated to other Ic drugs. Additionally, the influence of postrepolarization refractoriness caused by a class I drug on the action potential shortening during repetitive premature stimulation is compared with the effects of prolongation of absolute refractoriness induced by a class III drug.

Action Potentials↗

PubMed1992

The role of beta-adrenergic blocking agents in preventing sudden cardiac death.

The failure of encainide and flecainide to reduce mortality after infarction in the Cardiac Arrhythmia Suppression Trial and the failure of low-dose amiodarone to prevent sudden cardiac death in patients with a low left ventricular ejection fraction has shifted attention to other strategies, such as beta-adrenergic blocking agents, to prevent sudden cardiac death. Evidence suggesting that beta-adrenergic blocking agents might be useful, especially in patients with low left ventricular ejection fraction, is accumulating. Previous data from studies using beta-adrenergic blocking agents and the mechanisms by which beta-adrenergic blocking agents might be of value in preventing sudden cardiac death are reviewed. These considerations and the availability of new investigational beta-adrenergic blocking agents with vasodilator properties provide a new opportunity to test the hypothesis that beta-adrenergic blocking agents are useful in preventing sudden cardiac death, especially in patients with a low left ventricular ejection fraction.

Adrenergic beta-Antagonists↗

PubMed1992

[New anti-arrhythmia agents].

Use of class-I antiarrhythmic agents (encainide, flecainide or moricizine) to suppress asymptomatic ventricular premature depolarizations does not decrease, but rather increases mortality from cardiac events after myocardial infarction. These patients should not be treated with antiarrhythmic drugs until improved survival is shown in a controlled clinical trial. In other clinical conditions such as symptomatic tachyarrhythmias class-I agents should only be used if the expected benefit outweighs the risk of an adverse cardiac effect. The development of new class-I drugs does not seem promising. Esmolol is the first intravenous and ultrashort-acting beta-adrenoceptor blocker that can be used to treat supraventricular arrhythmias in the critical care setting; in addition, it displays high cardioselectivity. Specific class-III antiarrhythmic agents including sematilide and dofetilide have been shown to be effective against ventricular tachyarrythmias in preclinical studies, but their clinical value remains to be established. Torsades de pointes arrhythmia is an undesirable side-effect closely coupled to specific class-III action that may limit their future use. The known pharmacological profiles and limited controlled clinical studies make amiodarone and sotalol promising candidates for drugs that may improve survival of patients at risk for sudden cardiac death.

Adrenergic beta-Antagonists↗

PubMed1991

[Methodology in clinical trials of anti-arrhythmia agents in ventricular arrhythmias. Analysis and perspective following results of the CAST study].

The results of the Cardiac Arrhythmia Suppression Trial (CAST) have not finished modifying the methodology and strategy of development of new antiarrhythmic agents for the treatment of ventricular arrhythmias. The demonstration of a dissociation between a proved antiarrhythmic effect and increased mortality in coronary patients treated with encainide or flecainide, means that, in this situation, antiarrhythmic efficacy cannot be considered to be a substitute criterion of therapeutic benefit. The consequences of these results are as follows: in phase II, the dose-effect relationships should be studied in patients with chronic ventricular extrasystole without ischemic heart disease. This model is sufficiently predictive for the selection of the dosage to be tested in phase III; in phase III, studies of benign ventricular arrhythmias, antiarrhythmic efficacy is demonstrated by ambulatory ECG recordings. If these studies include patients with ischemic heart disease, the patients must be placed on betablocker therapy and the benefits in terms of reduction of mortality have to be shown by controlled trials versus placebo. In malignant life-threatening arrhythmias, open clinical trials may be performed using provocative electrophysiological studies. The inclusion of patients with implanted automatic defibrillator devices could constitute control groups for the placebo group. The future of antiarrhythmic agents for the treatment of ventricular arrhythmias greatly depends on the search for criteria of severity of arrhythmias and the validation of intermediate criteria of efficacy.

Anti-Arrhythmia Agents↗