QT Prolonging Drugs


Article Author:
Khashayar Farzam


Article Editor:
Vijai Tivakaran


Editors In Chief:
Scott Klenzak
Barry Liskow
Brian Farah


Managing Editors:
Avais Raja
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Carrie Smith
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Khalid Alsayouri
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James Hughes
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Nazia Sadiq
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Phillip Hynes
Tehmina Warsi


Updated:
6/29/2019 2:12:48 PM

Indications

The heart has an electrical system that allows it to contract in a rhythm. A key 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 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 largely limited to heart rates of 60 to 100 beats per minute and clinicians must factor in the heart rate when assessing the QTc.[8]

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 the most common form of polymorphic ventricular tachycardia; an unstable cardiac rhythm. This rhythm may cease on its own and go into sinus rhythm or it may degenerate into ventricular fibrillation. The most common symptom is syncope. Patients with torsade are administered a 2-4g bolus of magnesium sulfate and must undergo cardioversion if hemodynamically unstable. Isoproterenol can also be used after to increase the heart rate, thereby decreasing the absolute QT interval. It is generally accepted that QT prolongation past 500 ms carries an increased risk of torsades de pointes; however, if the QT prolongation is severely prolonged, ventricular fibrillation is a certainty.

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 who have 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 QT prolongation. However, subsets of cardiac patients may have an increased risk of mortality if they suffer from QT prolongation.[10]

Pharmacological agents are the most common cause of QT prolongation given the broad range of medications that may induce it. As well, torsade which is drug-induced is reversible by the discontinuation of the offending drug. 

QT-Prolonging Medications

Anti-psychotics: Haloperidol, ziprasidone, quetiapine, thioridazine, olanzapine, risperidone  

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.

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 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]

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 via 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 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]

Adverse Effects

QT prolongation increases the risk of torsades de pointes, a potentially lethal arrhythmia. Torsades de pointes is the most common 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 it may degenerate into ventricular fibrillation.

The clinical feature of this arrhythmia is often syncope. However, it is possible for it to 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 would be further exacerbated by these medications.[18]

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 and/or exceeds 500 ms.[19]

Monitoring of electrolytes, specifically potassium, magnesium, and calcium, should be done in patients who have 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

Treatment of QT prolongation requires a multi-factorial approach. Genetic causes require a specific diagnosis, which allows for the avoidance of aggravating factors. Usage of beta-blockers may lower the risk of torsades de pointes. 

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

At the time of admission and discharge, the nurse should make a note of all medications that affect the QT interval and notify the healthcare provider. Similarly, the pharmacist must keep track of all the medications the patient is prescribed and speak to the primary care provider if any medications can alter the QT interval. In most cases, medication-induced prolonged QT interval can be prevented by a proactive approach.


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QT Prolonging Drugs - Questions

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A 67-year-old male has a QTc of 517 ms on an electrocardiogram (ECG). Which of the following medications is contraindicated in this patient?



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A 71-year-old male presents to his primary care provider for medication refills. He has a past medical history of coronary artery disease, schizophrenia, and insomnia. He is being treated with numerous medications. An electrocardiogram (ECG) is performed and shows a heart rate of 67, regular rhythm, no ST-segment elevations or depressions, and a QTc of 519 ms. For which of the following arrhythmias is this patient at highest risk?



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A 76-year-old male with a past history of severe, oxygen-dependent chronic obstructive pulmonary disease (COPD) and hypothyroidism presents for evaluation of paroxysmal atrial fibrillation. He is in normal sinus rhythm. A Holter monitor reveals frequent paroxysms of atrial fibrillation with rapid ventricular rate. He has been anticoagulated for the past 6 months. You decide to start dofetilide for maintenance of sinus rhythm. Which of the following is the best management approach?



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A 65-year-old male with a past history of coronary artery disease, paroxysmal atrial fibrillation, and diastolic congestive heart failure was recently seen by his primary care provider for depression and started on fluoxetine. His routine medications include aspirin, atorvastatin, lisinopril, metoprolol, and amiodarone. At a follow-up visit, his EKG reveals sinus bradycardia with a heart rate of 59 beats/min and QT interval of 610 msec. The patient denies any cardiac symptoms. What is the appropriate management at this time?



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A 67-year-old male with a past medical history of paroxysmal atrial fibrillation, systolic congestive heart failure, hypertension, and hyperlipidemia presents for evaluation. He denies any symptoms of shortness of breath, orthopnea, or leg edema. He was evaluated yesterday in the emergency department for a urinary tract infection. He was started on levofloxacin. His medication regimen includes lisinopril, carvedilol, dofetilide, warfarin, and atorvastatin. An EKG reveals sinus rhythm with a heart rate of 88 beats/min and a QT interval of 610 milliseconds. What is the appropriate next step?



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A 57-year-old male with a past history of paroxysmal atrial fibrillation, systolic congestive heart failure, coronary artery disease, and diabetes mellitus is electively admitted for loading with dofetilide. On admission, an EKG reveals normal sinus rhythm with a QT interval of 432 milliseconds. After the third dose of dofetilide, the patient's EKG reveals a QT interval of 612 milliseconds. Which of the following would be the best next step in therapy?



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A 77-year-old female presents to the emergency department after a colonoscopy with symptoms of palpitations. She reports that she has had heart palpitations before but did not seek medical attention because she did not find them to be bothersome. An EKG reveals atrial fibrillation with rapid ventricular rate and a QT interval of 610 milliseconds. She denies a history of an atrial fibrillation diagnosis. She appears comfortable and is on room air. Her past history includes current diverticulitis, depression, and hypothyroidism. Her medications include levothyroxine, levofloxacin, and fluoxetine. You consider antiarrhythmic therapy versus cardioversion to sinus rhythm. Which of the following would be the best option?



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QT Prolonging Drugs - References

References

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