Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ 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. + MECHANISM OF TOXICITY Download Section PDF Listen +++ ++ 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. 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). 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. IV administration of bretylium initially causes release of catecholamines from nerve endings, followed by inhibition of catecholamine release. 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). 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. 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. 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). + TOXIC DOSE Download Section PDF Listen +++ ++ 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. ++ Ingestion of twice the daily therapeutic dose should be considered potentially life-threatening (usual therapeutic doses are given in Table II–3). An exception to this rule of thumb is amiodarone, which is distributed so extensively to tissues that even massive single overdoses produce little or no toxicity (toxicity usually occurs only after accumulation during chronic amiodarone dosing). + CLINICAL PRESENTATION Download Section PDF Listen +++ ++ Tocainide and mexiletine Side effects with therapeutic use may include dizziness, paresthesias, tremor, ataxia, and GI disturbance (nausea, vomiting, heartburn). A hypersensitivity syndrome (fever, rash, eosinophilia) has been described with mexiletine, and most commonly affects Japanese males. Overdose may cause sedation, confusion, coma, seizures, respiratory arrest, and cardiac toxicity (sinus arrest, atrioventricular [AV] block, asystole, and hypotension). As with lidocaine, the QRS and QT intervals are usually normal, although they may be prolonged after massive overdose. Flecainide, propafenone, and moricizine Side effects with therapeutic use include dizziness, blurred vision, headache, and GI upset. Ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia; see Table I–6) and sudden death may occur at therapeutic levels, especially in persons receiving high doses and those with reduced ventricular function. Propafenone has been associated with cholestatic hepatitis. Overdose causes hypotension, seizures, bradycardia, sinoatrial and AV nodal block, and asystole. The QRS and QT intervals are prolonged, and ventricular arrhythmias may occur. Flecainide may slow atrial fibrillation and convert it to atrial flutter with rapid conduction. Bretylium is no longer widely used and has been removed from advanced cardiac life support (ACLS) guidelines. The major toxic side effect of bretylium is hypotension caused by inhibition of catecholamine release. Orthostatic hypotension may persist for several hours. After rapid IV injection, transient hypertension, nausea, and vomiting may occur. Amiodarone, dronedarone, and dofetilide Acute overdose in a person not already on amiodarone is not expected to cause toxicity. Bradyarrhythmias, hypotension, and asystole have been observed during IV loading. Acute hepatitis and acute pneumonitis have rarely been associated with IV loading doses given over several days. Few overdoses of dofetilide have been reported but would be expected to produce QT-interval prolongation and torsade de pointes, as this is the major dose-related toxicity. With chronic use, amiodarone may cause ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia; see Table I–6) or bradyarrhythmias (sinus arrest, AV block). The most important life-threatening toxicity from amiodarone is pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis), which has a fatality rate of 10%. Amiodarone may also cause hepatitis, photosensitivity dermatitis, corneal deposits, hypothyroidism or hyperthyroidism, tremor, ataxia, and peripheral neuropathy. Mild elevation in liver enzymes is common; severe liver toxicity is rare. Chronic dronedarone use doubles the risk of death in patients with symptomatic heart failure. It is also contraindicated in patients with permanent atrial fibrillation. Dofetilide has been associated with QT prolongation and torsade de pointes, particularly in people whose renal function has deteriorated or who are taking other QT-prolonging drugs, and with the development of hypokalemia and/or hypomagnesemia. + DIAGNOSIS Download Section PDF Listen +++ ++ Is usually based on a history of antiarrhythmic drug use and typical cardiac and ECG findings. Syncope in any patient taking these drugs should suggest possible drug-induced arrhythmia. ++ Specific levels. Serum levels are available for most type Ia and type Ib drugs (see Table II–3); however, because toxicity is immediately life-threatening, measurement of drug levels is used primarily for therapeutic drug monitoring or to confirm the diagnosis rather than to determine emergency treatment. The following antiarrhythmic drugs may be detected in comprehensive urine toxicology screening: diltiazem, flecainide, lidocaine, metoprolol, phenytoin, propranolol, quinidine, and verapamil. Other useful laboratory studies include electrolytes, glucose, BUN and creatinine, liver enzymes, thyroid panel (chronic amiodarone), and ECG monitoring. ++Table Graphic Jump LocationTABLE II–3.ANTIARRHYTHMIC DRUGSView Table||Download (.pdf) TABLE II–3. ANTIARRHYTHMIC DRUGS Class Drug Usual Half-life (h) Therapeutic Daily Dose (mg) Therapeutic Serum Levels (mg/L) Major Toxicitya Ia Quinidine and related drugs Ib Tocainided 11–15 1,200–2,400 4–10 S,B,H Mexiletine 10–12 300–1,200 0.8–2 S,B,H Lidocaine (Anesthetics, Local) Phenytoin Ic Flecainide 14–15 200–600 0.2–1 B,V,H Encainideb,d 2–11 75–300 S,B,V,H Propafenoneb 2–10c 450–900 0.5–1 S,B,V,H Moricizined 1.5–3.5 600–900 0.02–0.18 B,V,H II Beta blockers III Amiodarone 50 days 200–600 1.0–2.5 B,V,H Bretylium 5–14 5–10 mg/kg (IV loading dose) 1–3 H Dofetilide 10 0.125–1 B,V Dronedarone 13–19 800 B Ibutilide 2–12 N/A B,V,H Sotalol (Beta-Adrenergic Blockers) IV Calcium antagonists Miscellaneous Adenosine <10 seconds N/A S,B,V,H aMajor toxicity: B, bradyarrhythmias; H, hypotension; S, seizures; V, ventricular arrhythmias.bActive metabolite may contribute to toxicity; level not established.cGenetically slow metabolizers may have half-lives of 10–32 hours. Also, metabolism is nonlinear, so half-lives may be longer in patients with overdose.dEncainide, morizicine, and tocainide are no longer sold in the United States.This table was updated with assistance from Elizabeth Birdsall, PharmD. + TREATMENT Download Section PDF Listen +++ ++ Emergency and supportive measures Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Note: Type Ia antiarrhythmic agents should not be used to treat cardiotoxicity caused by type Ia, type Ic, or type III drug. Continuously monitor vital signs and ECG for a minimum of 6 hours after exposure, and admit the patient for 24 hours of intensive monitoring if there is evidence of toxicity. Specific drugs and antidotes. In patients with intoxication by type Ia or type Ic drug, QRS prolongation, bradyarrhythmias, and hypotension may respond to sodium bicarbonate, 1–2 mEq/kg IV. The sodium bicarbonate reverses cardiac-depressant effects caused by inhibition of the fast sodium channel. Torsade de pointes should be treated with IV magnesium, repletion of potassium, and, if necessary, overdrive cardiac pacing. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I–38). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Enhanced elimination. Owing to extensive tissue binding with resulting large volumes of distribution, dialysis and hemoperfusion are not likely to be effective for most of these agents. Hemodialysis may be of benefit for tocainide or flecainide overdose in patients with renal failure, but prolonged and repeated dialysis would be necessary. No data are available on the effectiveness of repeat-dose charcoal.