QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile

Abstract

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the I(Kr) -, I(Ks) -, and I(Na) -blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD(90) -, MAP amplitude-, phase 0 dV/dt-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an I(Kr) blocker. IC(50) was estimated at 34 μm. In contrast, bupropion had hardly any effect on I(Ks) and I(Na) . Bupropion had no significant MAPD(90) -modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its I(Kr) -blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 dV/dt -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.

A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening

“…With regards to a possible mechanism for this finding, Caillier et al used patch clamp techniques to determine that bupropion did not significantly change sodium current amplitude or steady-state activation/inactivation. They used male guinea pig hearts and showed that the change in action potential from bupropion was similar to glycyrrhetinic acid and heptanol which are known to decrease cardiac intracellular coupling [75]. However, there is a study in guinea pigs where sodium bicarbonate did not show a significant effect on ECG changes induced by amitriptyline and doxepin which is contrary to human data [76].…”

“…Case report [71] In vitro data (references) Bupropion Case reports [72][73][74] Guinea pig hearts, rat neonatal myocytes, rat atria, canine ventricular tissue, crayfish axons [75,76] Human embryonic kidney cells [75] Propranolol Canine study [77] …”

Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs

“…The difference in bupropion potency between the current study and that of Caillier et al . () could be related to the use of alternative assay methodologies and drug‐protein binding in the presence/absence of serum. In the present study, hNa V 1.5 IC 50 values were determined in the absence of serum proteins, which might bind compounds and lower their effective free concentrations, whereas the hCx43 IC 50 value was determined in the presence of 10% serum.…”

Transcranial Magnetic Stimulation as an Antidepressant Alternative in a Patient With Brugada Syndrome and Recurrent Syncope

“…8 A recent report suggests that bupropion may inhibit cell-to-cell conduction at the gap junction without direct I Na inhibition, and this effect may explain the apparent proarrhythmic effect in this patient. 9 Bupropion therapy was discontinued. He was treated with mirtazapine monotherapy, which resulted in restoration of his baseline ECG.…”