ticagrelor

**Class/MOA:** Cyclopentyltriazolopyrimidine; reversible, noncompetitive (allosteric) antagonist of the platelet P2Y12 receptor (Gi-coupled). Blocking P2Y12 prevents ADP-mediated decrease in cAMP inhibition, so cAMP stays higher, GPIIb/IIIa activation is reduced, and platelet aggregation falls. Because binding is reversible, platelet function recovers faster after stopping (about 3–5 days, vs. 5–7 days for clopidogrel and 7–10 days for prasugrel, which bind irreversibly).

**Pharmacokinetics:** Active as the parent drug (not a prodrug), so onset is rapid (about 30 min–2 h) and not affected by CYP2C19 loss-of-function polymorphisms (a limitation of clopidogrel). It is metabolized by CYP3A4 into an active metabolite. Dosed twice daily (180 mg load, then 90 mg BID; 60 mg BID for extended therapy beyond 12 months post-MI). Aspirin maintenance must be ≤100 mg/day, because higher doses reduce ticagrelor's efficacy.

**Indications:** ACS (STEMI, NSTEMI, unstable angina), whether managed medically or with PCI, to reduce CV death, MI, and stent thrombosis (PLATO trial: superior to clopidogrel). Also secondary prevention in prior MI (PEGASUS-TIMI 54), and in high-risk stroke/TIA (e.g., THALES, short-term with aspirin) and stable CAD with diabetes (THEMIS) in selected patients.

**Adverse effects (high-yield):** - **Dyspnea** (about 10–15%): likely from inhibition of adenosine reuptake (ENT1) and increased adenosine, which stimulates pulmonary C-fibers. It is usually mild and transient and doesn't require stopping the drug. - **Bleeding**: the major risk, including non-CABG major bleeding. Contraindicated in active pathological bleeding and history of intracranial hemorrhage. - **Bradyarrhythmias/ventricular pauses**: adenosine effect. Use caution in sick sinus syndrome or high-grade AV block without a pacemaker. - **Elevated uric acid** (hyperuricemia/gout). - Elevated creatinine.

**Interactions:** Avoid strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir), which increase levels, and strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine), which decrease levels. Simvastatin/lovastatin doses should be limited to 40 mg. Ticagrelor may raise digoxin levels.

**Perioperative:** Hold for ≥5 days before elective surgery (especially CABG).

**Comparison pearls (boards):** - Clopidogrel: irreversible, prodrug (CYP2C19), thienopyridine. Risks include rare TTP. - Prasugrel: irreversible, thienopyridine, more potent. Contraindicated with prior stroke/TIA, and cautioned in age ≥75 or weight <60 kg. - Ticagrelor: reversible, non-thienopyridine, dyspnea, BID dosing. - Cangrelor: IV, reversible P2Y12 inhibitor, used during PCI. - Aspirin (COX-1 inhibitor) and GPIIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) work through different mechanisms.

**Reversal:** There is no specific, widely approved reversal agent. Management is supportive, with platelet transfusion generally ineffective because the drug stays active in circulation. Bentracimab, a monoclonal antibody fragment that binds ticagrelor, has been studied in clinical trials, but it is not established as standard care.