1. Nonsteroidal Anti- inflammatory Drugs ผศ. พญ. มาลียา มโนรถ

2. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Cell membrane phospholipids Phospholipase A 2 Arachidonic acid Cyclooxygenase (COX-1; COX-2) Endoperoxide (PGG, PGH) TXAPGI PGE PGF Steroids NSAIDs

3. Aspirin (acetylsalicylic acid) Newer NSAIDs –ibuprofen –indomethacin –diclofenac –meclofenamic acid –piroxicam –phenylbutazone

4. The Salicylates Salicylic acid Aspirin (ASA) Methyl salicylate Diflunisal Sasalate

5. Aspirin Acetylsalicylic acid : ASA 1763 Reverend Edmund Stone (powdered form of the bark of willow success in treating fever) 1853 : ASA was synthesized 1899 : use

6. Pharmacokinetics Rapidly absorbed : stomach, upper small intestine Hydrolyzed (in blood tissues ) acetic acid + salicylate Esterase Distributed throughout the body Bound to albumin

7. Pharmacokinetics Elimination of salicylate –First order at low doses (serum T 1/2 : 3- 5 hrs) –Zero order at high doses (serum T 1/2 = > 15 hrs) Excretion is via the kidney

8. Pharmacokinetics Metabolism of salicylate Aspirin Sodium salicylate Acetic acid Salicylate Conjugation glucuronic acid glycine Free salicylate Oxidation

9. Pharmacokinetics Alkalinization of the urine ญ rate of excretion of free salicylate

10. Mechanism of action Inhibit cyclooxygenase –COX-1 : many tissues (normal physiologic process) –COX-2I : inflammatory cells (major role in tissue injury) NSAIDs inhibit COX-1 as much as or more than COX-2 Aspirin : irreversible inhibits Newer agents : reversible inhibit

11. Clinical Use 1. Aspirin –low doses (< 300mg/day) : reducing platelet aggregation –intermediate doses (300-2,400 mg/day) : antipyretic and analgesic effects –high doses (2,400-4,000 mg/day) : ant- inflammatory effect

12. 2. Newer NSAIDs well absorbed after PO excreted via the kidney Ibuprofen : –T 1/2 : 2 h, relatively safe –better tolerated than ASA Naproxen & piroxicam : –longer T 1/2 (12-24 h)

13. 2. Newer NSAIDs Sulindac –sulfoxide (product) ฎ liver ฎ  sulfide (active) (enterohepatic cycling) –less suppress renal PG Diclofenac –Accumulates in the synovial fluid

14. 2. Newer NSAIDs Indomethacin –Not suggest for general use as analgesic –Should not be used in children (except Rx. PDA) Phenylbutazone –Main indications : short-term therapy of such painful condition as acute gouty arthritis

15. Adverse effects of Aspirin 1. GI disturbances 2. CNS : salicylism –Usually occurs with repeated administration of large doses 3. Other: ญ incidence Reye’s syndrome –lower dose : ญ serum uric acid –dose > 4 gm : ฏ serum uric acid

16. Newer NSAIDs GI disturbance (incidence < aspirin) At high therapeutic dosage : a significance risk of renal damage Phenylbutazone : should not be used chronically (aplastic anemia, agranulocytosis