JAMES M. WOOTEN, PharmD Assistant Professor of Medicine, University of Missouri-Kansas City School of Medicine, Kansas City. Dr Wooten is a member of the RN Editorial Board.

An estimated 1 to 2 million serious adverse drug reactions occur each year.^1-3 Adverse drug effects range from mild to fatal, and at the life-threatening end of that spectrum are cardiac arrhythmias, which can be induced both by cardiac and noncardiac drugs. Familiarity with these agents and their effects on heart rhythm will keep you alert to these adverse events.

TABLE 1 Noncardiac drugs that may cause arrhythmias

The how and why of arrhythmogenesis Some drugs induce arrhythmias by directly affecting the heart's conduction system and others act on the heart indirectly, through their effect on the sympathetic or parasympathetic nervous system or by causing other physiological changes, such as hypotension or electrolyte disorders. Not all patients are equally susceptible to drug-induced arrhythmias. Those at increased risk include the elderly and patients taking multiple medications. Patients with conditions such as heart failure, coronary artery disease, sick sinus syndrome, fluid and electrolyte imbalance, hypotension, or other cardiovascular problems, are probably at higher risk. Those conditions, as well as preexisting cardiac rhythm disturbances, can either cause or potentiate the formation of arrhythmias, particularly in the presence of arrhythmogenic drugs.

A wide range of drugs has been implicated in the development of cardiac arrhythmias. Tables 1 and 2 primarily include drugs that induce heart rhythm changes by directly affecting the heart or by affecting the release or metabolism of major transmitters, such as the catecholamines. Some are well known and some not so well known for their arrhythmogenic effects.

TABLE 2:Cardiac drugs that may cause arrhythmias

The types of arrhythmias induced by drugs vary widely, as do the agents that cause them. Some drugs simply increase or decrease heart rate, and others influence cardiac conduction and the refractory period. Drug-related or not, arrhythmias arise and are maintained by 3 basic mechanisms: abnormal impulse formation, abnormal impulse conduction, and triggered activity. Researchers recently discovered that a drug's ability to block a specific potassium current in the heart's conduction tissue causes many severe drug-induced arrhythmias. Disruption of this current—the human ether-a-go-go-related gene (HERG)-encoded delayed rectifier potassium current—may induce prolongation of the QT interval, which can lead to deadly arrhythmias. The FDA recently requested that drugs known to disrupt this current undergo further testing to determine the drug's true safety profile.⁴

Certain drugs, such as quinidine and other antiarrhythmics, affect automaticity, the intrinsic firing rate of autonomic tissue, and alter the heart's resting membrane potential. Other drugs, like propafenone (Rythmol) or flecainide (Tambocor), delay or block the conduction of electrical impulses, causing reentry arrhythmias, such as sustained ventricular tachycardia. Still others, like digoxin (Lanoxin), especially in cases of toxicity, may induce triggered rhythms—such as atrial or ventricular tachycardia—by delaying repolarization, thus prompting normally quiet myocardial fibers to become active.

Life-threatening form of tachycardia Serious arrhythmias can arise from a drug's effect on ventricular depolarization and repolarization, which correspond to the QT interval on an ECG. Prolongation of the QT interval can lead to the development of serious ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (a form of polymorphic ventricular tachycardia). Although torsades de pointes is usually self-limiting, it is potentially life-threatening because it can progress to ventricular fibrillation. Some patients develop torsades de pointes after long-term therapy with antiarrhythmic drugs, but most cases occur soon after initiating treatment with the offending agent. In patients with atrial fibrillation, torsades de pointes can develop after normal sinus rhythm is achieved.

Noncardiac drugs can also induce torsades de pointes, usually as a result of toxic blood concentrations of the agent. Several drugs were taken off the market—including the GI drug cisapride (Propulsid) and 2 second-generation antihistamines, astemizole (Hismanal) and terfenadine (Seldane)—because they were implicated in the development of this life-threatening arrhythmia. (Cisapride remains available via a limited-use protocol.) Warnings of the risk of prolongation of QT intervals and torsades de pointes were recently added to labeling for the antiemetic droperidol (Inapsine) following reports of these effects within the normal dosage range.