Combination drug therapy for ventricular arrhythmias

The role of drug combinations for the treatment of patients with ventricular arrhythmias is reviewed. The use of single drugs to suppress ventricular arrhythmias is often unsatisfactory; a drug may be ineffective or cause intolerable adverse effects. Simultaneous use of antiarrhythmic agents with different but compatible electrophysiologic effects may control arrhythmias refractory to single-drug therapy. Patients may tolerate combination therapy fairly well because dosages in combination therapy are often lower than those employed when either drug is used alone. Although comparison of drug trials is hampered by nonuniformity among study protocols, the data suggest that drug combinations can be effective in treating some patients. Pairs of drugs showing the most promise have been a class IA drug (procainamide, quinidine, or disopyramide) with a class IB drug (usually mexiletine), and a class IA drug with a beta blocker. Amiodarone should be combined with a class I drug only as a last resort. There is little evidence to support the simultaneous use of two class IA drugs. Selection of a drug combination should be guided by consideration of the patient's medical history, concurrent disease states, and risk of sudden cardiac death. The efficacy of combination therapy should be evaluated by electrophysiologic testing or ambulatory electrocardiography. Combination antiarrhythmic therapy should be reserved for patients in whom single-drug therapy has been ineffective or poorly tolerated. More studies are needed to further define the efficacy, safety, and role of drug combinations in the treatment of ventricular arrhythmias.     

Cardiac arrhythmias in childhood. Diagnostic considerations and treatment.

Determining safe and effective antiarrhythmic therapy in paediatric patients requires definition of the mechanism of the arrhythmia, determination of associated risk factors for treatment (such as the presence of congenital cardiac defects, myocarditis or cardiomyopathy), and monitoring for potential drug side effects related to the treatment. A number of modalities for non-invasive evaluation of arrhythmias is available, including ECG, 24-hour ambulatory Holter monitoring, and transtelephonic ECG transmission. Arrhythmias requiring medical treatment in children with normal cardiac anatomy and function include supraventricular tachycardia (SVT), ventricular tachycardia (VT) and primary atrial tachycardias. SVT is treated acutely with vagal manoeuvres or drugs which slow AV conduction [adenosine (adenine riboside), edrophonium, phenylephrine or verapamil]. When medical conversion is not achieved, transoesophageal overdrive pacing or direct current (DC) cardioversion may be required. Long term drug therapy for SVT includes first-line treatment with digoxin, verapamil or propranolol. Ventricular tachycardia is managed acutely with DC cardioversion and intravenous lidocaine (lignocaine). Chronic drug regimens include mexiletine, propranolol or amiodarone. In children with structural congenital heart disease or myocardial dysfunction, hazards of drug therapy for arrhythmias include depression of cardiac function, proarrhythmia (drug-induced worsening of arrhythmias), and conduction abnormalities. Care must be taken to choose medication regimens which are likely to be effective with minimum risk of potentiating abnormal haemodynamics or conduction.     

Targeting ryanodine receptors for anti-arrhythmic therapy

Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca(2+)) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca(2+) release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fibrillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca(2+) leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.     

Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy

It is now well established that nearly all functions of the body, including those that influence the pharmacokinetics and pharmacodynamics of medications, exhibit significant 24-hour variation. The electrical properties of the heart as well as cardiac arrhythmias also vary as circadian rhythms, even though the suboptimal methods initially used for their investigation slowed their identification and thorough characterization. The application of continuous Holter monitoring of the electrical properties of the heart has revealed 24-hour variation in the occurrence of ventricular premature beats with the peak in events, in diurnally active persons, between 6 a.m. and noon. After the introduction of implantable cardioverter-defibrillators, ventricular tachycardia or fibrillation were also found to peak in the same period of the day. Even defibrillator energy requirements show circadian variation, thus supporting the need for a temporal awareness in the therapeutic approach to arrhythmias. Imbalanced autonomic tone, circulating levels of catecholamines, increased heart rate and blood pressure, all established determinants of cardiac arrhythmias, show circadian variations and underlie the genesis of the circadian pattern of cardiac arrhythmias. Arrhythmogenesis appears to be suppressed during nighttime sleep, and this can influence the evaluation of the efficacy of antiarrhythmic medications in relation to their administration time. Unfortunately, very few studies have been undertaken to assess the proper timing (chronotherapy) of antiarrhythmic medications as means to maximize efficacy and possibly reduce side effects. Further research in this field is warranted and could bring new insight and clinical advantage.     

The safety of digoxin as a pharmacological treatment of atrial fibrillation

Digoxin has traditionally been the drug of choice for ventricular rate control in patients with chronic atrial fibrillation (AF), with or without heart failure (HF) with systolic dysfunction. In patients with permanent AF, digoxin monotherapy is ineffective to control ventricular rate during exercise, but the combination of digoxin with a beta-blocker or a non-dihydropyridine calcium channel antagonist can control heart rate both at rest and during exercise. Only a few randomised, controlled studies have evaluated the adverse effects of digoxin in patients with AF in a systematic way and side effects requiring drug withdrawal have rarely been reported. When reported, the most frequent adverse effects were cardiac arrhythmias (ventricular arrhythmias, AV block of varying degrees and sinus pauses). This evidence suggested that, in contrast to other antiarrhythmic drugs, digoxin is a safe drug in patients with AF. However, this safety profile can be erroneous due to the short follow-up of the studies and patient selection. Because patients with HF have been excluded in most studies, the safety profile of digoxin in this population has not been directly addressed. Early recognition that an arrhythmia is related to digoxin intoxication as well as recognition of concomitant medications or medical conditions that may directly alter the pharmacokinetic profile of digoxin, or indirectly alter its cardiac effects by pharmacodynamic interactions remain essential for safe and effective use of digoxin in patients with AF.     

The safety of digoxin as a pharmacological treatment of atrial fibrillation

Digoxin has traditionally been the drug of choice for ventricular rate control in patients with chronic atrial fibrillation (AF), with or without heart failure (HF) with systolic dysfunction. In patients with permanent AF, digoxin monotherapy is ineffective to control ventricular rate during exercise, but the combination of digoxin with a β-blocker or a non-dihydropyridine calcium channel antagonist can control heart rate both at rest and during exercise. Only a few randomised, controlled studies have evaluated the adverse effects of digoxin in patients with AF in a systematic way and side effects requiring drug withdrawal have rarely been reported. When reported, the most frequent adverse effects were cardiac arrhythmias (ventricular arrhythmias, AV block of varying degrees and sinus pauses). This evidence suggested that, in contrast to other antiarrhythmic drugs, digoxin is a safe drug in patients with AF. However, this safety profile can be erroneous due to the short follow-up of the studies and patient selection. Because patients with HF have been excluded in most studies, the safety profile of digoxin in this population has not been directly addressed. Early recognition that an arrhythmia is related to digoxin intoxication as well as recognition of concomitant medications or medical conditions that may directly alter the pharmacokinetic profile of digoxin, or indirectly alter its cardiac effects by pharmacodynamic interactions remain essential for safe and effective use of digoxin in patients with AF.     

Mechanism and therapy of cardiac arrhythmias in adults with congenital heart disease

Over the past few decades, surgical advances have helped to prolong the lives of many young patients with congenital heart disease (CHD). However, as these patients reach adulthood, they are at risk for many late sequelae of their disease or of their corrective surgery. One of the unique challenges associated with CHD is the high incidence of cardiac arrhythmias that arise from the myocardial substrate created by abnormal pressure/volume changes, septal patches, and suture lines. Medical therapy has proven to be disappointing in treating a majority of these cases. Nonetheless, radiofrequency catheter ablation (RFA), an effective tool in treating atrial and ventricular arrhythmias in structurally normal hearts, has been used to treat arrhythmias in adults with congenital heart disease. This review will discuss some of the common congenital heart diseases in adults and the arrhythmias associated with them, as well as the therapeutic modalities used to treat them. Finally, it will present Mount Sinai Hospital's experience in using RFA for the management of cardiac arrhythmias in adults with congenital heart disease.     

Tocainide. A review of its pharmacological properties and therapeutic efficacy

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.     

Current pharmacotherapeutic strategies for cardiac arrhythmias in heart failure

ABSTRACT

Introduction: Heart failure (HF) affects over 6 million Americans and is the most common cause of hospital readmissions in the United States. Cardiac arrhythmias are common comorbidities seen in patients with HF and are associated with an increase in morbidity and mortality. Pharmacotherapeutic agents along with device and ablation therapies are the mainstays of treatment for cardiac arrhythmias in HF.

Areas covered: An extensive literature review of articles and clinical trials on PUBMED on the topic of pharmacotherapy for cardiac arrhythmias in heart failure was conducted. This review article summarizes the above literature to describe the prevalence of the various types of arrhythmias in HF, the recommended pharmacotherapies for the treatment of these arrhythmias in HF and the evidence that supports these recommendations.

Expert opinion: Cardiac arrhythmias are common in HF and are the leading cause of death in this patient population. The management of cardiac arrhythmias in HF is challenging. Pharmacotherapy is the primary though increasingly adjunctive therapy for most cardiac arrhythmias. Further, antiarrhythmic drugs must be used with caution in this patient population due to their potential adverse effects.     

Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

As a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals. In the dosage range 600 to 900 mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis. Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.     

A benefit-risk assessment of class III antiarrhythmic agents.

With beta-blockers as the exception, increasing doubt is emerging on the value of antiarrhythmic drug therapy following a series of trials that have either shown no mortality benefit or even an excess mortality. Vaughan Williams class I drugs are generally avoided in patients with structural heart disease, and class IV drugs are avoided in heart failure. Unfortunately, arrhythmias are a growing problem due to an increase in the incidence of atrial fibrillation and sudden death. The population is becoming older and more patients survive for a longer time period with congestive heart failure, which again increases the frequency of both supraventricular as well as ventricular arrhythmias. Class III antiarrhythmic drugs act by blocking repolarising currents and thereby prolong the effective refractory period of the myocardium. This is believed to facilitate termination of re-entry tachyarrhythmias. This class of drugs is developed for treatment of both supraventricular and ventricular arrhythmias. Amiodarone, sotalol, dofetilide, and ibutilide are examples of class III drugs that are currently available. Amiodarone and sotalol have other antiarrhythmic properties in addition to pure class III action, which differentiates them from the others. However, all have potential serious adverse events. Proarrhythmia, especially torsade de pointes, is a common problem making the benefit-risk ratio of these drugs a key question. Class III drugs have been evaluated in different settings: primary and secondary prevention of ventricular arrhythmias and in treatment of atrial fibrillation or flutter. Based on existing evidence there is no routine indication for antiarrhythmic drug therapy other than beta-blockers in patients at high risk of sudden death. Subgroup analyses of trials with amiodarone and dofetilide suggest that patients with atrial fibrillation may have a mortality reduction with these drugs. However, this needs to be tested in a prospective trial. Similarly, subgroups that will benefit from prophylactic treatment with class III antiarrhythmic drugs may be found based on QT-intervals or - in the future - from genetic testing. Class III drugs are effective in converting atrial fibrillation to sinus rhythm and for the maintenance of sinus rhythm after conversion. This is currently by far the most important indication for this class of drugs. As defined by recent guidelines, amiodarone and dofetilide have their place as second-line therapy except for patients with heart failure where they are first line therapy being the only drugs where the safety has been documented for this group of high risk patients.     

Advances in the pharmacologic treatment of ventricular arrhythmias

Introduction: Despite many advances in nonpharmacologic management of ventricular arrhythmias, antiarrhythmic drugs remain important in both the acute conversion and chronic prevention of ventricular arrhythmias.

Areas covered: Key trials related to antiarrhythmic drug use are reviewed, emphasizing the impact of recent discoveries. Sodium channel blockers are discussed with an emphasis on recently identified specialized uses. Beta blockers, amiodarone, sotalol, and dofetilide are discussed together in the context of structural heart disease, because they do not increase mortality in this group of patients. Other medications found to reduce ventricular arrhythmia burden are discussed last.

Expert opinion: Since most patients with ventricular arrhythmias have structural heart disease, pharmacologic treatment is limited to amiodarone, d-,l-sotalol, and dofetilide (off-label indication), in conjunction with defibrillator implantation. While amiodarone has superior reduction in arrhythmias, its long-term extracardiac toxicities can cause significant morbidity. A trial of sotalol is reasonable if there are no contraindications, recognizing that over 20% of patients have to discontinue it because of adverse effects. Beta blockers are first line therapy for most patients. Genetic testing is particularly informative regarding treatment approach in long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Research should continue to focus on developing more effective antiarrhythmic medications with less long-term toxicity.     

Safety of flecainide

Flecainide is a class Ic antiarrhythmic agent that has an important role as part of rhythm control strategies in patients with atrial fibrillation (AF). Early clinical data on the use of flecainide showed an increase in arrhythmias and mortality compared with placebo in patients with a previous myocardial infarction and asymptomatic or mildly symptomatic ventricular arrhythmias. These findings only apply to a specific group of patients with left ventricular dysfunction and ischaemic heart disease, but had a negative impact on the use of class Ic antiarrhythmics across all indications and patient groups. The aim of this review was to evaluate the available safety data for flecainide in the literature and to assess its current use in patients with AF. Current European guidelines now recommend the use of flecainide in carefully selected groups of patients with AF who do not have structural heart disease. This includes for the cardioversion of recent-onset AF, pretreatment prior to direct current cardioversion, out-of-hospital acute oral therapy ('pill-in-the-pocket' approach) and for the ongoing maintenance of sinus rhythm. Potential cardiac adverse effects of flecainide include proarrhythmia, conduction abnormalities and negative inotropic effects. Dizziness is the most frequent non-cardiac side effect, followed by blurred vision and difficulty focusing; these are almost all mild, transient and tolerable. Data from recent clinical trials in patients with supraventricular arrhythmias suggest that flecainide has a good tolerability profile in groups of appropriately selected patients. Caution is required when using flecainide in patients with renal dysfunction, and there are a number of drug interactions, but these are well documented and manageable. Overall, flecainide is a good choice for the pharmacological management of AF. It has a good safety record and low incidence of adverse effects, rare end-organ toxicity and a low risk of ventricular proarrhythmia. To ensure that the benefits of treatment outweigh any potential risks, careful patient selection and monitoring is required.     

Safety of antidepressant drugs in the patient with cardiac disease: a review of the literature

Patients with cardiac disease, specifically ischemic heart disease and heart failure, have a higher frequency of major depressive disorder than patients without cardiac disease. The pathophysiologic reason for this is not completely understood. Previous depression, other debilitating illnesses, and type A personality are risk factors for the development of depression in cardiac patients. Depression has been shown to lower the threshold for ventricular arrhythmias. Therefore, treatment of depression potentially may prolong life in these patients. Antidepressant options that have been evaluated include several of the tricyclic antidepressants, trazodone, bupropion, and several of the selective serotonin reuptake inhibitors. Individual antidepressant drugs vary in their pharmacologic activity and side-effect profiles. Although clinical data are limited, it is important to individualize therapy in order to minimize cardiac adverse effects. Clinicians are encouraged to evaluate patients with cardiac disease for major depressive disorder and to consider antidepressant drug therapy for these patients when appropriate.     

Atrial fibrillation: rate control often better than rhythm control

(1) The treatment aims in atrial fibrillation are to reduce patients' symptoms and to prevent both embolism and deterioration of any underlying heart disease. Therapy consists of anticoagulant or antiplatelet drugs, treatment of any underlying heart disease, and heart rate control. (2) Digoxin, betablockers, diltiazem and verapamil slow the heart rate but rarely restore sinus rhythm. Amiodarone, disopyramide, flecainide, quinidine and sotalol can be used to prevent relapse of atrial fibrillation after electrical cardioversion, but they all have potentially serious adverse effects. New trials of antiarrhythmic treatments have been published since our last review of this subject. (3) In one trial in 403 patients, amiodarone was more effective than sotalol and propafenone in restoring and maintaining sinus rhythm. After 15 months of follow-up, there were fewer strokes among patients treated with amiodarone, but there was no difference between the three drugs in the overall incidence of cardiovascular events. (4) A clinical trial with 4060 patients compared rhythm control (mainly with amiodarone, sotalol or propafenone; sometimes combined with electrical cardioversion) and rate control (with digoxin, betablocker, diltiazem or verapamil; systematically combined with anticoagulant therapy). The antiarrhythmic treatment restored sinus rhythm in more than half the patients in the long term. But rhythm control did not reduce the risk of death or serious cardiovascular events during a mean follow-up period of 3.5 years. Rhythm control caused more adverse events than rate control; subgroup analyses (weak evidence) suggest that rhythm control may also have caused more deaths among patients over 65 and among patients with coronary heart disease. (5) In another trial, electrical cardioversion followed by antiarrhythmic therapy (mainly sotalol) sustainably restored sinus rhythm in more than one-third of 522 patients. But, compared with rate control treatment plus anticoagulant therapy, rhythm control did not reduce the risk of cardiovascular events, and was associated with a larger number of serious adverse cardiac effects. (6) Other recent trials confirm the risk of serious adverse effects, including severe arrhythmia with sotalol (especially at the start of treatment), and adverse thyroid and pulmonary effects with amiodarone. (7) Combined radiofrequency ablation and cardiac stimulation improved symptoms in some patients with incapacitating atrial fibrillation who had not responded to other treatments. However, this approach carries a risk of serious adverse effects, and its impact on the risk of cardiovascular events and death is not known. (8) In practice, an attempt should be made to restore sinus rhythm with amiodarone and/or electrical cardioversion, in symptomatic, recent or paroxysmal atrial fibrillation in patients under 65 who have no signs or symptoms of coronary heart disease. In other situations, rate control is the first-line option, using digoxin, betablockers (other than sotalol) or calcium channel blockers (diltiazem or verapamil). Whatever the option, treatment must be combined with anticoagulant or antiplatelet therapy, and with treatment of any underlying heart disease.     

Reassessment of benefit-risk ratio and treatment algorithms for antiarrhythmic drug therapy after the cardiac arrhythmia suppression trial

The Cardiac Arrhythmia Suppression Trial (CAST) has led to serious reconsideration of both the benefit-risk ratio of antiarrhythmic drug therapy and the appropriate therapeutic approach to various cardiac arrhythmias. Class IC drugs, such as encainide and flecainide, should not be used to treat asymptomatic postinfarction arrhythmias. Furthermore, because the CAST raises serious questions about the concept of treating asymptomatic but "potentially malignant" (prognostically important) arrhythmias guided by ambulatory monitoring, the prophylactic use of any of the antiarrhythmic agents (except beta blockers) must be considered inappropriate and potentially harmful until otherwise established by specific clinical trials. For prophylaxis of malignant ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation), treatment may still begin with standard agents in classes IA, IB, or both, preferably guided by electrophysiologic testing alone or in combination with noninvasive testing. Class IC therapy may be most useful in those patients in this group who do not have such high-risk characteristics for proarrhythmia as a history of multiple myocardial infarctions (MIs), congestive heart failure, or low ejection fraction. Amiodarone is moderately effective for treating these arrhythmias but is reserved as second- or third-line therapy because of its potential organ toxicity. Sotalol, a beta blocker with class III activity, is often effective and relatively well tolerated in these patients and may become a preferred drug when approved. For symptomatic but nonmalignant ventricular arrhythmias, a more conservative approach is more appropriate than in the past, with therapy reversed for those with debilitating symptoms. An initial trial of beta blockade is often appropriate before class I agents are considered.(ABSTRACT TRUNCATED AT 250 WORDS)     

The risk of cardiovascular side effects with anti-anginal drugs

ABSTRACT

Introduction: Angina pectoris is a common presenting symptom of underlying coronary artery disease or reduced coronary flow reserve. Patients with angina have impaired quality of life; and need to be treated optimally with antianginal drugs to control symptoms and improve exercise performance. A wide range of antianginal medications are approved for the treatment of angina, and often more than one class of antianginal drugs are used to adequately control the symptoms. This expert opinion highlights the likely cardiac adverse effects of available antianginal drugs, and how to minimize these in individual patients and especially during combination treatment.

Areas covered: All approved antianginal drugs, including the older and newly approved medications with different mechanism of action to the older drugs as well as some of the unapproved herbal medications. The safety profiles and potential cardiac side effects of these medications when used as monotherapy or as combination therapy are discussed and highlighted.

Expert opinion: Because of the different cardiac safety profiles and possible side effects, we recommend selection of initial drug or adjustment of therapy based on the resting heart rate; blood pressure, hemodynamic status; and resting left ventricular function, concomitant medications and any associated comorbidities.     

The effect of antiarrhythmic agents on myocardial contractility and arrhythmia frequency

Most patients requiring antiarrhythmic therapy for ventricular arrhythmias have underlying organic heart disease which causes left ventricular dysfunction. Treatment of these patients' arrhythmias requires knowledge of the hemodynamic as well as antiarrhythmic effects of the available agents. These effects may differ during acute and chronic oral therapy. Several of the newer agents and quinidine are very effective in suppressing ventricular ectopic activity, allowing demonstration of drug effect during ambulatory monitoring. The clinical significance of this for prevention of sudden death has yet to be shown. However, prevention of ventricular tachycardia or fibrillation in the electrophysiology laboratory and suppression of ambient ectopy may generally be separate phenomena, as has been demonstrated for amiodarone.     

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.     

Beta-blockers as antiarrhythmic agents

Drugs that suppress beta-adrenergic signaling by competitively inhibiting agonist binding to beta-adrenergic receptors ("beta-blockers") have important antiarrhythmic properties. They differ from most other antiarrhythmic agents by not directly modifying ion channel function; rather, they prevent the arrhythmia-promoting actions of beta-adrenergic stimulation. beta-Blockers are particularly useful in preventing sudden death due to ventricular tachyarrhythmias associated with acute myocardial ischemia, congenital long QT syndrome, and congestive heart failure. They are also quite valuable in controlling the ventricular rate in patients with atrial fibrillation. This chapter reviews the properties of beta-adrenoceptor signaling, the basic mechanisms of cardiac arrhythmias on which beta-blockers act, the ion channel mediators of beta-adrenergic responses, the evidence for clinical antiarrhythmic indications for beta-blocker therapy and the specific pharmacodynamic and pharmacokinetic properties of beta-blockers that differentiate the various agents of this class.