1. NSAIDs

2. Introduction One of the most commonly used in the world
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. COX-2: Regulated COX-1: Constitutive
Homeostatic
Protection of gastric mucosa
Platelet activation
Renal functions
Macrophage differentiation
Pathologic
Inflammation
Pain
Fever

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
hospitalization and 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