Interaction among hERG channel blockers is a potential mechanism of death in caffeine overdose

The clinical toxicology of caffeine: A review and case study

“…Thus, this is also unlikely to play a significant role in caffeine’s mechanisms except perhaps in cases of large, toxic if not lethal overdoses. Similarly, caffeine has also shown activity as a potassium channel inhibitor but only at extremely high concentrations [ 110 , 111 ]. Other molecular targets such as the γ-aminobutyric acid receptor type A or GABA(A) have been proposed, but the Ki value for caffeine is 280 μmol (around 54.3 mg/L) and is once again unlikely to be achieved with normal or therapeutic consumption [ 101 , 102 ].…”

“…For example, caffeine has been shown to act as an inhibitor of the Human Ether-a-go-go (hERG) potassium channel which is found in different tissues including the heart [ 110 , 111 ]. The blockage of this channel has been implicated in the cause of cardiac arrhythmia in certain circumstances by causing QT prolongation [ 111 ]. However, as with many other molecular targets, hERG requires rather high concentrations for significant interaction with caffeine.…”

“…For example, the IC50 is around 5 mM (around 971 mg/L), making it highly unlikely to play a role in this particular death. However, authors have pointed out that around a 5–10% inhibition of this channel could be achieved with a concentration of 300 μmol (around 58 mg/L) [ 111 ]. Furthermore, caffeine may begin to have a small effect upon intracellular calcium release at these concentrations (i.e., at 250 μmol or approximately 48.5 mg/L) while in vitro data have shown potential pro-arrhythmic action attributed to an effect upon the cardiac ryanodine receptor (RyR2) cytosolic calcium sensitivity and increased RyR2 opening frequency [ 66 , 67 , 101 , 107 ].…”

“…Additionally, as some authors have found, the inhibition of hERG can be dramatically increased when two compounds with inhibitory effects are combined [ 111 ]. Thus, it is also possible that one of the constituents in the energy drink may have such activity and also contributed to the death by lowering the threshold for inhibition.…”

Koffein, das am häufigsten konsumierte Psychostimulans: eine narrative Übersichtsarbeit

“…Hierzu gehören eine Inhibition der Phosphodiesterase [19,91,92], eine intrazelluläre Calciumfreisetzung in der Skelett-und Herzmuskulatur sowie im Nervengewebe durch Bindung an und Aktivierung von Calciumfreisetzenden Kanälen (z. B. durch Aktivierung von Ryanonidin-Rezeptoren) [61,[91][92][93][94], eine Inhibition von Natriumkanälen [95,96], Modulation der Funktion des GABA A -Rezeptors [60,61] und Inhibition der Acetylcholinesterase [97]. Bei der Aufnahme von Koffein in üblichen Dosierungen sind diese Mechanismen jedoch nicht relevant [62].…”