Arrhythmias
Corey Diamond, PharmD
In October, the American Heart Association (AHA) published a new scientific statement on drug-induced arrhythmias to address the growing list of drug classes with proarrhythmic properties, both supraventricular and ventricular. These drugs are widely recognized for their contribution to morbidity and mortality within the hospital setting. However, their exact prevalence isn’t entirely clear.
This statement should serve as a resource for pharmacists and clinicians alike to aid in the recognition of drug-induced arrhythmias—a common condition in the hospital setting, unfortunately.
When put into context of the average number of medications profiled on patients each year in the hospital, this publication should renew the need to keep drug-induced arrhythmias in the forefront of a clinician’s differential diagnosis.
Included in the AHA statement are seven tables with the most common agents known to cause arrhythmias, broken down via pathology.
This article summarizes the most relevant information from the statement for practicing clinical pharmacists. The full report is available at http://apha.us/AHAdruginducedarrhythmias.
Bradyarrhythmias
Offending agents. The precise incidence and risk factors for bradyarrhythmias are unclear and cannot be narrowed to a singular class. In general, the most common agents known to cause the condition are those that effect the automaticity of the sinus or atrioventricular node.
Drugs that either stimulate the sympathetic nervous system (chiefly beta-blockers) or inhibit the parasympathetic nervous system (acetylcholinesterase inhibitors) are some of the more apparent causes of bradyarrhythmias, as their mechanisms are relatively straightforward. However, some classes of drugs, especially antidepressants such as citalopram, escitalopram, and fluoxetine, may not be a first consideration.
Initial management and monitoring. The step in management of drug-induced bradyarrhythmia is to discontinue the agent. Although death from bradycardia is uncommon, pharmacists should still exercise caution in adding on probradyarrhythmic medications unnecessarily, as there may still be downstream consequences.
In patients who suffer from bradyarrhythmias due to acute agent toxicities, a number of counter agents may be used, including charcoal lavage or glucagon for beta-blocker and calcium channel blocker toxicity. A high-dose regular insulin bolus and infusion has been demonstrated to improve hemodynamics in patients with refractory drug-induced (e.g., adenosine, amiodarone, flecainide, propafenone, sotalol, quinidine, and disopyramide) bradyarrhythmias associated with atrioventricular (AV) node inhibition.
Atrial fibrillation (AF) and atrial flutter (AFL)
Offending agents. Drugs known to cause AF/AFL include cardiovascular medication, alcohol, stimulants, anticancer agents, and immune modulators. Pharmacists should be aware of agents with catecholamine properties—essentially beta-agonists—such as dobutamine, dopamine, and epinephrine.
The bisphosphonates drug class may fly under the pharmacist’s radar, however. Although the precise mechanism is unclear, bisphosphonates may cause AF via the release of inflammatory cytokines that shorten the atrial contraction period. In addition, new evidence now suggests that trastuzumab—an HER2 receptor inhibitor for breast cancer—may cause AF via ion channel remodeling triggered by oxidative stress.
Initial management and monitoring. While many drugs may precipitate AF/AFL, pharmacists can be on the lookout for a few key risk factors for specific drugs if a concern exists.
Adenosine, for example, may increase the risk for atrial flutter in patients with premature atrial complexes. Alcohol may produce AF/AFL as doses exceed 30 g per day (equivalent to about one to three drinks per day). Advanced age, AF history, or heart failure may increase the likelihood of dobutamine-induced AF.
Pharmacists can mitigate the risk of AD/AFL by starting low and going slow with dosage, as well as avoiding likely stimulants. The good news is that—unlike with bradyarrhythmias—most patients, if hemodynamically stable, will convert to normal sinus rhythm upon discontinuation of the offending agent.
Atrial tachycardia (AT)
Offending agents. Similarly to those that cause AF/AFL, drugs that may exacerbate or trigger AT include stimulants such as catecholamines/beta-agonists. In addition, particular concentrations of proarrhythmic drugs are associated with a greater risk of AT, such as theophylline levels greater than 20 mg per mL and digoxin levels exceeding 2 ng per mL. Any condition that may increase digoxin serum levels can therefore increase the risk of AT, such as kidney disease, hypomagnesemia, or drug–drug interactions.
Initial management and monitoring. For prevention, much like with AF and AFL, the best intervention pharmacists can make is advocating for the avoidance of stimulant use or recommending alternatives. In addition, pharmacists should closely monitor digoxin or theophylline serum concentrations. Treatment of drug-induced AT can include use of rate control antiarrhythmics, overdrive pacing, or catheter ablation.
Atrioventricular nodal reentrant tachycardia (AVNRT)
Offending agents. While AVNRT makes up about 60% of all supraventricular tachycardias, the exact drug-induced percentage is unknown. In general, drugs that enhance AV node conduction carry a greater risk of triggering AVNRT. These types of drugs, unsurprisingly, tend to be stimulants, such as amphetamines, caffeine, and other catecholaminergics that increase sympathetic tone.
Initial management and monitoring. As always, discontinuing the offending agent is the first step. Current AHA/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines for supra-ventricular tachycardia specifically recommend vagal maneuvers and I.V. adenosine for initial treatment.
Second-line treatment with a nondihydropyridine calcium channel blocker or beta-blocker may be acceptable as well for short-term management.
Monomorphic ventricular tachycardia (VT)
Offending agents. MonomorphicVT typically occurs in patients with underlying structural heart disease, often precipitated by conduction abnormalities that are a result of cardiac remodeling and fibrosis. While drug-induced monomorphic VT is not entirely common, there has been documented association within the literature with sodium channel inhibitors and particularly those of class IC, such as flecainide or propafenone. Similarly to AT, digoxin and theophylline may precipitate monomorphic VT via intracellular calcium overload.
Initial management and monitoring. Pharmacists should take particular heed in starting these medications, especially class IC sodium channel inhibitors in patients with a history of preexisting structural heart disease.
Digoxin and theophylline therapeutic monitoring is warranted to the same extent as with AT. Pharmacists should recognize that current AHA/ACC/HRS guidelines recommend pharmacological intervention in patients with monomorphic VT only if patients are hemodynamically stable; otherwise they should be cardioverted.
Use of I.V. amiodarone, lidocaine, or procainamide has shown efficacy in reversing this form of VT. Pharmacists should also recall that, if there is suspicion of VT induced by local anesthetics, such as bupivacaine or lidocaine, lipid emulsions have confirmed efficacy for toxicity reversal.
Brugada syndrome
Offending agents. Brugada syndrome, a type of genetic arrhythmia characterized by the type 1 ECG pattern, may occasionally be triggered by drugs that disrupt sodium potassium or calcium currents, such as sodium channel blockers, tricyclic antidepressants, and general anesthetics. Initial management and monitoring.
Initial management and monitoring. Brugada syndrome often presents asymptomatically but rarely may escalate to VT or ventricular fribrillation. Once a patient is symptomatic, Brugada syndrome is confirmed via ECG. Most patients may be managed through nonpharmacological methods, such as with implantable cardioverters.
AHA/ACC/HRS guidelines currently contain a class I recommendation for quinidine or catheter ablation for patients who are not candidates for an intracardiac device.
Torsades de pointes (TdP)
Offending agents. In addition to information in the AHA statement, pharmacists should use the Arizona Center for Education and Research on Therapeutics (AzCERT) as a resource. The center currently preserves an updated compendium of QT-prolonging agents.
Initial management and monitoring. In general, the most effective action a pharmacist may take to reduce risk of TdP in patients taking QT-prolonging drugs is actively monitoring and correcting electrolyte levels.
Current AHA/ACC/HRS guidelines recommend potassium and magnesium target serum concentrations (>4.0 mEq/L and 2.0 mEq/L, respectively). Because of their ubiquity, not all QT-prolonging agents can be avoided. If this is the case, the pharmacist should try to maintain a QT interval of less than 500 ms, if possible, with daily monitoring.