**2. Mechanisms of action of the components of DAPT**

DAPT comprises of aspirin together with a P2Y12 inhibitor. These agents have different mechanisms of actions. This section will focus solely on the mechanism of action related to antithrombotic effects of dual antiplatelet therapy.

#### **2.1 Mechanism of action of aspirin**

Aspirin is an anti-inflammatory drug, which possesses both anti-inflammatory and antioxidant properties [14]. The primary mechanism of action of aspirin is centered on the irreversible inhibition of cyclooxygenase (COX 1) enzyme, thus preventing the conversion of arachidonic acid into prostaglandin G2 and prostaglandin H2, subsequently inhibiting thromboxane A2 synthesis. Aspirin acetylates and forms a covalent bond with serine residues in COX active site at position 529, thus inhibiting cox 1 enzyme [15, 16]. Other activities of aspirin include mitochondrial oxidative phosphorylation and modulation of NF-KB signals [14].

#### **2.2 Mechanism of action of P2Y12 inhibitors**

P2Y12 inhibitors, otherwise known as P2Y12 antagonists, act by blocking P2Y12 adenosine diphosphate (ADP) receptors on platelet surface membrane, subsequently inhibiting thrombocyte activation/aggregation [17]. P2Y12 inhibitors can be classified into two groups: thienopyridines and nucleoside/nucleotide derivatives [16].

Thienopyridines are competitive and irreversible P2Y12 inhibitors [16]. Drugs in this class can be further subdivided into three generations: first-, second-, and thirdgeneration thienopyridines.

Ticlopidine is a first-generation thienopyridines that was withdrawn due to major side effects such as GI disorders, cytopenia, and allergies. Clopidogrel is a prodrug

### *Dual Antiplatelet Therapy DOI: http://dx.doi.org/10.5772/intechopen.105139*

of second-generation thienopyridine derivatives, which is a drug of first choice in DAPT. Clopidogrel active metabolite binds to P2Y12 receptor to form an irreversible covalent bond, which inhibits ADP-dependent platelet activation and aggregation [18]. Dual antiplatelet therapy with aspirin and clopidogrel has been associated with more than 3% platelet reactivity [19] and 10% ischemic occurrences after 12 months of treatment.

Third-generation thienopyridine (prasugrel) was developed with rapid absorption and higher bioavailability than clopidogrel [16, 18].

Some drugs in this class are mainly reversible P2Y12 inhibitors such as ticagrelor and cangrelor. Ticagrelor is a more potent, efficacious, and fast acting P2Y12 inhibitor when compared with other P2Y12 inhibitors such as clopidogrel and prasugrel [20]. Ticagrelor acts by binding to P2Y12 receptor site other than the ADP binding site. In addition, ticagrelor binds to equilibrative nucleoside transporter 1 (ENT 1) in platelets and red blood cells to block the reuptake of adenosine [21].


The P2Y12 inhibitors have peculiar features, advantages and disadvantages, as well as adverse effects. These effects have been summarized in **Table 1**.


*KEY: DAPT: dual antiplatelet therapy, MACE: major adverse cardiovascular events, ACS: acute coronary syndrome, PCI: percutaneous cardiovascular intervention, AF: atrial fibrillation, MI: myocardial infarction, CVS: cardiovascular, CABG: coronary artery bypass graft, STEMI-ST: elevation myocardial infarction. Source: [22, 23].*

#### **Table 1.**

*Advantages, disadvantages, and side effects of P2Y12 inhibitors.*
