Why does ticagrelor induce dyspnea?

Abstract

SummaryIn studies that compared the reversible P2Y 12 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 P2Y 12 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 P2Y 12 inhibitors, also increase the incidence of dyspnea; 2) it is biologically plausible that inhibition of P2Y 12 on sensory neurons increases the sensation of dyspnea; 3) inhibition of P2Y 12 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 P2Y 12 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 P2Y 12 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 P2Y 12 .

Compared efficacy of clopidogrel and ticagrelor in treating acute coronary syndrome: a meta-analysis

“…Dyspnea is another pivotal parameter as adverse effect in addition to bleeding. In our study, ticagrelor exerted increased dyspnea incidence in comparison of clopidogrel, which mainly due to its function in increasing the inhibition of P2Y12 on sensory neurons and the endogenous adenosine concentration [ 46 – 48 ].…”

The clinical efficacy and safety evaluation of ticagrelor for acute coronary syndrome in general ACS patients and diabetic patients: A systematic review and meta-analysis

“…It may be that ticagrelor causes an increase in the endogenous adenosine concentration [46, 47] and the inhibition of P2Y 12 on sensory neurons [48]. …”

Dyspnoea management in acute coronary syndrome patients treated with ticagrelor

“…Current hypotheses include stimulation of pulmonary vagal C fibres by increased levels of extracellular adenosine due to ticagrelor’s known antagonism of adenosine reuptake via equilibrative nucleoside transporter-1 (ENT-1) 3 , 11 or the inhibition of P2Y 12 receptors located on C fibres of sensory neurons. 12 The reversible nature of sensory neuron P2Y 12 receptor inhibition could play a role, since cangrelor and elinogrel (other similar reversible agents) also increase dyspnoea occurrence. 12 …”

“… 12 The reversible nature of sensory neuron P2Y 12 receptor inhibition could play a role, since cangrelor and elinogrel (other similar reversible agents) also increase dyspnoea occurrence. 12 …”