1. MEDICINAL CHEMISTRY- III introduction Wed. 2/ 5/ 1432H Prof. Dr. Wafaa Zaghary wzaghary@ksu.edu.sa PHC 426

2. Different ‘types’ of pain, not just different degrees of pain Multiple chemical mediators of pain Optimal therapy matches the analgesic(s) with the type(s) of pain Different ‘types’ of pain, not just different degrees of pain Multiple chemical mediators of pain Optimal therapy matches the analgesic(s) with the type(s) of pain

3. NSAIDs (non steroidal anti- inflammatory drugs)

4. Nonsteroidal Anti- Inflammatory Drug A therapeutic agent which relieves pain and fever by inhibiting the inflammatory response. These drugs are available over the counter and by prescription. Some common examples include aspirin, ibuprofen, Celebrex, and less commonly acetaminophen (Tylenol).

5. Benefits of NSAIDs Decrease pain and inflammation associated with rheumatic diseases. Some studies show that Cox-2 inhibition may play a role in the modulation of intestinal polyps and colorectal cancer. Other studies show that Cox-2 inhibition may prevent Alzheimer’s disease.

6. NSAID use NSAIDs are available OTC NSAIDs can be toxic on their own People who take NSAIDs (elderly people) often take many drugs which can lead to dangerous interactions NSAIDs are metabolized by multiple hepatic pathways

7. Common Side Effects Common side effects to ALL NSAIDs are: Abdominal pain Diarrhea Nausea Fluid retention These side effects occur in about 30% of all people taking NSAIDs.

8. Adverse effects Nephrotoxic Bleeding problems Increase blood pressure FDA requires medication guide be dispensed with every NSAID prescription – www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf FDA fact: >70,000 hospitalizations per year and 10,000- 20,000 deaths per year can be associated with NSAID use

9. Possible Side Effects Cox-1 inhibitors GI ulceration, perforation, toxicity Kidney failure Congestive heart failure Cox-2 inhibitors GI problems May delay ulcer healing Increased risk of CV disease Kidney failure * Increased risk factors include being male, advanced age, and history of ulcers.

10. Startling Statistic N Engl J Med 1999;340:1888-1899 # of Deaths per Year

11. Categories of NSAIDs There are two major categories for non-steroidal anti-inflammatory drugs The first is non-selective anti- inflammatory drugs. The second is selective anti- inflammatory drugs, COX-2 inhibitors.

12. The Inflammatory Response The body’s response to a stimuli which causes pain and/or tissue damage. Physiologically capillaries become “leaky” through vasodilation. The response is initiated by the chemical messengers prostaglandins.

13. Biosynthesis of Prostaglandins The goal is to inhibit the biosynthesis of prostaglandins in order to relieve the symptoms caused by the inflammatory response. Prostaglandins are synthesized from arachidonic acid in a pathway mediated by the Cyclooxygenase enzymes.

14. FitzGerald, G. A. et al. N Engl J Med 2001;345:433-442 Production and Actions of Prostaglandins and Thromboxane

15. COX ExpressionFunctionInhibitors COX-1 constitutively throughout the body organ pain, platelet function, stomach protection NSAIDs including aspirin COX-2 Inducible and constitutively in brain, kidney Inducible: inflammati on, pain, fever Constitutive: synaptic plasticity NSAIDs, COX 2 inhibitors including celecoxib (Celobrex ) COX-3 Constitutively, high in brain, heart pain pathways, not inflammation pathways acetaminophen some NSAIDs

16. Cox-1 vs. Cox-2 inhibitors

17. Selective COX-II Inhibitors Anti-inflammatory with less adverse effects, especially GI events. Potential toxicities: kidney and platelets - ? increased risk of thrombotic events Role in Cancer prevention Role in Alzheimer’s disease

20. ASPIRIN Major Actions Antipyretic action Block the production of PGE 2 to reset the hypothalamic temperature set point

21. ASPIRIN Major Actions Antiplatelet/antithrombotic Decreases platelet production of TXA 2 by COX-1 to limit platelet aggregation and vasoconstrictiion

22. ASPIRIN/ NSAIDs ADVERSE GI EFFECTS BLEEDING ULCERATION OBSTRUCTION

23. Textbooks: Williams, D.A. and Lemeke, T.L., Foye’s Principle of Medicinal Chemistry, Lippincott Williams & Wilkins, Philadelphia, PA., 5th Edition, 2002.

24. References 1. Tramer MR, et al. quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain. 2000 Mar;85(1-2):169-82. 2. DeBisschop M. What are the risks of long-term NSAIDs and COX-2 inhibitors? J of Family Practice. 2003 Mar;52(3):199- 200. 3. Deviere J. Do selective cyclo-oxygenase inhibitors eliminate the adverse events associated with nonsteroidal anti- inflammatory drug therapy? 4. Oviedo JA, Wolfe MM. Clinical potential of cyclo-oxygenase-2 inhibitors. Biodrugs. 2001;15(9):563-72. 5. Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990’s. Arch Internal Medicine. 2000 Jul 24;160(14):2093-9.

25. References 6.Hawkey CJ. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scandinavian Journal of Gastroenterology 1996; vol. 220: 124-7. 7.Wolfe MM, Liechenstein DO, Sigh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med 1999;340:1888-1899 8.FDA and International Guidelines on Efficacy and Safety of Cox-2 Inhibitors