Drug-induced QT prolongation

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QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

Contents

Background

A QT interval is a value that is measured on an electrocardiogram. Measurements begin from the start of the Q wave to the end of the T wave. The value is an indication of the time it takes for a ventricle from the beginning of a contraction to the end of relaxation. The value for a normal QT interval is similar in males and females from birth up to adolescence. During infancy, a normal QTc is defined as 400±20 milliseconds. Before puberty, the 99th percentile of QTc values is 460 milliseconds. After puberty, this value increases to 470 milliseconds in males and 480 milliseconds in females.[ citation needed ]

Torsades de pointes (TdP) is an arrhythmia. More specifically, it is one form of a polymorphic ventricular tachycardia that presents with a long QT interval. Diagnosis is made by electrocardiogram (ECG), which shows rapid irregular QRS complexes. The term "torsades de pointes" is translated from French as "twisting of the peaks" because the complexes appear to undulate, or twist around, the EKG baseline. TdP can be acquired by inheritance of a congenital long QT syndrome, or more commonly from the ingestion of a pharmacologic drug. During TdP episodes, patients have a heart rate of 200 to 250 beats/minute, which may present as palpitations or syncope. TdP often self-resolves, however, it may lead to ventricular fibrillation and cause sudden cardiac death.[ citation needed ]

Risk factors

Although it is difficult to predict which individuals will be affected from drug-induced long QT syndrome, there are general risk factors that can be associated with the use of certain medications. [1]

Generally, as the dose of a drug increases, the risk of QT prolongation increases as well. In addition, factors such as rapid infusion, concurrent use of more than one drug known to prolong QT interval, diuretic treatment, electrolyte derangements (hypokalemia, hypomagnesemia, or hypocalcemia), advanced age, bradyarrhythmias, and female sex have all been shown to be risk factors for developing drug-induced QT prolongation. [2] TdP has been shown to occur up to three times more often in female patients compared with males, likely as a result of post-pubertal hormonal influence on cardiac ion channels. The QTc interval is longer in females, as well as having a stronger response to IKr-blocking agents. In males, the presence of testosterone upregulates IKr channels and therefore decreases QT interval. [2] Stated otherwise, estrogens prolong the QT interval, while androgens shorten it and decrease the response to IKr-blocking agents.[ citation needed ]

Structural heart disease, such as heart failure, myocardial infarction, and left ventricular hypertrophy, are also risk factors. Diuretic-induced hypokalemia and/or hypomagnesemia taken for heart failure can induce proarrthymia. The ischemia that results from myocardial infarctions also induce QT prolongation.[ citation needed ]

Drugs that cause QT prolongation

The main groups of drugs that can cause QT prolongation are antiarrhythmic medications, psychiatric medications, and antibiotics. Other drugs include antivirals and antifungals.

Antiarrhythmic agents

Source: [3]

  • Class IA
    • Class IA antiarrhythmic drugs work by blocking sodium and potassium channels. Blocking sodium channels tend to shorten the action potential duration, while blocking potassium channels prolongs the action potential. When the drug concentration is at a low to normal concentration, the potassium channel blocking activity takes precedence over the sodium channel blocking activity [4]
      • Disopyramide
      • Procainamide
      • Propafenone
      • Quinidine
        • Because of the predominance of the potassium blocking activity, TdP is seen more frequently with therapeutic levels of quinidine. Sodium blocking activity is dominant with subtherapeutic levels, which does not lead to QT prolongation and TdP.
  • Class III
    • Class III antiarrhythmic drugs are potassium channel blockers that cause QT prolongation and are associated with TdP.
    • Amiodarone
      • Amiodarone works in many ways. It blocks sodium, potassium, and calcium channels, as well as alpha and beta adrenergic receptors. Because of its multiple actions, amiodarone causes QT prolongation but TdP is rarely observed.
    • Dofetilide
    • Ibutilide
      • Ibutilide differs from other class III antiarrhythmic agents in that it activates the slow, delayed inward sodium channels rather than inhibiting outward potassium channels.
    • Sotalol
      • Sotalol has beta-blocking activity. Approximately 2 to 7 percent of patients taking at least 320 mg/day experience proarrhythmia, most often in the form of TdP. [5] The risks and effects are dose-dependent.

Psychiatric medications

Psychiatric medications include antipsychotics and antidepressants that have been shown to lengthen the QT interval and induce TdP, especially when given intravenously or in higher concentrations. [3]

Antibiotics

Source: [3]

Other agents

Source: [3]

Pathophysiology

IKr blockade

On EKG, the QT interval represents the summation of action potentials in cardiac muscle cells. QT prolongation therefore results from action potential prolongation, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, IKr, which is encoded by the hERG gene, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, which is reflected as QT prolongation. [2]

Diagnosis

Most patients with drug-induced QT prolongation are asymptomatic and are diagnosed solely by EKG in association with a history of using medications known to cause QT prolongation. [6] A minority of patients are symptomatic and typically present with one or more signs of arrhythmia, such as lightheadedness, syncope, or palpitations. [6] If the arrhythmia persists, patients may experience sudden cardiac arrest.[ citation needed ]

Management

Treatment requires identifying and removing any causative medications and correcting any underlying electrolyte abnormalities. [7] While TdP often self-resolves, cardioversion may be indicated if patients become hemodynamically unstable, as evidenced by signs such as hypotension, altered mental status, chest pain, or heart failure. [7] Intravenous magnesium sulfate has been proven to be highly effective for both the treatment and prevention of TdP. [7]

Managing patients with TdP is dependent on the patient's stability. Vital signs, level of consciousness, and current symptoms are used to assess stability. Patients who are stable should be managed by removing the underlying cause and correcting electrolyte abnormalities, especially hypokalemia. An EKG should be obtained, a cardiac monitor should be attached, IV access should be established, supplemental oxygen should be given, and blood samples should be sent for appropriate studies. Patients should be continually re-evaluated for signs of deterioration until the TdP resolves. In addition to correcting the electrolyte abnormalities, magnesium given intravenously has also been shown to be helpful. Magnesium sulfate given as a 2 g IV bolus mixed with D5W can be given over a period of 15 minutes in patients without cardiac arrest [8] Atrial pacing or administering isoproterenol can normalize the heart rate.[ citation needed ]

Unstable patients exhibit signs of chest pain, hypotension, elevated heart rate, and/or heart failure. Patients who develop cardiac arrest will be pulseless and unconscious. Defibrillation and resuscitation is indicated in these cases. Patients with cardiac arrest should be given IV magnesium sulfate over a period of two minutes.[ citation needed ]After diagnosing and treating the cause of LQTS, it is also important to perform a thorough history and EKG screening. Immediate family members should also be screened for inherited and congenital causes of drug-induced QT syndrome.[ citation needed ]

Incidence

Unfortunately, there is no absolute definition that describes the incidence of drug-induced QT prolongation, as most data is obtained from case reports or small observational studies. Although QT interval prolongation is one of the most common reasons for drug withdrawal from the market, the overall incidence of drug-induced QT prolongation is difficult to estimate. [9] One study in France estimated that between 5-7% of reports of ventricular tachycardia, ventricular fibrillation, or sudden cardiac death were in fact due to drug-induced QT prolongation and torsades de pointes. [10] An observational study from the Netherlands showed that 3.1% of patients who experienced sudden cardiac death were also using a QT-prolonging drug. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Dofetilide</span> Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 μg of dofetilide. It is not available in Europe or Australia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Ventricular tachycardia</span> Abnormally fast rhythm of the hearts ventricles

Ventricular tachycardia is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period of time are referred to as an electrical storm. Short periods may occur without symptoms, or present with lightheadedness, palpitations, shortness of breath, chest pain, and decreased level of consciousness. Ventricular tachycardia may lead to coma and persistent vegetative state due to lack of blood and oxygen to the brain. Ventricular tachycardia may result in ventricular fibrillation (VF) and turn into cardiac arrest. This conversion of the VT into VF is called the degeneration of the VT. It is found initially in about 7% of people in cardiac arrest.

<span class="mw-page-title-main">Flecainide</span> Antiarrhythmic medication

Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. Its use does not decrease a person's risk of death. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">QT interval</span> Measurement made on an electrocardiogram

The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. An abnormally long or abnormally short QT interval is associated with an increased risk of developing abnormal heart rhythms and sudden cardiac death. Abnormalities in the QT interval can be caused by genetic conditions such as long QT syndrome, by certain medications such as sotalol or pitolisant, by disturbances in the concentrations of certain salts within the blood such as hypokalaemia, or by hormonal imbalances such as hypothyroidism.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Jervell and Lange-Nielsen syndrome</span> Medical condition

Jervell and Lange-Nielsen syndrome (JLNS) is a rare type of long QT syndrome associated with severe, bilateral sensorineural hearing loss. Those with JLNS are at risk of abnormal heart rhythms called arrhythmias, which can lead to fainting, seizures, or sudden death. JLNS, like other forms of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. It is caused by genetic variants responsible for producing ion channels that carry transport potassium out of cells. The condition is usually diagnosed using an electrocardiogram, but genetic testing can also be used. Treatment includes lifestyle measures, beta blockers, and implantation of a defibrillator in some cases. It was first described by Anton Jervell and Fred Lange-Nielsen in 1957.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Ibutilide</span> Chemical compound

Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Ranolazine</span> Drug used to treat angina

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Therapeutic benefits appear smaller in females than males. It is taken by mouth.

<span class="mw-page-title-main">E-4031</span> Chemical compound

E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">AZD1305</span> Chemical compound

AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa).

References

  1. ↑ Roden DM, Woosley RL, Primm RK (1986). "Incidence and clinical features of the quinidine-associated long QT syndrome: Implications for care". American Heart Journal. 111 (6): 1088–93. doi:10.1016/0002-8703(86)90010-4. PMID   3716982.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. 1 2 3 Kallergis EM, Goudis CA, Simantirakis EN, Kochiadakis GE, Vardas PE (2012). "Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review". Scientific World Journal. 2012: 212178. doi: 10.1100/2012/212178 . PMC   3347892 . PMID   22593664.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. 1 2 3 4 Olsen, K. M. (2005). "Pharmacologic agents associated with QT interval prolongation". The Journal of Family Practice. Suppl (Suppl): S8–S14. PMID   15938993.
  4. ↑ Hohnloser, SH; Singh, BN (1995). "Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications". Cardiovascular Electrophysiology. 6 (10 Pt 2): 920–36. doi:10.1111/j.1540-8167.1995.tb00368.x. PMID   8548113. S2CID   23136846.
  5. ↑ Ben-David, J; Zipes, DP (1993). "Torsades de pointes and proarrhythmia". Lancet. 341 (8860): 1578–1582. doi:10.1016/0140-6736(93)90708-o. PMID   8099651. S2CID   44309083.
  6. 1 2 Khan IA (2002). "Long QT syndrome: diagnosis and management". American Heart Journal. 143 (1): 7–14. doi:10.1067/mhj.2002.120295. PMID   11773906.
  7. 1 2 3 Kallergis EM, Goudis CA, Simantirakis EN, Kochiadakis GE, Vardas PE (2012). "Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review". Scientific World Journal. 2012: 212178. doi: 10.1100/2012/212178 . PMC   3347892 . PMID   22593664.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Tzivoni, D; Schuger, C; Benhorin, J; Keren, A; Stern, S (1988). "Treatment of torsade de pointes with magnesium sulfate". Circulation. 77 (2): 392–397. doi: 10.1161/01.cir.77.2.392 . PMID   3338130.
  9. ↑ El-Sherif N, Turitto G, Boutjdir M (2018). "Acquired long QT syndrome and torsade de pointes". Pacing and Clinical Electrophysiology. 41 (4): 414–421. doi:10.1111/pace.13296. PMID   29405316. S2CID   46795997.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Molokhia M, Pathak A, Lapeyre-Mestre M; et al. (2008). "Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France". British Journal of Clinical Pharmacology. 66 (3): 386–95. doi:10.1111/j.1365-2125.2008.03229.x. PMC   2526236 . PMID   18637888.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Straus, SM; Sturkenboom, MC; Bleumink, GS; Dieleman, JP; van der Lei, J; de Graeff, PA; Kingma, JH; Stricker, BH (2005). "Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death". European Heart Journal. 26 (19): 2007–12. doi: 10.1093/eurheartj/ehi312 . PMID   15888497.

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