Clopidogrel and Ticagrelor

Mechanism

Pharmacological Class and Group

Antiplatelet agents belonging to the class of Adenosine Diphosphate P2Y12 Receptor Inhibitors. Clopidogrel is a second-generation thienopyridine that acts as a prodrug that requires metabolic activation and binds irreversibly; Ticagrelor is a cyclopentyltriazolopyrimidine with direct and reversible action.

Mechanism of Action

Adenosine diphosphate (ADP) released by activated platelets stimulates their G protein-coupled transmembrane purinergic receptors P2Y1 and P2Y12. The P2Y12 receptor is the main mediator of platelet aggregation amplification, coupling to the G_i subunit to suppress adenylate cyclase activity and induce terminal activation of glycoprotein receptors. IIb/IIIa that bind fibrinogen.

Comparative P2Y12 Receiver Blocking Profile

1. Clopidogrel (Irreversible Inhibition mediated by Prodrug): It is an inactive prodrug that requires a hepatic phase I conversion in two steps of molecular oxidation. Its active metabolite contains a free thiol group that binds covalently and irreversibly to the cysteine residues (Cys17 and Cys270) of the platelet receptor P2Y12, canceling the binding capacity of ADP to the receptor for life.

2. Ticagrelor (Direct Reversible Inhibition of Allosteric Type): It is an active molecule that does not require prior hepatic metabolic steps to exert its action. It binds reversibly and non-competitively to a distinct allosteric site of the P2Y12 receptor, blocking ADP-induced intracellular signaling without directly competing for its primary binding site:

Ticagrelor Reversible Allosteric Binding Blocking the active conformation of the P2Y12 Receptor

As a reversible binding, the degree of platelet inhibition decreases as plasma levels of the drug fall, which accelerates the return of normal platelet function after discontinuation of treatment compared to clopidogrel.

Pharmacokinetics

High Resolution Pharmacokinetics

Indicators and dose

Clinical Indications and Uses

• Acute Coronary Syndrome (ACS): Indicated as part of double antiplatelet therapy (DAPT) associated with ASA. Ticagrelor shows superiority over clopidogrel (PLATO clinical trial) and is of choice in high-risk patients.
• Prevention of Stent Thrombosis: After percutaneous coronary intervention (PCI) with placement of drug-eluting or conventional metallic stents.
• Secondary Prevention of Ischemic Stroke and Infarction: Clopidogrel is the drug of choice in monotherapy in patients with real digestive intolerance or confirmed allergy to ASA.
• Symptomatic Peripheral Arteriopathy: Clopidogrel reduces the incidence of major vascular events in a similar way to ASA.

Dosage and Clinical Adjustment

Clopidogrel:

• Loading Dose (SCA/ICP): 300 mg to 600 mg immediately orally.
• Usual Maintenance Dose: 75 mg once a day orally continuously.

Ticagrelor:

• Loading Dose (SCA): 180 mg starting orally.
• Usual Maintenance Dose: 90 mg twice daily orally (strictly every 12 hours) for a recommended period of 12 months after acute coronary syndrome.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Active pathological bleeding of severe range (active intracranial hemorrhage, active upper gastrointestinal bleeding).
• Hypersensitivity to the drug or excipients.
• Severe decompensated liver failure (risk of bleeding due to concurrent coagulopathy).

Relative Contraindications

• Planning for major coronary bypass surgery: Requires prior suspension of the drug (minimum 5 days for clopidogrel and 5 days for ticagrelor) to avoid catastrophic surgical bleeding.
• History of intracranial hemorrhage (especially for ticagrelor).
• Asthma or symptomatic bradyarrhythmias (ticagrelor can induce benign dyspnea by stimulation of adenosine receptors).

Adverse Effects and Toxicity

• Systemic Hemorrhage (main ADR): Major and minor bleeding from any location.
• Benign Dyspnea (Ticagrelor 15% - 20%): Temporary dyspnea that usually resolves spontaneously in the first weeks of treatment. It is due to the fact that ticagrelor inhibits the equilibrative nucleoside transporter 1 (ENT1), accumulating local adenosine in the lungs, which overstimulates vagal dyspnea receptors. It is not associated with bronchospasm or deterioration of real ventricular function.
• Ventricular Pauses / Bradycardia: Ticagrelor can induce asymptomatic transient sinus pauses by stimulation of nodal adenosine.
• Thrombotic Thrombocytopenic Purpura (TTP): Very rare idiosyncratic ADR (< 0.001%) associated with the use of thienopyridines.

Pharmacogenomics Alert: Genetic Resistance to Clopidogrel

About 15% to 30% of the general population have loss-of-function genetic variants in the gene that encodes the liver isoenzyme CYP2C19 (mainly the CYP2C19*2 and CYP2C19*3 alleles). Carriers of these mutations are classified as "slow metabolizers":

Slow CYP2C19 Metabolizer ↓ Conversion of Clopidogrel to active form Loss of protective efficacy

In these patients, the use of clopidogrel is associated with unacceptably high rates of therapeutic failure with the development of acute stent thrombosis and recurrent infarctions. In patients with acute coronary syndromes undergoing angioplasty, it is advisable to prioritize the use of ticagrelor or prasugrel (which do not depend on activation by CYP2C19) in accordance with current specialty guidelines.

Relevant Drug Interactions

• Proton Pump Inhibitors (Omeprazole and Esomeprazole): They competitively inhibit the hepatic CYP2C19 isoenzyme. Its joint administration with clopidogrel drastically reduces its metabolic activation, reducing the antiplatelet effect. If a gastric mucosal protector is required, it is advisable to prefer pantoprazole or rabeprazole (which do not inhibit the CYP2C19 pathway):

Clinical

Prescription Pearl: Safe PPI Selection with Clopidogrel

For patients on dual antiplatelet therapy with clopidogrel who require prophylaxis against gastrointestinal bleeding, routine use of omeprazole or esomeprazole should be avoided. The recommended selection of choice is pantoprazole:

Clopidogrel + Omeprazole Loss of antiplatelet effect vs Clopidogrel + Pantoprazole Preserved antiplatelet efficacy

Pantoprazole uses secondary hepatic metabolic pathways of cellular sulfoconjugation, preserving intact the activity of the CYP2C19 enzyme for the activation of clopidogrel.