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:
- Ellidokuz
E et al. Aliment Pharmacol Ther 2003;18:151-155.
- Briejer
MR et al. Pharmacol Rev 1995;47:631-51.
- Takeucki
Y et al. J Auton Nerv Syst 1996;58:115-20.
- Mannelli
M et al. Hypertension 1999;34:398-402.
- Magnano
AR et al. Am Coll Cardiol 2002;39:1820-6.
- Roussak
JB et al. Br Med J 1984;289:1579.
- Giaccone
G et al. Lancet 1984;2:1336-7.
-
Drolet
B et al. Circulation 2000;102:1883-5.
