Summary
In studies that compared the reversible P2Y12 inhibitor ticagrelor with the irreversible
inhibitor clopidogrel, dyspnea was observed more frequently among ticagrelor-treated
patients than among clopidogreltreated patients. Because dyspnea was not associated
with acidosis, pulmonary or cardiac dysfunction, alterations in the mechanisms and
pathways of the sensation of dyspnea may be involved in its pathogenesis. It has been
hypothesised that the sensation of dyspnea in ticagrelor-treated patients is triggered
by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration
in the circulation. However, dipyridamole, a much stronger inhibitor of adenosine
clearance than ticagrelor, usually does not cause dyspnea. We hypothesise that inhibition
of P2Y12 on sensory neurons increases the sensation of dyspnea, particularly when
reversible inhibitors are used. We base our hypothesis on the following considerations:
1) cangrelor and elinogrel, which, like ticagrelor, are reversible P2Y12 inhibitors,
also increase the incidence of dyspnea;2) it is biologically plausible that inhibition
of P2Y12 on sensory neurons increases the sensation of dyspnea;3) inhibition of P2Y12
on platelets (which do not have a nucleus) by clopidogrel is permanent, despite the
once daily administration and the short plasma half-life of the inhibitor;4) in contrast,
inhibition of P2Y12 on neurons by clopidogrel may be temporary and transient, because
neurons have a nucleus and can therefore rapidly replace the inhibited receptors with
newly synthetised ones;5) inhibition of P2Y12 on neurons by reversible inhibitors
is permanent, because the plasma drug concentration is maintained high by repeated
dosing, in order to ensure permanent inhibition of platelet P2Y12.
Keywords
ADP receptors - arterial thrombosis - nervous system
