Adenosine and the Cardiovascular System

Allison B. Reiss; David Grossfeld; Lora J. Kasselman; Heather A. Renna; Nicholas A. Vernice; Wendy Drewes; Justin Konig; Steven E. Carsons; Joshua DeLeon

Disclosures

Am J Cardiovasc Drugs. 2019;19(5):449-464. 

In This Article

The Role of Adenosine and Thienopyridine Derivatives as Anti-platelet Agents

Intracoronary atherothrombosis, a major cause of acute coronary events, is largely a consequence of platelet activation, aggregation and adhesion.[109,110] Platelet inhibition is an essential part of optimal medical therapy in the treatment of acute coronary events.[111–113]

Platelets express A2A and A2B receptors, but do not express the A1 or A3 adenosine receptor.[114,115] When adenosine binds to A2A receptors expressed on platelets, it stimulates adenylate cyclase, leading to an increase in intracellular cAMP within the platelet, which robustly inhibits platelet activation.[116] Not surprisingly, this effect is seen with highly selective A2A receptor agonists, including CGS-21680 and ATL-146e.[117–119] CGS-21680 is the classical gold standard A2A agonist.[120] To date, no A2A agonist has been used directly in humans for anti-platelet effects.

Although platelet activation by adenosine is thought to be primarily mediated through the A2A receptor, mice deficient in the A2b receptor show increased platelet aggregation accompanied by upregulation of the ADP receptor P2Y1.[121] The platelet activation process in part is the result of the interaction between ADP and platelet P2Y purinergic receptors. The P2Y1 receptor is required for induction of platelet aggregation by ADP and can initiate the process of platelet aggregation, but is not sufficient for a full aggregation response to ADP.[122]

The P2Y12 receptor in particular is integrally involved in the ADP stimulated glycoprotein IIb/IIIa receptor activation that prompts increased platelet degranulation, thromboxane production, completion of the aggregation process and prolonged platelet aggregation.[123,124] Platelet inhibitors including, but not limited to, thromboxane inhibitors (aspirin), ADP antagonists (or P2Y12 inhibitors), the thienopyridines (clopidogrel and prasugrel), and nonthienopyrdines (ticagrelor) are medical therapy options for the inhibition of thrombotic formation and processes.[123] Thienopyridines inhibit platelet activation and aggregation due to their ability to antagonize the P2Y12 receptors.[123,125] Dual anti-platelet therapy of aspirin and clopidogrel in multiple large clinical trials has proven efficacious in the prevention of complications in patients post-acute coronary syndrome events and percutaneous coronary intervention stent revascularization.[123,126] Despite the proven efficacy of this combination, clopidogrel has pharmacodynamic limitations that result in reduced effectiveness.[127,128] Clopidogrel, a prodrug, requires a two-step metabolic activation process catalyzed by a cytochrome P450 (CYP) to generate the active metabolite that inhibits the P2Y12 receptor.[129–131] Eighty-five percent of the prodrug is hydrolyzed before intestinal absorption.[132] These clopidogrel properties cause a delay of several hours from ingestion of drug to attainment of therapeutic drug levels.[123] Further, clopidogrel has demonstrated a variability in response between patients due to variation in the CYP gene that codes for CYP-450 enzymes.[133] These enzymes are involved in hepatic conversion of clopidogrel prodrug to its active metabolite. Another consideration is an association between polymorphisms of the CYP2C19 allele with reduced clopidogrel activity.[123,134]

In contrast, newer P2Y12 agents like the third-generation P2Y12 inhibitor ticagrelor act faster and have a stronger, more consistent anti-platelet effect.[135,136] Ticagrelor is a direct-acting and reversibly binding P2Y12 ADP receptor blocker that also inhibits adenosine uptake via the ENT.[137] This can prolong the short half-life of adenosine and increase extracellular concentration. Incubation of human erythrocytes and human, canine, and rodent cell lines in ticagrelor leads to inhibition of adenosine uptake, but in vivo studies at physiologically relevant concentrations of ticagrelor show no appreciable effect on adenosine levels in healthy human subjects.[135,138–141]

Ticagrelor has greater efficacy than clopidogrel, leading to improved prognosis for patients with acute coronary syndrome.[142,143] In a study by Li et al.,[135] ticagrelor and clopidogrel were compared regarding their effect on adenosine, ADA, and cAMP levels in the blood, as well as anti-platelet effect, in patients with non-ST-segment elevation acute coronary syndrome receiving dual anti-platelet therapy, who were reperfused via percutaneous coronary intervention. There were no significant differences in clinical baseline qualities in adenosine, ADA or cAMP levels between patient groups. After percutaneous coronary intervention, patients either received a loading dose of 180 mg of ticagrelor followed by 90 mg every 2 days, or a 300-mg loading dose of clopidogrel and then 75 mg daily. As measured by immunoassay upon admission and 48 h after coronary angiography, there was a significant increase in cAMP and adenosine levels in the ticagrelor group, but no difference in ADA levels between the patients receiving ticagrelor or clopidogrel. Thrombelastograph hemostasis analyzer measures showed minimal correlation between inhibition of platelet aggregation and adenosine/cAMP concentration in the plasma. However, the average inhibition of platelet aggregation was 93.5% greater in patients given ticagrelor compared to those given clopidogrel. Major adverse cardiac events were noted after a 30-day follow-up and were higher in the clopidogrel group (5.8%) compared to ticagrelor (2.9%). However, rate of hospitalization showed no distinction between groups; nor did significant bleeding, dyspnea, or AV block at the 30-day follow-up.

Prasugrel, a new-generation thienopyridine anti-platelet agent unaffected by genetic variations in CYP2C19, has also been shown to be superior to clopidogrel in preventing similar clinical outcomes in patients with acute coronary syndrome, who underwent percutaneous coronary intervention in the Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON) trial.[144,145] Compared with dipyridamole, an ENT1 inhibitor, which was mentioned earlier, ticagrelor has a lower affinity for the ENT. Other P2Y12 antagonists, cangrelor, elinogrel, and metabolites of clopidogrel and prasugrel, did not show any notable activity or interaction with the transporters. In patients with P2Y12 deficiency, ticagrelor has still been shown to be superior to dipyramidole in anti-platelet effects in whole blood, possibly because ticagrelor is not only an ENT1 antagonist, but can oppose P2Y12-mediated inhibition of adenylyl cyclase.[138]

The Platelet Inhibition and Patient Outcomes (PLATO) study supplied further evidence of reduced cardiovascular mortality with ticagrelor as compared to clopidogrel.[146,147] This study did show that ticagrelor had a greater incidence of dyspnea and ventricular pauses.[138,148] These combined considerations led investigators to hypothesize that ticagrelor may have pleiotropic properties with clinically pertinent, non-platelet-related effects.[149,150] Increased adenosine half-life and plasma concentrations indicate potential for clinically relevant consequences because of the biological effects associated with adenosine, as described throughout this review. Most recently, dyspnea induced as a side effect of ticagrelor was found to be unrelated to adenosine levels.[151]

A recent in vitro study combined adenosine agonists, testing both selective and non-selective compounds, with a P2Y12 inhibitor and found that both non-selective and A2A selective agonists, but not an A2B selective agonist, were effective in amplifying the anti-aggregatory effect of the P2Y12 antagonist.[152] This opens up the possibility of dual therapy targeting platelet aggregation involving adenosine.

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