1. Nonsteroidal Anti- inflammatory Drugs (NSAIDs) Common therapeutic indications Common adverse effects Different pharmacokinetics and potency Different chemical families Common mechanism of action (cyclooxygenase inhibition) Different selectivities to COX I and II Similarities more striking than Differences

4. Common Pharmacological Effects Analgesic (CNS and peripheral effect) may involve non-PG related effects Antipyretic (CNS effect) Anti-inflammatory (except acetaminophen) due mainly to PG inhibition. Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes Some are Uricosuric

5. Common Adverse Effects Platelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) Acute Renal Failure in susceptible Sodium+ water retention and edema Analgesic nephropathy Prolongation of gestation and inhibition of labor. Hypersenstivity (not immunologic but due to PG inhibition)

6. NSAID ↑ Leukocyte-Endothelial Interactions Capillary Obstruction Ischemic Cell Injury Proteases + Oxygen Radicals Endo/Epithelial Cell Injury Mucosal Ulceration Loss of PGE 2 and PGI 2 mediated inhibition of acid secretion and cytoprotective effect Loss of PGI 2 induced inhibition of LTB 4 mediated endothelial adhesion and activation of neutrophils

7. The Salicylates - Aspirin Effect on Respiration: triphasic 1.Low doses: uncoupling phosphorylation → ↑ CO 2 → stimulates respiration. 2.Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation 3.Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

8. GI system 1.Dose dependent hepatitis 2.Reye’s syndrome Metabolic 1.Uncoupling of Oxid. Phosphorylation 2.Hyperglycemia and depletion of muscle and hepatic glycogen Endocrine: corticosteroids, thyroid Aspirin

9. Antipyretic, analgesic Anti-inflammatory: rheumatic fever, rheumatoid arthritis, other rheumatological diseases. High dose needed (5-8 g/day) Prophylaxis of diseases due to platelet aggregation (CAD, post-op DVT) Pre-eclampsia and hypertension of pregnancy (?excess TXA 2 ) Aspirin - Therapeutic Uses

10. Generation of Lipoxins by Aspirin

11. Role of Lipoxins in Anti-inflammatory effects of Aspirin

12. Effect of NSAID’s on Platelet-Endothelial Interactions

13. Use of Aspirin in Unstable Angina

15. Headache - timmitus - dizziness – hearing impairment – dim vision Confusion and drowziness Sweating and hyperventilation Nausea, vomiting Marked acid-base disturbances Hyperpyrexia Dehydration Cardiovascular and respiratory collapse, coma convulsions and death Aspirin Toxicity - Salicylism

16. Decrease absorption - activated charcoal, emetics, gastric lavage Enhance excretion - alkalinize urine, forced diuresis, hemodialysis Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc… Aspirin Toxicity - Treatment

17. Other NSAID’s Phenylbutazone: additional uricosuric effect. Aplastic anemia. Indomethacin: Common ADR’s. CNS most common: halucinations, depression, seizures Propionic acids: better tolerated. Differ in pharmacokinetics Acetaminophen: differes in effects and ADR’s from rest. Main toxicity: hepatitis due to toxic intermediate which depletes glutathione. Treat with N-acetylcysteine.

19. Attempts to Decrease Toxicity of NSAID’s – Nitroaspirins

21. 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

22. VIGOR - Summary of GI Endpoints † p < 0.001. * p = 0.005. 0 1 2 3 4 5 Confirmed Clinical Upper GI Events Confirmed Complicated Upper GI Events All Clinical GI Bleeding RR: 0.46 † (0.33, 0.64) RR: 0.43 * (0.24, 0.78) RR: 0.38 † (0.25, 0.57) Rates per 100 Patient-Years Rofecoxib Naproxen ( ) = 95% CI. Source: Bombardier, et al. N Engl J Med. 2000.

23. Patients with Events (Rates per 100 Patient-Years) Event Category Rofecoxib N=4047 Naproxen N=4029 Relative Risk (95% CI) Confirmed CV events 45 (1.7)19 (0.7)0.42 (0.25, 0.72) Cardiac events 28 (1.0)10 (0.4)0.36 (0.17, 0.74) Cerebrovascular events 11 (0.4) 8 (0.3)0.73 (0.29, 1.80) Peripheral vascular events 6 (0.2)1 (0.04) 0.17 (0.00, 1.37) VIGOR - Confirmed Thrombotic Cardiovascular Events Source: Data on file, MSD

24. Effect of Celecoxib & Rofecoxib on PGIM * p<0.05 vs. placebo. 0 40 80 120 160 200 Placebo N=7 Celecoxib 400 mg N=7 Ibuprofen 800 mg N=7 Urinary PGI-M (pg/mg creatinine) (Mean ± SE) ** * Placebo N=12 Rofecoxib 50 mg QD N=12 Indomethacin 50 mg TID N=10 ** Single Dose Rx † Two Weeks Rx †† 0 40 80 120 160 200 † Proc. Natl. Acad Sci. USA 1999;96:272-277. Urinary 2,3 dinor-6-keto-PGF 1  (PGIM) †† J. Pharmacol. Exp. Ther. 1999;289:735-741. **p<0.01 vs. placebo.

25. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Months of Follow-up 02468101214 Cumulative Incidence % Rofecoxib (OA) Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study Rofecoxib (VIGOR) Naproxen (VIGOR) FDA files Ibuprofen, Diclofenac, Nabumetone (OA)

26. Treatment of Gout