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The Mechanism for Metoclopramide Induced QT Prolongation

Summary:

  • Metoclopramide is known to increase the QT/RR slope and QT variance that can facilitate  the development of Torsades.
  • There are three proposed mechanisms for metoclopramide's ability to increase the risk of this undesirable phenomenon, which include:
    • Affecting the sympatho-vagal balance within the heart through its D2 receptor antagonism
    • Agonist activity on the 5-HT4 receptor similar to cisapride
    • D2 antagonism that can prolong repolarization through a blockade of potassium currents
  • The culmination of these pharmacological characteristics may create the right milieu within certain patients that can contribute to a prolongation of the QT interval and result in the development of life-threating polymorphic ventricular tachycardia (i.e., Torsades de pointes).

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed:
October 2015

Explanation

  • While the exact mechanism for this adverse drug effect is not fully known, it is thought that metoclopramide has pharmacologic characteristics that can contribute to the prolongation of the QT interval and risk for polymorphic ventricular tachycardia.  The ventricular tachycardia of greatest concern is Torsades de points, which if does not resolve quickly on its own or is intervened on, can be life threatening.  Metoclopramide is known to increase the QT/RR slope and QT variance that can facilitate  the development of Torsades.

    There are three proposed mechanisms for metoclopramide's ability to increase the risk of this undesirable phenomenon. These include:

    • Affecting the sympatho-vagal balance within the heart through its D2 receptor antagonism.  Specifically, metoclopramide may activate the sympathetic nervous system by an unloading of the baroreceptors within the arteries because of its cholinergic agonist effect in the central nervous system and an enhancement of norepinephrine release from sympathetic nerve endings that ultimately causes a change in the QT interval independent of effects on the heart rate (which when it increases normally shortens the QT interval).
    • In addition to metoclopramide's 5-HT3 antagonist activity, it can also act as an agonist of the 5-HT4 receptor similar to cisapride, which is also known to cause QT prolongation.  The pharmacologic similarity of metoclopramide and cisapride on 5-HT4 receptors is suggestive that its direct stimulation may affect the dynamic nature of the QT interval.
    • Lastly, metoclopramide is known to have D2 receptor antagonism.  Domperidone and other D2 receptor antagonists (e.g., antipsychotics) are known to increase the QT interval.  One study showed that domperidone's D2 antagonism within an isolated heart can prolong repolarization through a blockade of potassium currents.  This is also seen with class III antiarrhythmic medications (e.g, amiodarone, dofetilide, and sotalol).

    The culmination of these pharmacological characteristics may create the right milieu within certain patients that can contribute to a prolongation of the QT interval and result in the development of life-threatening polymorphic ventricular tachycardia (i.e., Torsades de pointes).  Patient characteristics that could be more concerning for this undesirable effect include: evidence of structural heart disease, congenital QT prolongation, impaired renal function (due to reduced clearance), electrolyte abnormalities (e.g., low potassium and magnesium), and the concomitant use of other QT prolonging medications.

    References:

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MESH Terms & Keywords

  • Metoclopramide, Reglan, QT Prolongation, Reglan QT Prolongation, Torsades