Continuing Education Activity

The heart has an electrical system that allows it to contract in a rhythm. A vital aspect of this electrical system is depolarization and repolarization. The focus of this activity is on the QT interval. It is measured from the Q wave until the T wave, and the QT interval clinically represents the repolarization of the ventricles. Many commonly used medications exhibit QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant caution in healthy patients. This activity outlines the mechanism of action, significant adverse effects, contraindications, monitoring, and toxicity of QT-prolonging medications, so the interprofessional team can direct patient therapy in treating conditions where patients are using these agents, in particular when they have multiple such agents.

Objectives:

• Describe the possible mechanisms by which drugs might prolong the QT interval.
• Summarize the at-risk patient populations for QT-prolonging medications.
• Review the necessary monitoring when patients are using medications that can cause QT prolongation.
• Explain the importance of improving care coordination among the interprofessional team to enhance and monitor the delivery of care for patients who are using medications that can prolong the QT interval.

Indications

The heart has an electrical system that allows it to contract in a rhythm. A vital aspect of this electrical system is depolarization and repolarization. The electrical activity is conducted through the sinoatrial (SA) node and atrioventricular (AV) node and into the ventricles. This electrical activity is clearly outlined on an electrocardiogram (ECG) with P waves, the QRS complex, and T waves. The P wave represents the electrical activity of the atrium. The QRS complex shows the depolarization of the ventricles. Lastly, the T wave shows the repolarization of the ventricles.[1][2]

The focus of this article is on the QT interval. It is measured from the Q wave until the T wave, and the QT interval clinically represents the repolarization of the ventricles. When measured on an ECG, the QT interval lengthens when the heart is beating slower and shortens when the heart is beating faster. That is why an adjusted version of the QT interval is used: QTc. This allows for an accurate QT interval at lower and higher heart rates. There are different formulas used to obtain the QTc interval.[3][4]

• Bazett
• Fridericia
• Framingham

Bazett's is the most commonly used formula and is done by dividing the QT interval by the square root of the R-R interval.[5] Fridericia is a similar formula, except it uses the cube root of the R-R interval.[6][7] Framingham is a more complex formula, but the literature has shown it may be the most superior formula. Bazett's is automatically calculated on most ECG machines, and its limitations are underestimation and overestimation of the QTc in the cases of bradycardia and tachycardia, respectively. Its accuracy is limited mainly to heart rates of 60 to 100 beats per minute, and clinicians must factor in the heart rate when assessing the QTc.[8] Optimal accuracy is achieved in the 60 to 80 heart rate range.

A normal QTc in a male is 440 ms or less, and in a female, it is 460 ms or less. Those with prolonged QT are at risk for one of the potentially deadly arrhythmias known as torsades de pointes. It is a form of polymorphic ventricular tachycardia, an unstable cardiac rhythm. This rhythm may cease on its own and go into sinus rhythm or degenerate into ventricular fibrillation. It is important to distinguish torsades de pointes from other forms of polymorphic ventricular tachycardia. For an arrhythmia to be classified as torsades de pointes, it must also occur in the setting of QT prolongation. Other forms of polymorphic ventricular tachycardia can occur with a normal QT interval and usually occur due to ischemia.

The most common symptom of Torsades de Pointes is syncope. If hemodynamically unstable, patients with torsades are administered a 2 to 4 g bolus of magnesium sulfate and must undergo cardioversion. Isoproterenol can also be used to increase the heart rate, thereby decreasing the absolute QT interval. However, this medication has limited availability in many settings. Other second-line options can include lidocaine. Amiodarone, while used for ventricular tachycardia, should generally not be used as it has some QT-prolonging properties. Phenytoin has also been identified as a potential third-line treatment option.

It is generally accepted that QT prolongation past 500 ms carries an increased risk of torsades de pointes. The degree of QT prolongation is correlated to the level of risk, with severe prolongations being associated with much higher risk. The most common etiology is acquired prolongation due to medication use, followed by electrolyte abnormalities. Less common are various conditions. 

Prolonged QT Etiologies

• Pharmacological
• Long QT syndrome
• Jervell and Lange-Neilson syndromes[9]
• Romano-Ward syndrome
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Hypothyroidism
• Hypothermia

Literature has shown that people with diabetes and those suffering from certain inflammatory diseases may suffer from mildly prolonged QT. This is also true in those with heart disease. No major evidence in the general population indicates changes in mortality are associated with mild QT prolongation. However, subsets of cardiac patients may have an increased mortality risk if they suffer from QT prolongation, especially when combined with other risk factors.[10]

Pharmacological agents are the most common cause of QT prolongation, given the broad range of medications that may induce it. Treatment is primarily aimed at discontinuing the offending drug, as it usually leads to normalization of the QT interval. 

QT-Prolonging Medications

Antipsychotics: Haloperidol, ziprasidone, quetiapine, thioridazine, olanzapine, risperidone, droperidol 

Antiarrhythmics: Amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide

Antibiotics: Macrolides, fluoroquinolones

Antidepressants: Amitriptyline, imipramine, citalopram, amitriptyline

Others: Methadone, sumatriptan, ondansetron, cisapride

A vast number of medications prolong the QT interval. They are preferably classified based on the degree of QT prolongation they induce. This is specifically medication-dependent. Caution is advised when combining QT-prolonging medications or when using these medications in those with electrolyte abnormalities, such as hypokalemia. Clinically, patients at risk of electrolyte derangements must also be considered. Specifically, those experiencing extrarenal losses and/or those on diuretics are at risk for electrolyte abnormalities and hence may have unknown prolonged QTc. 

Many commonly used medications, such as diphenhydramine and azithromycin, exhibit QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant immediate caution in healthy patients. These medications bind to the human ether-related gene (hERG) channels and reduce electrical conduction through the potassium ion channels. This results in delayed repolarization of the heart.[11] The actual risk of torsades de pointes remains unknown with these medications. 

Mechanism of Action

The QT interval is measured from the beginning of the QRS complex to the end of the T wave. Mechanisms that prolong the action potential duration can prolong the QT interval. Specifically, this occurs by delaying the third phase of repolarization. When the hERG channels are altered, there are changes made to the potassium ion channels. This causes an impairment of the channel's ability to conduct the electrical activity. The result is prolonged cardiac repolarization.

This mechanism can occur via genetic changes to hERG and/or drug binding to these channels. Different drugs will induce changes in the hERG channels to variable degrees. Hence, different medications induce different levels of QT prolongation.[11][12][13]

Administration

QT-prolonging drugs can exist in various forms and be administered depending on the indication. This includes oral, rectal, intravenous, intramuscular, and other forms of administration. Any medication that is absorbed systemically can prolong the QT interval if they have QTc prolonging properties. 

Adverse Effects

QT prolongation increases the risk of torsades de pointes, a potentially lethal arrhythmia. Torsades de pointes is a form of polymorphic ventricular tachycardia; it is initiated when a premature ventricular contraction occurs in the setting of a prolonged QT interval. This is known as the "R on T" phenomenon.[14] It may cease on its own and return to sinus rhythm or degenerate into ventricular fibrillation. Not all polymorphic ventricular tachycardia is torsades de pointes, as this rhythm must occur in the setting of a prolonged QT interval. 

The clinical feature of this arrhythmia is often syncope. However, it can be asymptomatic. If it degenerates into ventricular fibrillation, death is the likely outcome if there is no intervention.[15][16][17]

Contraindications

Patients diagnosed with long QT syndrome or any genetic causation of prolonged QT syndrome should use these medications with caution. Patients with hypokalemia, hypomagnesemia, and hypocalcemia should be put on QT-prolonging medications with caution. Certain electrolyte derangements prolong QT, which these medications would further exacerbate.[18] Patients on diuretics or those experiencing symptoms such as diarrhea may have electrolyte abnormalities. Many of these patients may not have had electrolytes checked prior to being administered a QT-prolonging medication, and hence there must be cautious when prescribing these medications. 

Medication interactions are another form of dangerous contraindication. Certain QT-prolonging medications are substrates of the cytochrome P450 (CYP450) system. If a patient is using a CYP450 inhibitor medication at the same time, there is a risk of significantly greater QT prolongation.

Monitoring

Patients using medications that prolong the QT interval should ideally be monitored with an ECG. Some medications induce minimal QT prolongation, and if there is no preexisting QT prolongation, then monitoring is unnecessary. A normal QTc in men is 440 ms or less, and in women, it is 460 ms or less. It is ideal to have patients within those parameters when on a QT-prolonging medication. A longer QTc is tolerated until it approaches or exceeds 500 ms.[19]

The monitoring of electrolytes, specifically potassium, magnesium, and calcium, should be done in patients with QT prolongation. The risk of further QT prolongation and torsades de pointes is increased when electrolyte abnormalities coexist with these medications.

Enhancing Healthcare Team Outcomes

Prevention and treatment of QT prolongation require an interprofessional approach. Genetic causes require a specific diagnosis, which allows for avoiding aggravating factors. The usage of beta-blockers may lower the risk of torsades de pointes. 

Pharmacological etiologies of QT prolongation are treated by ceasing the offending medication. Any coexisting electrolyte abnormalities should be treated. Optimization of potassium, magnesium, and calcium is essential to minimize the risk of torsades de pointes.[20]

At the time of admission and discharge, the nurse should note all medications that affect the QT interval and notify the team. Cardiology nurses are responsible for monitoring patients, administering treatments, and reporting any change in clinical status to the clinician. Similarly, the pharmacist must keep track of the patient's medications and speak to the provider if any drugs can alter the QT interval. In most cases, medication-induced prolonged QT intervals can be prevented by an interprofessional, proactive approach. [Level 5]