Drug Interactions of ADP receptor Blockers (Antiplatelets)

· ADP receptor Blockers (Antiplatelets) include Thienopyridines (Clopidogrel, Prasugrel, Ticlopidine) and Non-Thienopyridines (Ticagrelor, Cangrelor, Elinogrel ).
· The risk of adverse effects could be reduced by healthcare professionals through the screening, education, and follow up on suspected drug interactions.

1. Drug Interactions of Antiplatelets ( Part 2 ) ( Drug Interactions of ADP receptor Blockers ) D r P.Naina Mohamed P h D Pharmacologist

2. Introduction ADP receptor Blockers include Thienopyridines ( Clopidogrel, Prasugrel And Ticlopidine ) Non- Thienopyridines ( ticagrelor, cangrelor and elinogrel ). Thienopyridines and Non-Thienopyridines inhibit P2Y 12 receptors which are involved in platelet aggregation. P2Y 12 receptors are Purinergic receptors and they belong to the G i protein-coupled ( G i PCR ) receptors. P2Y 12 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. Interaction between one or more coadministered medications leading to change in their effectiveness or toxicity, is termed as “ Adverse drug interaction ”. Antiplatelets can interact with prescription drugs, Over-the-counter (OTC) medications, Herbal products, Dietary supplements, Vitamins, Foods, Diseases, and Genetics (family history ).

3. Antiplatelets Irreversible cyclooxygenase (COX) inhibitors Aspirin ADP receptor Blockers ( Thienopyridines ) Clopidogrel  Prasugrel Ticlopidine ADP receptor Blockers ( Non - Thienopyridines ) Ticagrelor cangrelor Elinogrel Adenosine reuptake inhibitors Dipyridamole Glycoprotein IIB/IIIA inhibitors  (IV use only) Abciximab   Eptifibatide   Tirofiban Phosphodiesterase inhibitors Cilostazol Protease-activated receptor-1 (PAR-1) antagonists Vorapaxar  

4. Activation of purinergic receptors ( P2Y 1  and P2Y 12 ) Activation of P2Y 1 receptors Adenosine diphosphate (ADP ) binds with P2Y 1  receptors to initiate the platelet response. Activation of P2Y 12 receptors ADP binds with P2Y 12  receptors to promote the platelet response. ADP receptor blockers Thienopyridines ( Clopidogrel, Prasugrel, Ticlopidine) and Non-Thienopyridines ( Ticagrelor, cangrelor , Elinogrel ) inhibit P2Y 12  receptors to exhibit Antiplatelet activity. https ://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187865/

5. Mechanism of action of ADP receptor Blockers http:// www.tandfonline.com/doi/abs/10.1080/09537109876799 Thienopyridines ( Clopidogrel, Prasugrel , Ticlopidine) are prodrugs and metabolized by CYP enzymes ( CYP2C9 and CYP2C19) to produce active metabolites which bind to P2Y 12  receptors. But , Non-Thienopyridines ( Ticagrelor, cangrelor , Elinogrel ) do not require to get metabolized to block P2Y 12  receptors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187865 /

6. ADP blockers & Aspirin The signs and symptoms of bleeding should be monitored, If aspirin and ADP blockers (Clopidogrel, Prasugrel , Ticlopidine , ticagrelor, etc ) are used concurrently. http :// www.tandfonline.com/doi/abs/10.1080/09537105310001645960

7. ADP blockers & Dipyridamole Monitoring of signs and symptoms of bleeding is warranted, If DIPYRIDAMOLE and ADP blockers (Clopidogrel, Prasugrel , Ticlopidine , ticagrelor, etc ) are used concurrently. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187865 /

8. Thienopyridines & BuPROPion if buPROPion is used concomitantly with a Thienopyridine , dose adjustment of buPROPion may be necessary based on clinical response. http:// jpet.aspetjournals.org/content/308/1/189.long

9. Clopidogrel & Proton Pump Inhibitors (PPI s ) https ://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110685 / lansoprazole and dexlansoprazole have less effect on the antiplatelet activity of Clopidogrel compared to omeprazole and esomeprazole. http :// www.sciencedirect.com/science/article/pii/S073510971200246X?via%3Dihub Avoid prescribing omeprazole and esomeprazole for patients taking clopidogrel. The PPI s like pantoprazole or rabeprazole would be suitable for patients taking Clopidogrel as do not affect the pharmacokinetics and antiplatelet efficacy of Clopidogrel. http:// onlinelibrary.wiley.com/wol1/doi/10.1038/clpt.2010.219/abstract http:// www.sciencedirect.com/science/article/pii/S1875213613003008?via%3Dihub

10. Clopidogrel & Cimetidine concomitant use of cimetidine , with Clopidogrel should be avoided. Consider using other H2 blockers such as ranitidine or famotidine or antacid. https :// www.nature.com/ajg/journal/v104/n12/full/ajg2009525a.html

11. Clopidogrel & Calcium Channel Blockers (CCBs) Caution is advised if Calcium Channel Blockers (CCBs ) and Clopidogrel are used concurrently. and monitor patients for loss of Clopidogrel efficacy . https:// th.schattauer.de/en/contents/archive/issue/1069/manuscript/12874.html http:// onlinelibrary.wiley.com/doi/10.1111/1755-5922.12138/full

12. Clopidogrel & SSRI s or SNRI s Pharmacodynamic interaction: http :// jamanetwork.com/journals/jamainternalmedicine/fullarticle/217660 Pharmacokinetic interaction : http :// onlinelibrary.wiley.com/doi/10.1046/j.1472-8206.2003.00193.x/full Use caution with the concomitant use of clopidogrel and SSRI s or SNRI s .   http://onlinelibrary.wiley.com/doi/10.1111/fcp.12021/full

13. Clopidogrel & Repaglinide The blood glucose should be monitored and the dose of Repaglinide should be adjusted, if Clopidogrel and Repaglinide used concomitantly. http:// onlinelibrary.wiley.com/doi/10.1038/clpt.2014.141/full

14. Clopidogrel & Paclitaxel Concomitant use requires Monitoring. http :// onlinelibrary.wiley.com/wol1/doi/10.1002/cpt.674/abstract

15. Clopidogrel & Azole Antifungals If possible, concomitant use of Clopidogrel with ketoconazole can be avoided. Concomitant use of http :// onlinelibrary.wiley.com/wol1/doi/10.1038/sj.clpt.6100139/abstract

16. Clopidogrel & Grapefruit Juice (GFJ) The patients taking Clopidogrel should be advised to avoid drinking grapefruit juice (GFJ). http ://onlinelibrary.wiley.com/wol1/doi/10.1038/clpt.2013.192/abstract

17. Clopidogrel & Felbamate It is advisable to avoid felbamate in patients taking Clopidogrel. http:// www.sciencedirect.com/science/article/pii/S1555415510004320 http:// jamanetwork.com/journals/jama/fullarticle/185262

18. Clopidogrel & ETRAVIRINE Avoid the concomitant use of Clopidogrel with ETRAVIRINE , if possible. http://www.sciencedirect.com/science/article/pii/S1555415510004320 http://jamanetwork.com/journals/jama/fullarticle/185262

19. Ticlopidine & Tizanidine M onitor for signs and symptoms of hypotension if Tizanidine is used concurrently with ticlopidine . https:// academic.oup.com/jamia/article/19/5/735/715212/High-priority-drug-drug-interactions-for-use-in

20. Ticlopidine & Theophylline serum concentrations of Theophylline should be closely monitored when ticlopidine is added, discontinued, or when dosing changes occur. Dosing adjustments of theophylline may be necessary. http:// onlinelibrary.wiley.com/doi/10.1038/clpt.1987.39/abstract https:// link.springer.com/article/10.2165%2F00003088-199120010-00005

21. Conclusion 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.

22. References Stockley’s Drug Interactions, 9e Karen Baxter Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e Laurence L. Brunton , Bruce A. Chabner , Björn C. Knollmann Basic & Clinical Pharmacology, 12e Bertram G. Katzung , Susan B. Masters, Anthony J. Trevor A Manual of Adverse Drug Interactions J.P. Griffin, P.F. D'Arcy Clinical Manual of Drug Interaction Principles for Medical Practice Gary H. Wynn‏, Jessica R. Oesterheld ‏, Kelly L. Cozza ‏, Scott C. Armstrong ‏ Handbook of Drug Interactions: A Clinical and Forensic Guide Ashraf Mozayani , Lionel Raymon

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