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PRINCIPLES OF ANTIARRHYTHMIC DRUG THERAPY
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The treatment of patients with tachyarrhythmias has evolved dramatically over the past several decades. However, even with advances in catheter ablation and implantable cardioverter-defibrillators, antiarrhythmic drug therapy remains a cornerstone in the treatment of nearly every form of cardiac arrhythmia. An in-depth knowledge of the pharmacology of antiarrhythmic drugs, including their pharmacokinetics and pharmacodynamics, is essential to their successful and safe implementation (Table 87–1).
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MECHANISMS UNDERLYING ANTIARRHYTHMIC AND PROARRHYTHMIC EFFECTS
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The development of cardiac arrhythmias and drug-induced proarrhythmias can be a result of abnormal impulse formation (ie, enhanced automaticity and triggered activities) and/or reentry. This section provides a brief overview of ionic and cellular mechanisms underlying the antiarrhythmic and proarrhythmic effects of the drugs.
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Ion Channel Physiology
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Antiarrhythmic drugs exert their effects on cardiac electrical impulse formation and propagation via their interaction with ionic channels or with membrane receptors and cellular pumps that subsequently influence ionic currents across the cell membrane. Cardiac ionic currents commonly targeted by antiarrhythmic drugs include inward sodium current (INa), L-type calcium current (ICa,L), and delayed rectifier outward potassium current (IK), which consists of two components—a rapidly activating component (IKr) and a slowly activating component (IKs). Although transient outward potassium current (Ito) is not commonly influenced by currently available antiarrhythmic drugs, it has been shown to contribute importantly to the genesis of polymorphic ventricular tachycardia and ventricular fibrillation.1 Therefore, antiarrhythmic drugs with selective Ito blockade will be favored in future drug development.
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Antiarrhythmic drugs that block the sodium channel appear to bind selectively to the channel during designated states and dissociate from the channel during the other states. Therefore, a sodium channel blocker will block the sodium channel differently depending on pathologic conditions. The maximal velocity of change ...