Cardiotoxic Antiemetics Metoclopramide and Domperidone Block Cardiac Voltage-Gated Na+ Channels.

BACKGROUND: Metoclopramide and domperidone are prokinetic and antiemetic substances often used in clinical practice. Although domperidone has a more favorable side effect profile and is considered the first-line agent, severe cardiac side effects were reported during the administration of both substances. Cardiac Na channels are common targets of therapeutics inducing cardiotoxicity. Therefore, the aim of this study was to investigate whether the differential cardiotoxicities of metoclopramide and domperidone correlate with the block of Na channels.

METHODS: Effects of metoclopramide and domperidone on the human α-subunit Nav1.5 expressed in human embryonic kidney 293 cells and on Na currents in neonatal rat cardiomyocytes were investigated by means of whole-cell patch clamp recordings.

RESULTS: Tonic block of resting Nav1.5 channels was more potent for domperidone (IC50 85 ± 25 μM; 95% confidence interval [CI], 36-134) compared with metoclopramide (IC50 458 ± 28 μM; 95% CI, 403-513). Both agents induced use-dependent block at 10 and 1 Hz, stabilized fast and slow inactivation, and delayed recovery from inactivation. However, metoclopramide induced considerably smaller effects compared with domperidone. Na currents in rat cardiomyocytes displayed tonic and use-dependent block by both substances, and in this system, domperidone (IC50 312 ± 15 μM; 95% CI, 22-602) and metoclopramide (IC50 250 ± 30 μM; 95% CI, 191-309) induced a similar degree of tonic block.

CONCLUSIONS: Our data demonstrate that the clinically relevant cardiotoxicity of domperidone and metoclopramide corresponds to a rather potent and local anesthetic-like inhibition of cardiac Na channels including Nav1.5. These data suggest that Nav1.5 might be a hitherto unrecognized molecular mechanism of some cardiovascular side effects, for example, malignant arrhythmias of prokinetic and antiemetic agents.