11.03.2020

Drug-induced QT Prolongation: A Review

In this month’s case study, we explore the risk of torsades de pointes (TdP), a rare type of arrhythmia. Despite several common palliative medications carrying known risk of QT prolongation, it remains difficult to predict the relative risk associated with their administration. Pharmacists can assist by identifying QT-prolonging medications and other drug-related considerations to help clinicians balance prescribing decisions with other patient-specific risk factors. We encourage you to download this month’s case study to share with your colleagues or continue reading below.

Long QT syndrome (LQTS) is a disorder of cardiac repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG).1 LQTS can be congenital or acquired and is associated with an increased risk of polymorphic ventricular tachycardia, also known as torsades de pointes (TdP). TdP is a rare type of arrhythmia, however is life-threatening thus warranting attention and recognition of precipitating risk factors. Drug-induced LQTS is the most common cause of acquired LQTS and will be the focus of this resource.1,2

THE QT INTERVAL

The ECG tracing represents the conduction pathway through the heart during each beat and is depicted generally as waves. A brief review of normal electrophysiology of cardiac conduction reveals that cardiac cells at rest are considered polarized, meaning no electrical activity takes place. A heart beat begins in the sinoatrial (SA) node, initiated as a sinus impulse and a wave of depolarization (action potential that prompts heart contraction) that spreads over the right and left atria, forming the P wave. Next, the wave is conducted from the atrioventricular (AV) node to the ventricles over the His bundle to the right and left bundle branches and the Purkinje system. The resulting atrial repolarization (return to the heart’s resting state) and early ventricular depolarization result in the QRS complex. Ventricular depolarization and subsequent repolarization lead to the completion of the cycle, forming the T-wave.3

The periods between each wave and complex are made up of intervals and segments. The QT interval represents the time required for the heart to repolarize after ventricular depolarization begins, from the start of the QRS complex to the end of the T wave. A normal QT interval duration is 420 milliseconds (msec) or less if heart rate is 60 beats per minute (bpm).3 Within this interval there is rapid movement of ions including sodium, potassium and calcium across cellular membranes. A malfunction in ion movement that causes an excess of sodium moving in or a decrease of potassium moving out may cause a surplus of positively charged ions and an extended repolarization phase, resulting in a prolonged QT interval.4

Heart rate can affect the time for repolarization with rapid heart rate producing a shortened QT interval. To correct for this, the QT interval is often expressed as the heart rate-corrected QT interval, or QTc. The QTc interval is considered prolonged if the values are greater than 450 msec in males and greater than 470 msec in females. The risk of cardiac events correlates with the extent of QTc prolongation. Ventricular arrhythmias, such as TdP, have been associated with a QTc greater than 500 msec.4

Hospice and palliative care (HPC) patient goals of care often do not make allowance for procedural interventions such as ECG tracing. Without an ECG as a baseline and/or ongoing measure of the QT interval, HPC professionals must rely on recognition of symptoms, identification of risk factors and mitigating the ultimate risk to patients.

SYMPTOMS ASSOCIATED WITH QT-PROLONGATION

TdP reduces cardiac output and causes tissue hypoxia. As a result, episodes of TdP lasting greater than 10 seconds produce syncope, sometimes resulting in tonic-clonic seizure activity, and death if the arrhythmia does not self-terminate. Some episodes of TdP may only last a few seconds and may not cause loss of consciousness but may cause the patient to experience one or more of the following symptoms:5

  • Lightheadedness
  • Dizziness
  • Palpitations
  • Transient shortness of breath
  • Seizures

ASSESSING FOR NON-DRUG RISK FACTORS

Several non-pharmacological factors that influence QT prolongation are listed below. These factors, when combined with certain medications, further increase a patient’s risk of TdP:4,6

  • Prolonged QTc > 500 msec
  • Congenital LQTS
  • Age > 65 years
  • Female gender (baseline QTc are generally 20 milliseconds greater than males)
  • Heart failure
  • Myocardial infarction
  • Bradycardia (slow heart rate prolongs repolarization)
  • Heart block
  • Electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia)
  • Liver failure (cirrhosis) and/or renal failure (GFR ≤ 30ml/min) (QT-prolonging drug(s) may accumulate)

IDENTIFYING QT-PROLONGING MEDICATIONS

Many drugs are associated with QT prolongation which makes it necessary to take a standardized approach to maintaining medication benefits while mitigating TdP risk.6 CredibleMeds® is an online resource that promotes the safe use of medicines and is best known for the “QT Drugs Lists” that categorize TdP risk for medications as “known risk,” “possible risk,” “conditional risk” and “drugs to avoid in congenital LQTS”. This site is updated regularly with free registration and access to resources.5

Palliative Medications with Known Risk of TdP & Recommended to Avoid in Congenital LQTS:5,6

  • Antiarrhythmics: Class IA agents (e.g., quinidine, disopyramide, procainamide) and Class III agents (e.g., sotalol, dofetilide, amiodarone)
  • Antimicrobials: Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin), macrolides (e.g., erythromycin, azithromycin), and antifungal agents (e.g., fluconazole (Diflucan®), ketoconazole, itraconazole)
  • Conventional antipsychotics (e.g., haloperidol, chlorpromazine, thioridazine)
  • Donepezil (Aricept®)
  • Methadone
  • Ondansetron (Zofran®)
  • Selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram (Celexa®), escitalopram (Lexapro®))

Palliative Medications with Possible Risk of TdP:5

  • Select analgesics: Tramadol (Ultram®), buprenorphine (Butrans®), hydrocodone extended-release (Hysingla®, Zohydro®)
  • Atypical antipsychotics (e.g., aripiprazole (Abilify®), clozapine (Clozaril®), pimavanserin (Nuplazid®))
  • Select antidepressants: Tricyclic antidepressants (TCAs) (e.g., desipramine, nortriptyline), mirtazapine (Remeron®) and venlafaxine (Effexor®)
  • Select antiemetics: Promethazine (Phenergan®), dolasetron (Anzemet®), granisetron (Kytril®), and palonosetron (Aloxi®)

Other Drug-Related Considerations:

  • Avoid high doses or concentrations by implementing the lowest effective dose of QT-prolonging drugs and administer orally – the associated QT prolongation risk is route- and dose-dependent for several medications1,7
  • Cytochrome P450 (CYP450) system drug interactions: Recognize that many QT-prolonging medications are metabolized by CYP450. It’s important to identify them as well as medications that may inhibit them.4 For example, ranolazine (Ranexa®) and grapefruit juice are inhibitors of isoenzyme 3A4. Methadone is a 3A4 substrate and concurrent use with either of these agents increases methadone concentrations and further increases the risk of QT prolongation.8
  • Avoid concurrent use of more than one drug that can prolong the QT interval, when possible1,4-6
  • Use diuretics with caution due to correlation with electrolyte abnormalities1,4-6

SUMMARY

Despite several common palliative medications carrying known risk of QT prolongation, it remains difficult to predict the relative risk associated with their administration. Pharmacists can assist by identifying QT-prolonging medications and other drug-related considerations to help clinicians balance prescribing decisions with other patient-specific risk factors. CredibleMeds® is a reputable resource with LQTS tools, facts and literature citations to supplement these discussions.5

References:

  1. Berul CI. Acquired long QT syndrome: Definitions, causes, and pathophysiology. In: UpToDate. Asirvatham S, et al, ed. Waltham, MA: UpToDate, Inc. Updated Jan 13, 2020.
  2. Dave J. Torsade de Pointes. In: Medscape Drugs & Diseases – Cardiology. Updated January 31, 2017. Article link
  3. Rosenthal L. Normal Electrocardiography (ECG) Intervals. In: Medscape Drugs & Diseases – Protocols. Updated May 18, 2020. Article link
  4. Thompson JL, Crossman RR. Drug-induced QT prolongation. U.S. Pharmacist. February 20, 2007. Article link
  5. CredibleMeds®. Resources for HealthCare Professionals. Accessed November 1, 2020. Site link
  6. Miranda DG, McMain CL, Smith AJ. Medication-Induced QT-Interval Prolongation and Torsades de Pointes. U.S. Pharmacist. February 18, 2011. Article link
  7. Uritsky TJ, et al. Ten tips palliative care pharmacists want the palliative care team to know when caring for patients. J Palliat Med. 2018;21(7):1017-1023.
  8. Clinical Resource, Cytochrome P450 (CYP) Drug Interactions. Pharmacist’s Letter/Prescriber’s Letter. June 2020.

 

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