NSAIDs

1. NSAIDs

2. Introduction • One of the most commonly used in the world • 17000000 regular users, 50% over the age 60 • Will increase in the future • 5 to 7 percent of hospital admissions

3. Main actions 1.) Analgesic -effective against mild to moderate pain, do not cause dependence 2.) Anti-inflammatory 3.) Anti-pyretic 4.)Anti-platelet- prevent thromboxane production, derived from prostaglandins and cause platelet aggregation Others 5.) Useful in treatment of dysmenorrhea, associated with increased prostaglandin synthesis and increased uterine contractility 6.) Used to close the patent ductus arteriosus

4. Familiar NSAIDs • Acetylsalicylic acid • Ibuprofen • Naproxen • Indomethacin • Diclofenac • Piroxicam • Celecoxib

5. Pharmacokinetics • NSAID absorbed in stomach and small intestine into bloodstream • 90% - 95% of NSAID is bound to plasma proteins • 5% - 10% dissolved into plasma and exerts clinical effects • Metabolized in liver and excreted by kidney, but not on first pass through

6. NSAIDs Mechanism of action • Inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides • 2 isoforms of enzyme - COX-1 constitutive, present in platelets, stomach and kidney - COX-2 inducible by cytokines & endotoxins at sites of inflammation e.g., joints

7. Eicosanoid Cascade

8. Homeostatic Protection of gastric mucosa Platelet activation Renal functions Macrophagedifferentiation Pathologic Inflammation Pain Fever COX-2:Regulated COX-1:Constitutive

9. Selective VER Non-Selective • Similar to non-specific COX inhibitors • Anti-inflammatory • Analgesic • Some renal effects, e.g. sodium excretion, blood pressure • Different from non- specific COX-inhibitors • No anti-platelet effects • Reduced endoscopic GI erosion and ulceration • Bronchial spasm

10. NSAID Effects • Complete effects are achieved in two weeks in acute inflammatory conditions • Analgesia achieved with 50% - 75% dosage needed for anti-inflammatory effects

11. Side Effects • In 2001: • 100,000 hospitalizations (estimated) • 17,000 deaths (estimated) • $2 billion dollars in medical care

12. Side Effects • GI Irritation • Renal Damage or Dysfunction • Liver Damage or Dysfunction • Anemia • Skin reactions • CNS Effects: • Nervousness, Tinnitus, HA

13. GASTROINTESTINAL • Dyspepsia, peptic ulcer disease, and bleeding • 103000 hospitalization and 16500 deaths • 2% peptic ulcer

14. Who is at risk peptic ulcer? • Increasing age, particularly >60 • Higher NSAID dose • A past history of gastroduodenal toxicity from NSAIDs or peptic ulcer disease • Concurrent use of glucocorticoids, anticoagulants, bisphosphonates, or other NSAIDs

15. How can decrease peptic ulcer? • Use of alternative analgesics • Lowest dose • Selective COX2 • Misoprostol • PPI

16. HEPATIC INJURY • Elevations of serum aminotransferases • Liver failure is quite rare • Cholestasis

17. RENAL EFFECTS • Acute renal failure • ACUTE INTERSTITIAL NEPHRITIS AND NEPHROTIC SYNDROME • CHRONIC KIDNEY DISEASE

18. CARDIOVASCULAR EFFECTS • Coronary risk • Exacerbate heart failure • Hypertension

19. PULMONARY EFFECTS • Bronchospasm • Pulmonary infiltrates

20. HEMATOLOGIC EFFECTS • Neutropenia • Antiplatelet effects

21. CENTRAL NERVOUS SYSTEM • Aseptic meningitis • Psychosis • Cognitive dysfunction • Headaches • Tremor

22. SKIN REACTIONS • Various skin reactions • Toxic epidermal necrolysis (TEN) and the Stevens-Johnson syndrome

23. Minimizing toxicity with: • Patient evaluation for risk of developing NSAID-induced toxicity

24. The "safest" NSAID • Nonacetylated salicylates, ibuprofen

25. PREGNANCY AND LACTATION • It is best to avoid NSAIDs if possible during pregnancy • Miscarriage • Aspirin has a role in prevention of preeclampsia and the treatment of the antiphospholipid syndrome • NSAIDs are excreted in breast milk in very small amounts