Drug Interactions of Antiplatelets (Part 2):

Drug Interactions of ADP Receptor Blockers:

More presentations from Naina Mohamed, PhD

©   ADP receptor Blockers include

Ø Thienopyridines (Clopidogrel, Prasugrel And Ticlopidine)

Ø Non-Thienopyridines (Ticagrelor, Cangrelor and Elinogrel).

©   Thienopyridines and Non-Thienopyridines inhibit P2Y₁₂ receptors, which are involved in platelet aggregation.

©   P2Y₁₂ receptors are Purinergic receptors and they belong to the Gi protein-coupled (GiPCR) receptors.

©   P2Y₁₂ receptors function as chemoreceptors for adenosine diphosphate (ADP).

©   Thienopyridines are Prodrugs and are metabolized by CYP enzymes to inhibit P2Y₁₂ receptors irreversibly.

©   Non-Thienopyridines do not require metabolic activation and they produce reversible inhibition of P2Y₁₂ receptors.

                    

 ·      Thienopyridines (Clopidogrel, Prasugrel, Ticlopidine) are prodrugs and metabolized by CYP enzymes (CYP2C9 and CYP2C19) to produce active metabolites which bind to P2Y₁₂ receptors.

·      But, Non-Thienopyridines (Ticagrelor, cangrelor, Elinogrel) do not require to get metabolized to block P2Y₁₂ receptors.

©   Drugs increasing ADP receptor Blockers associated bleeding include…

Ø Aspirin

Ø Dipyridamole

©   Concomitant use of Thienopyridines like Clopidogrel and Ticlopidine with BuPROPion may result in decreased exposure of Hydroxybupropion (Active metabolite of buPROPion) due to the inhibition of CYP2B6-mediated buPROPion metabolism by Thienopyridines. The dose of buPROPion may be adjusted based on clinical response, if buPROPion is used concomitantly with a Thienopyridine.

©   Clopidogrel is a prodrug, it is activated by CYP enzyme CYP2C19, and other enzymes like CYP3A4, CYP1A2, CYP2B6 and CYP2C9 are also involved in the metabolic activation of Clopidogrel.

©   The drugs inhibiting CYP2C19 enzyme like Proton Pump Inhibitors (PPIs) (Omeprazole, Esomeprazole, etc), Cimetidine, Felbamate and Etravirine may inhibit the activation of Clopidogrel and hence decreased antiplatelet activity and increased risk of thrombotic events occur.

©    CYP3A4 inhibitors such as Calcium Channel Blockers (CCBs) (Amlodipine, Verapamil, Diltiazem, Nifedipine, etc), Azole Antifungals (Ketoconazole, Fluconazole, etc) and Grapefruit Juice (GFJ) may decrease the antiplatelet activity of Clopidogrel.

©   Glucuronide metabolite of Clopidogrel inhibit the CYP2C8 mediated metabolism of Repaglinide and Paclitaxel and their respective toxicities are enhanced.

©   Ticlopidine can increase the toxicity of Theophylline and Tizanidine by inhibiting their metabolisms.

©   Drug interactions can result in significant morbidity and mortality and thus minimizing the risk for drug interactions should be a goal in drug therapy.

©   The patients on antiplatelet therapy should bring a list of all of the drugs they are taking including prescription drugs, over-the-counter drugs, and any supplements, herbal or otherwise, during their visit to the doctor or pharmacist.

©   The risk of adverse effects could be reduced by healthcare professionals through the screening, education, and follow up on suspected drug interactions.

©   If possible, the patients are recommended to fill all their prescriptions at one pharmacy.

©   Pharmacists can play a crucial role in identifying possible drug interactions by asking patients about their herbal and other alternative medicine product use.