COX Inhibitors and Blood Coagulation

1. COX Inhibitors and Blood Coagulation PHM 142 – Tuesday September 16th, 2014 Chris Gallant Edmond Chiu Maggie Huynh Bavithra Kumar PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

2. What is COX? • Enzyme cyclooxygenase1 • Responsible for the formation of prostanoids1 • 3 main groups of prostanoids include: • prostaglandins • prostacyclins • thromboxanes *These are all involved in inflammatory responses/are inflammatory mediators*

3. What is COX? Two forms of cyclooxygenase enzymes exist: COX-1 -> present in most tissues1 • e.g in GI tract it maintains the normal lining of the stomach. The enzyme is also involved in kidney and platelet function. 2,3 COX-2 -> primarily present at sites of inflammation1

4. What is Blood Coagulation? Adapted from reference 5

5. COX’s Relationship to Blood Coagulation • COX plays a role in cessation of bleeding 4-6 • COX activates a chemical known as thromboxane A2 4-6 • The aggregation of platelets, in concert with the clotting process, results in a fibrin clot which stops bleeding and aids repair of the blood vessel. 7

6. What are COX inhibitors? • A class of drugs that target the cyclooxygenase enzyme and act as an effective treatment to pain and inflammation. Also known as nonsteroidal anti-inflammatory drugs (NSAIDs).8 • Can be nonspecific (target both COX-1 and COX-2) or specifically target COX-2.8 • COX-2 inhibition is desirable since this will reduce pain and inflammation in certain areas, while COX-1 inhibition is associated with side effects, such as stomach lining damage and gastric ulcers.8 http://img.wikinut.com/img/297i4cfbldfkof_v/jpeg/0/Ibuprofen-Advil-tablets.jpeg http://a.espncdn.com/photo/2007/1112/pg2_a_aleve_300.jpg

7. How COX Inhibitors Work • Decrease the production of prostaglandins, which promote pain, inflammation and fever.9 • Prostaglandins also protect the lining of the stomach and intestines, promote blood clotting, and affect kidney function.9 • COX inhibitors are taken orally, and after absorption into the bloodstream they bind to the cyclooxygenase enzymes. COX-1 is found in all tissues constitutively, while COX-2 is induced by inflammation.9 • Binding can be reversible or irreversible.7 http://www.cheapmedicinechest.com/wp-content/uploads/2010/03/Figure-2-Nonselective-nonsteroidal-anti-inflammatory-drugs.png http://publications.nigms.nih.gov/structlife/images/ch4_valine.gif

8. Aspirin and COX: Mechanism of Action • Serine acetylation3 • Non-selective3 • Irreversible3 Adapted from reference 4

9. Issues with COX-2 specific inhibitors • COX-2 inhibition reduces prostacyclin production, which is an important prostaglandin that prevents platelet clumping.9 • Without prostacyclin, platelets can build up and clump, leading to increased heart attacks and strokes in patients. Since COX-1 is unaffected, thromboxane A2 contributes to thrombosis as well.9 • Examples are Vioxx and Bextra, which have both been discontinued.9 http://img.timeinc.net/time/covers/1101050228/map/viox.gif

10. Case Study • COX-2 inhibitors used to treat pain after surgery 10,11 • Possible complications? • Increased risk of thrombosis • Concern in Coronary-Artery Bypass Grafting (CABG)?

11. Factors Considered • CABG increases thromboembolic events: • Platelet activation • Pre-exisiting cardiovascular conditions12 • Sheer stress from atherosclerosis • Ischemia13 • During procedure14 • COX-2 inhibitors increase risk of thrombosis

12. Clinical Data Figure adapted from reference 15

13. Conclusion of Study • Risk outweighs benefits16 • Advised to discontinue use of COX-2 specific inhibitors after CABG16 • Drug discontinued in 2005

14. Skit • To exemplify case study in clinical setting • Enjoy!

15. Summary Slide • COX is an enzyme cyclooxygenase responsible for the formation of prostanoids which are involved in inflammatory response • COX plays a role in cessation of bleeding and activates a chemical known as thromboxane A2 which relates to blood coagulation and platelet aggregation • COX inhibitors nonspecifically bind to COX-1 and COX-2 or specifically bind to COX-2. Binding to COX-2 is desirable for reducing inflammation, pain and fever as it also avoids gastric ulceration. This effect is caused by reducing prostaglandin production. • COX-2 inhibitors should be avoided when risk of thromboembolic events is higher

16. References • Eustice, C. (2014, May 19). What Is Cyclooxygenase (COX)?. About Health . Retrieved September 15, 2014, from http://osteoarthritis.about.com/od/osteoart • Lipsky, A. J. (n.d.). Clinical Considerations for Gastric Protection in the Presence of NSAID Therapy. Medscape. Retrieved September 15, 2014, from http://www.medscape.org/viewarticle/4739 • University, Department of Epidemiology and Preventative Medicine. (n.d.). How Aspirin Works. How Aspirin Works. Retrieved September 15, 2014 from http://www.aspree.org/AUS/aspree- content/aspirin/how-aspirin-works.aspx • Ophardt, Charles. "Prostaglandins." Virtual Chembook. N.p., n.d. Web. 15 Sept. 2014. <http://www.elmhurst.edu/~chm/vchembook/555prostagland.html>. • "How The Blood Clots." How Does Blood Clot? Coagulation Explained, Diagram, Blood Clotting Process, Stages, Hemostasis. N.p., 2010. Web. 15 Sept. 2014. • Rhoades, Rodney , and David Bell. "Blood Clotting." Inkling. WoltersKluwer, n.d. Web. 15 Sept. 2014. https://www.inkling.com/read/medical-physiology-rodney-rhoades-david-bell-4th/chapter-9/blood- clotting. • Stenina, Olga, and Edward Plow. "MET orchestrates cancer and blood coagulation." Nature.com. Nature Publishing Group, n.d. Web. 15 Sept. 2014. <http://www.nature.com/nm/journal/v11/n4/fig_tab/nm0405- 376_F1.html>. • McGettigan, P. and Henry, D. (2000). Current problems with non-specific COX inhibitors. CurrPharm Des, 6(17): 1693-1724. • Eustice, Carol. Cyclooxygenase: COX-1 and COX-2 explained. About Health, http://osteoarthritis.about.com/od/osteoarthritismedications/a/cyclooxygenase.htm (accessed September 10th, 2014).

17. References Daniels, S. E., Grossman, E. H., Kuss, M. E., Talwalker, S., & Hubbard, R. C. (2001). A double-blind, randomized comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post—oral surgery pain model. Clinical therapeutics, 23(7), 1018-1031. Ng, A., Smith, G., & Davidson, A. C. (2003). Analgesic effects of parecoxib following total abdominal hysterectomy†‡. British Journal of Anaesthesia, 90(6), 746-749. Konstantopoulos, K., Grotta, J. C., Sills, C., Wu, K. K., & Hellums, J. D. (1995). Shear- induced platelet aggregation in normal subjects and stroke patients.Thrombosis and haemostasis, 74(5), 1329-1334. Park, J. L., & Lucchesi, B. R. (1999). Mechanisms of myocardial reperfusion injury. The Annals of thoracic surgery, 68(5), 1905-1912. Wan, S., LeClerc, J. L., & Vincent, J. L. (1997). Inflammatory response to cardiopulmonary bypass mechanisms involved and possible therapeutic strategies. CHEST Journal, 112(3), 676-692. Nussmeier, N. A., Whelton, A. A., Brown, M. T., Langford, R. M., Hoeft, A., Parlow, J. L., ... & Verburg, K. M. (2005). Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. New England Journal of Medicine, 352(11), 1081- 1091.