Advances in Antiarrhythmic Drug Therapy

Contents

Foreword: Contemporary Issues in Antiarrhythmic Drug Therapy xi

Ranjan K.Thakur andAndrea Natale

Preface: Advances in Antiarrhythmic Drug Therapy xiii

Peter R. KoweyandGeraldV. Naccarelli

Basic Electrophysiology 325

Augustus O. Grant

Available evidence suggests that the ion channels that generate the normal actionpotential are also the basis for the arrhythmias that occur in disease states. There-fore, a thorough understanding of the function of the ion channels that generate theaction potential is an important foundation for understanding the bases of arrhyth-mias and their treatment. This need is made all the more pressing by the discoveriesin molecular genetics and membrane biophysics that have elucidated the funda-mental mechanisms of a broad range of cardiac arrhythmias.

Pharmacokinetics/Pharmacodynamics of Antiarrhythmic Drugs 341

Julia H. Indik and Raymond L.Woosley

This article describes the pharmacology of antiarrhythmic medications. Althoughthesemedications are broadly considered in terms of their blockade of either sodiumor potassium channels, they act by a variety of pharmacodynamic mechanisms.Elimination may be via hepatic metabolism or renal mechanisms, or a combination.In particular, interactions between antiarrhythmic medications and other drugs thatinterfere with hepatic metabolism by P450 enzymes is a source for toxicity.

How Does Genetics Influence the Efficacy and Safety of Antiarrhythmic Drugs? 359

Katherine T.Murray

Recent progress in genomic sequencing has begun to elucidate the basic mecha-nisms for several adverse responses, as well as the clinical efficacy, for antiarrhyth-mic drugs. DNA variants in drug metabolizing enzymes have been implicated inexcessive drug accumulation, and genetic variability in drug targets can identifyindividuals at increased risk for serious side effects, in particular proarrhythmia. Itis hoped that future advances in the area of genomic medicine will lead to moreindividually tailored or personalized pharmacologic therapy in the management ofcardiac arrhythmias.

Antiarrhythmic Drugs: Age, Race, and Gender Effects 369

DeborahWolbrette

Women have a higher risk of developing torsade de pointes when taking QT-pro-longing antiarrhythmic drugs. Elderly women with heart failure may have the highestrisk of proarrhythmia. Greater caution should be used when treating women withthese drugs, especially when additional risk factors for developing proarrhythmia

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are present. Women with congenital heart disease frequently experience arrhyth-mias during pregnancy, and use of antiarrhythmic drugs in this setting poses aspecial challenge. In the elderly population, the risk of antiarrhythmic drug usemay outweigh the benefit, especially in individuals with asymptomatic arrhythmias.Limited data suggest potential ethnic differences in arrhythmic substrates and inproarrhythmic response to antiarrhythmic drugs.

Antiarrhythmic Drug Therapy of Supraventricular Tachycardia 379

StevenA. Rothman

Pharmacologic therapy is commonly used for the acute treatment and termination ofparoxysmal supraventricular tachycardia (SVT) and continues to be an importantlong-term option for some patients. Drug choice depends on the correct diagnosisof the arrhythmia and an understanding of its mechanism. Pharmacologic agentscommonly used in the acute and chronic treatment of SVT are reviewed alongwith their effect on the various types of SVT. Drugs that are well tolerated with min-imal side effects are preferred over agents with perhaps more efficacy but higher riskof toxicity.

Pharmacologic Conversion of Atrial Fibrillation and Atrial Flutter 393

AlessandroMarinelli andAlessandro Capucci

Atrial fibrillation and atrial flutter are common arrhythmias in everyday clinical set-tings. Pharmacologic cardioversion (CV) is a simple and widely used strategy forthe treatment of these arrhythmias, and many drugs are currently available. Thechoice of drug is strongly influenced by the time elapsed from atrial fibrillation onsetand by a patient’s clinical subset. Electrical direct-current CV is the treatment ofchoice in long-lasting forms; nevertheless, some agents also show efficacy in thissetting. In addition, promising results come from studies on the efficacy and safetyof new antiarrhythmic drugs and from therapeutic approaches that reduce the needfor hospitalization and improve quality of life.

Chronic Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation UsingAntiarrhythmic Drugs: Update 2010 409

John P.MorrowandJames A. Reiffel

Atrial fibrillation (AF) is a growing public health concern. For most patients the treat-ment of AF involves antiarrhythmic drugs. Despite the widespread use of antiar-rhythmic drugs for the conversion of AF and maintenance of normal sinus rhythm,their use is limited by modest efficacy, frequent intolerance, and the potential for se-rious ventricular proarrhythmia and organ toxicity. Better medications are urgentlyneeded. Optimizing the way current agents are used is vital in the interim. This articlediscusses such issues.

Rate Control in Atrial Fibrillation 419

Isabelle C. Van Gelder andHessel F. Groenveld

Rate control may now be adopted as a first-choice therapy in a variety of patients,especially older relatively asymptomatic patients with hypertension or other under-lying heart diseases. The goal of rate control therapy is to minimize symptoms, im-prove quality of life, decrease the risk of development of heart failure, and preventthromboembolic complications. A lenient rate control approach may be the initial

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therapeutic strategy. If symptoms persist, a stricter rate control approach may beadopted. Although long-term randomized studies are lacking, the evidence availablesuggests that a b-blocker with or without digoxin is the first-choice rate controltherapy.

AcuteAntiarrhythmic Therapy of Ventricular Tachycardia andVentricular Fibrillation 429

Mohan N.Viswanathan and Richard L. Page

Ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) are oftenassociated with underlying structural heart disease and require prompt assessmentand treatment. Acute treatment involves initial hemodynamic stabilization of the pa-tient followed by suppressive treatment with pharmacologic and nonpharmacologicapproaches for reducing the risk of recurrence of ventricular arrhythmias and poten-tial development of sudden cardiac death. This article reviews acute antiarrhythmicdrug therapy for ventricular arrhythmias based on the clinical presentation.

Chronic Suppression of Ventricular Tachyarrhythmias in Patients with ICDs 443

Michael S. Zawanehand Bruce S. Stambler

In this review, we examine the data evaluating the role of adjuvant therapy with anti-arrthymic drugs (AADs) in chronic suppression of ventricular tachyarrhythmias in thepatient with an ICD. It must be noted that all uses of AADs for this indication repre-sent “off-label” prescription. No AAD is approved by the Food and Drug Administra-tion (FDA) specifically as a therapy to reduce ICD shocks.

Aggravation of Arrhythmia byAntiarrhythmic Drugs (Proarrhythmia) 459

PhilipJ. Podrid

Arrhythmia aggravation by antiarrhythmic drugs (proarrhythmia) can be caused byworsening or a change of a preexisting arrhythmia, development of a new arrhyth-mia, or development of a bradyarrhythmia. Aggravation of arrhythmia usually occurswithin several days of beginning an antiarrhythmic drug or increasing the dose of thedrug. The time of occurrence is based on the particular drug and its pharmacokineticproperties. Although there are no ways to predict the patient at risk for developingarrhythmia aggravation with any specific agents, risk factors include QT interval pro-longation, elevated serum levels of the drug, electrolyte abnormalities, presence ofheart failure, a history of a sustained ventricular tachyarrhythmia, and underlyingmyocardial ischemia.

Advances in Antiarrhythmic Drug Therapy: New and Emerging Therapies 471

Arnold Pinter and Paul Dorian

Despite major advances in the nonpharmacologic therapy for arrhythmias in thepast decades, there is still a substantial role for antiarrhythmic drugs especiallyin the treatment of atrial fibrillation and ventricular tachycardia, the most effectiveof which is amiodarone. Dronedarone has been developed by modifying the amio-darone molecule, thus retaining its multichannel blocking action while still reducingits toxicity. New potassium channel blockers such as vernakalant are currentlyunder development for the treatment of atrial fibrillation and flutter. So-called up-stream therapies such as renin-angiotension system antagonists, statins, and n-3polyunsaturated fatty acids offer promise for the treatment of antiarrhythmia. Thisarticle reviews dronedarone, which is already approved and available; antiarrhyth-mic agents that are the most advanced in development; and upstream therapy foratrial fibrillation.

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Principles of Anticoagulation and New Therapeutic Agents in Atrial Fibrillation 479

Pamela S.N. Goldman andMichael D. Ezekowitz

Anticoagulation is required in cardiac arrhythmias, specifically atrial fibrillation (AF)and atrial flutter, to reduce the risk of thromboembolism. Principles of anticoagula-tion of both AF and atrial flutter are similar because the location and nature of thearrhythmias are similar. Approximately 2 million people in the United States are af-fected by AF, and the prevalence is expected to exceed 10 million by the year2050. Warfarin is known to reduce stroke risk by 68% in patients with AF and isthe most effective agent for this indication, although it is not without risk. Antithrom-botic therapy with antiplatelets or anticoagulants is recommended for most patientswith AF. This review discusses the principles of anticoagulation and the mechanismof action, pharmacologic profile, and phase of development of the therapeuticagents used as anticoagulants.

Index 493