What is the mechanism of action of Brillinta (ticagrelor)?

Mechanism of Action of Ticagrelor (Brilinta)

Ticagrelor is a direct-acting, reversible, and selective P2Y12 receptor antagonist that blocks ADP-mediated platelet aggregation through non-competitive inhibition at a site distinct from the ADP binding site, likely through an allosteric mechanism. 1, 2

Pharmacological Properties

Ticagrelor belongs to the cyclopentyl-triazolopyrimidine class of antiplatelet agents, which differs structurally and functionally from thienopyridines (clopidogrel, prasugrel) in several important ways:

• Direct action: Unlike thienopyridines, ticagrelor does not require hepatic conversion to an active metabolite 1, 3
• Reversible binding: Binds reversibly to the P2Y12 receptor, allowing for faster offset of action 1, 3
• Non-competitive inhibition: Acts at a site distinct from the ADP binding site 1, 4
• Rapid onset: Achieves platelet inhibition within 30 minutes, with peak effect at approximately 2 hours 1, 2
• Half-life: 6-12 hours, requiring twice-daily dosing 1, 2

Molecular Mechanisms

Ticagrelor's antiplatelet effects occur through multiple mechanisms:

1. P2Y12 receptor antagonism: Primary mechanism - blocks ADP-induced platelet aggregation by preventing ADP from binding to its receptor 1, 3

2. Inverse agonism: Blocks the constitutive agonist-independent activity of the P2Y12 receptor, limiting basal Gi-coupled signaling and thereby increasing cAMP levels 4

3. ENT1 transporter inhibition: Inhibits the equilibrative nucleoside transporter 1 on platelets, leading to:

   • Accumulation of extracellular adenosine
   • Activation of Gs-coupled adenosine A2A receptors
   • Increased basal cyclic adenosine monophosphate (cAMP)
   • Enhanced vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) 4

Clinical Pharmacodynamics

• Provides more rapid, potent, and consistent platelet inhibition compared to clopidogrel 2, 3
• Achieves greater inhibition of ADP-induced platelet aggregation than clopidogrel, even in patients previously treated with clopidogrel 3
• Platelet function recovers more quickly after discontinuation (3-5 days) compared to thienopyridines (5-7 days) due to its reversible binding 1, 2

Side Effects Related to Mechanism

Ticagrelor's unique mechanism contributes to specific side effects:

1. Dyspnea: Occurs in up to 15% of patients, usually mild to moderate in severity 2, 5

   • Likely related to adenosine-mediated effects due to ENT1 inhibition

2. Ventricular pauses/bradycardia: Usually asymptomatic 3, 5

   • Potentially related to adenosine-induced effects on cardiac conduction

3. Bleeding risk: Increased non-CABG related bleeding compared to clopidogrel, though overall major bleeding rates are similar 2, 6

Clinical Implications of Mechanism

• The reversible binding allows for faster offset of action, which is advantageous when surgery is needed (discontinue 5 days before planned surgery) 2, 5
• The direct-acting nature provides more consistent antiplatelet effects without genetic variability issues seen with clopidogrel 3, 5
• The greater potency translates to superior clinical outcomes in ACS patients, including reduced cardiovascular mortality 2, 7

Ticagrelor's unique pharmacological profile makes it particularly valuable in high-risk ACS patients and those who may require procedures, though the twice-daily dosing requirement and specific side effects must be considered when selecting antiplatelet therapy.