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Because of their actions on the heart, antiarrhythmic drugs are extremely toxic, and overdoses are often life-threatening. Several classes of antiarrhythmic drugs are discussed elsewhere in Section II: type Ia drugs (quinidine, disopyramide, and procainamide); type II drugs (beta blockers); type IV drugs (calcium antagonists); and the older type Ib drugs (lidocaine, Anesthetics, Local, and phenytoin). This section describes toxicity caused by type Ib (tocainide and mexiletine); type Ic (flecainide, encainide, propafenone, and moricizine); and type III (bretylium, amiodarone, dronedarone, and dofetilide) antiarrhythmic drugs. Sotalol, which also has type III antiarrhythmic actions, is discussed in the section on beta-adrenergic blockers.


  1. Type I drugs in general act by inhibiting the fast sodium channel responsible for initial cardiac cell depolarization and impulse conduction. Type Ia and type Ic (which also block potassium channels) slow depolarization and conduction in normal cardiac tissue, and even at normal therapeutic doses the QT (types Ia and Ic) and QRS intervals (type Ic) are prolonged. Type Ib drugs slow depolarization primarily in ischemic tissue and have little effect on normal tissue or on the ECG. In overdose, all type I drugs have the potential to markedly depress myocardial automaticity, conduction, and contractility.

  2. Type II and type IV drugs act by blocking beta-adrenergic receptors (type II) or calcium channels (type IV). Their actions are discussed elsewhere (type II, Beta-Adrenergic Blockers; type IV, Calcium Channel Antagonists).

  3. Type III drugs act primarily by blocking potassium channels to prolong the duration of the action potential and the effective refractory period, resulting in QT-interval prolongation at therapeutic doses.

    1. IV administration of bretylium initially causes release of catecholamines from nerve endings, followed by inhibition of catecholamine release.

    2. Amiodarone is also a noncompetitive beta-adrenergic blocker and has sodium and calcium channel–blocking effects, which may explain its tendency to cause bradyarrhythmias. Amiodarone may also release iodine, and chronic use has resulted in altered thyroid function (both hyper- and hypothyroidism).

    3. Dronedarone is an analog of amiodarone but does not contain iodine and does not affect thyroid function. It exhibits properties of all four antiarrhythmic classes.

    4. Dofetilide is used to maintain sinus rhythm in patients with atrial fibrillation. It is associated with QT prolongation and a risk for torsade de pointes, as discussed further in the following text.

  4. Relevant pharmacokinetics. All the drugs discussed in this section are widely distributed to body tissues. Most are extensively metabolized, but significant fractions of tocainide (40%), flecainide (40%), dofetilide (80%), and bretylium (>90%) are excreted unchanged by the kidneys (see also Table II–66).


In general, these drugs have a narrow therapeutic index, and severe toxicity may occur slightly above or sometimes even within the therapeutic range, especially if two or more antiarrhythmic drugs are taken together.

  1. Ingestion of twice the daily therapeutic dose should be ...

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