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 Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils Loss of PGE2 and PGI2 mediated inhibition of acid secretion and cytoprotective effect ↑ Leukocyte-Endothelial Interactions Capillary Obstruction Proteases + Oxygen Radicals Ischemic Cell Injury Endo/Epithelial Cell Injury Mucosal Ulceration

7. The Salicylates - Aspirin • Effect on Respiration: triphasic • Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates respiration. • Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation • Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

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

9. Aspirin - Therapeutic Uses • 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 TXA2)

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

14. Use of Aspirin in Unstable Angina

15. Aspirin Toxicity - Salicylism • 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

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

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

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

24. Effect of Celecoxib & Rofecoxib on PGIM Urinary 2,3 dinor-6-keto-PGF1a (PGIM) Two Weeks Rx†† Single Dose Rx† 200 200 160 160 120 120 Urinary PGI-M (pg/mg creatinine) (Mean ± SE) * 80 80 ** ** ** 40 40 0 0 Placebo N=7 Celecoxib 400 mg N=7 Ibuprofen 800 mg N=7 Placebo N=12 Rofecoxib50 mg QDN=12 Indomethacin50 mg TIDN=10 * p<0.05 vs. placebo. †Proc. Natl. Acad Sci. USA 1999;96:272-277. **p<0.01 vs. placebo. ††J. Pharmacol. Exp. Ther. 1999;289:735-741.

25. Rofecoxib (VIGOR) Naproxen (VIGOR) Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study 3.5 3.0 2.5 Ibuprofen, Diclofenac, Nabumetone (OA) 2.0 Rofecoxib(OA) Cumulative Incidence % 1.5 1.0 0.5 0.0 0 2 4 6 8 10 12 14 Months of Follow-up FDA files

26. Treatment of Gout