Why does ticagrelor induce dyspnea?
ABSTRACT 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 clopidogrel-treated 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.
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ABSTRACT: Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.Thrombosis and Haemostasis 04/2014; 112(2). · 5.76 Impact Factor
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ABSTRACT: This review constitutes a critical evaluation of recent publications describing an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1, providing protection of adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists.Journal of the American College of Cardiology 01/2014; · 15.34 Impact Factor
- International Journal of Cardiology 11/2014; 179C:238-239. · 6.18 Impact Factor