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 anti-arrhythmic medicines, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antihistamines, opioid analgesics and complementary medicines. On an EKG, 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.

Background[edit]

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[edit]

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[edit]

Antiarrhythmic agents[edit]

Source:[3]

  • Class IA
    • Class IA antiarrthymic 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
      • Flecainide
      • 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.

Psychotropic medications[edit]

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

Antibiotics[edit]

Source:[3]

Other agents[edit]

[3]

Pathophysiology[edit]

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[edit]

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[edit]

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 pulsesless 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[edit]

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[edit]

References[edit]

  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.CS1 maint: multiple names: authors list (link)
  2. ^ a b c 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.CS1 maint: multiple names: authors list (link)
  3. ^ a b c d Olsen, K. M. (2005). "Pharmacologic agents associated with QT interval prolongation". The Journal of Family Practice (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. ^ a b 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. ^ a b c 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.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.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.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.

Further reading[edit]