ANTIINFLAMATORY DRUG

PROSTAGLANDIN

OBAT-OBAT ANTIINFLAMASI NONSTEROID

BEKERJA DGN MENGHAMBAT ENZIM SIKLO-OKSIGENASE YG PLG SERING DIGUNAKAN ADLH ASPIRIN

ANTI INLAMATORY DRUGS ACETAMINOPHEN

ANTI INLAMATORY DRUGS

ACETAMINOPHEN

ASPIRIN

OTHER NON SELECTIVE NSAID

COX-2 SELECTIVE INHIBITOR

ANALGESIK
ANTIINLAMASI KUAT

ANTIINFLAMASI (-)

ANTIINFLAMASI SEDANG/RINGAN SALICYLATE (aspirin) PYRAZOLONE (dipyrone) INDOL (indomethacine)

ANILINE (Paracetamol)
PROPIONIC ACID (Ibuprofen) ANTHRANICIL ACID (Mefenamic acid) ARYLACETIC ACID (Diclofenac)

MECHANISM OF ACTON
DISTURBANCE OF CELL MEMBRANES

PHOSPOLIPIDS

ARACHIDONIC ACID ASPIRIN CYCLOOXIGENASE ENDOPEROXIDASE PROSTAGLANDIN

EFFECTS
ANALGESIC REDUCE THE MANIFESTATIONS OF INFLAMATION ANTIPYRETIC HOMEOSTATIC FUNCTION REDUCE PROSTAGLANDIN-MEDIATED CYTOPROTECTION IN THE GASTROINTESTINAL TRACT

PHARMACOKINETICS AND CLINICAL USE

Aspirin Pharmacokinetics - The salicylates Rapidly absorbed from the stomach and upper small intestine - yielding a peak plasma level with 1-2 hours - Rapidly hydrolyzed to acetic acid and salicylat by esterases - excreted unchanged

Mechanisms of Action
1. Anti-inflammatory Effects - Aspirin is nonselective inhibitor of both COX isoform - Irreversibly, inhibits platelet aggregation - Inhibiting the granulocytes adherence to damaged vasculature, stabilizing lysosome, and inhibiting the chemotaxis of leucocytes and macrophages - High doses (2400-4000 mg/d)

2. Analgesic Effects - Most effective in reducing pain of mild to moderate intensity - Intermediate (300-2400 mg/d) have antipyretic dan analgesic 3. Antipyretic Effects - Reduces elevated temperature - Probably mediated by both COX inhibition and inhibition of IL-1 4. Antiplatelet Effects - Single low doses (81 mg daily)

Clincal Uses
Analgesia, Antipyresis, and Anti-inflammatory Effects - For mild to moderate pain - Combined with opioid analgesics for treatment of cancer pain - High-dose for treatment of rheumatic fever, rheumatoid arthritis and other inflammatory join conditions

Adverse Effects
Usual dosage Gastric upset (intolerance), gastric and duodenal uncers, hepatotoxicity, asthma, rashes, and renal toxicity Higher doses Salicylism, tinnitus, decreased hearing and vertigo (rever), hyperpnea, metabolic acidosis

COX-2 SELECTIVE INHIBITOR

1. Celecoxib
- As effective as other NSAID - Fewer endoscopic ulcer than NSAID - No more edema or renal effects

2. Etoricoxib - a second-generation COX-2 - 60 mg once daily for acute osteoarthritis - 120 mg for acute gouty arthritis

3. Meloxicam - Therapeutic dose 7,5 mg/d - For treatment of rheumatic diseases, osteoarthritis, rheumatoid arthritis 4. Rofecoxib For treatment of rheumatic diseases, osteoarthritis, rheumatoid arthritis, analgesic and antipyretic 5. Valdecoxib A new highly selective cox-2 inhibitor Dosage is 20 mg twice daily No effect on platelet aggregation or bleeding time

NON SELECTIVE COX INHIBITORS

1. Diclofenac Phenylacetic acid derivate A preparation diclofenac combining and misoprostol decreases gastrointestinal ulceration. Another combination of diclofenac and omeperazol for prevention of recurrent bleeding.

0,1 % diclofenac for prevention of postoperative ophthalmic inflammation A topical gel containing 3 % diclofenac for solar keratoses Suppository form for preemptive analgesis and postoperative nausea

2. Diflunisial Diflunisial is derived from salicylat acid It undergoes an enterohepatic cycle Effective for cancer pain A 2 % diflunisial for pianful oral lession 3. Etodolac Acetic acid derivate More Cox-2 selective than most other NSAID, with a cox-2:cox1 about 10 For post operative pain Less gastric toxicity

4. Flurbibiprofen Propionic acid derivate Oral : 200-400 mg/d for gout, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis IV: for perioprative analgesia in minor ear, neeck and nose surgery Topical: intraoperative miosis 5. Ibuprofen Phenylpropionat acid derivate Doses: < 240 mg daily for analgesic but anti-inflammatory efficacy 400 mg efficacy in postsurgical dental pain Used to treat patent ductus arteriosus Anti-inflammatory effect = aspirin GI irritation and bleeding< aspirin

6. Indomethacin Potent cox inhibitor, inhibit phospholipase A and C, reduce neutrophil migration, decrease T cell and B cell proliferation Clinical use Gout, ankylosing, patent ductus arteriosus, juvenile rheumatoid, nephrotic syndrom, diabetes insipidus, postepisiotomy pain, conjunctival inflammatory, gingival inflammatory Adverse Effects abdominal pain, headache, dizziness, confusion, trombocytopenia, aplastic anemia

7. Ketoprofen Propionic acid derivate With probenecid elevates ketoprofen level and prolongs its plasma half-life The effectiveness at dosages 100-300 mg/d

8. Ketorolac For systemic use mainly as an analgesic Used to replace morphine Mild to moderate pain 9. Mefenamic acid less effective than aspirin Not be used for longer than 1 week Should not be given to children 10. Nabumetone Acetic acid derivate Prodrug, half-life more than 24 hours It may be less damaging to the stomach, SE mirror of other NSAID

11. Naproxen Naphthylpropionic acid derivate effective for the usual rheumatologic indications Gastrointestinal bleeding is low Rare case of allergic pneumonitis, leukocytoclastic vasculitis and pseudoporphyria 12. Oxaprozin Propionic acid derivate Very long half-life (50-60 hours) Can be given once a day

13. Phenylbutazone Pyrazolone derivate Its toxicities, particularly the hematologic effect (aplastic anemia) Rarely used today 14. Piroxicam Oral: dosages 20 mg/d Used for the usual rheumatic indication High concentration also inhibits polymorphonuclear leukocyte migration, decrease oxygen radical production and inhibits lymphocyte funtion Dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding

15. Sulindac Sulfoxide prodrug Indication Rheumatic disease Suppresses familial intestinal polyposis Adverse effects Reversible renal failure and nephrotic syndrome, trombocytopenia, agranulocytosis

2. Other NSAID - Are well absorbed after oral administration - Ibuprofen a half-life of about 2 hour - Indomethacin is potent NSAID - Naproxen and piroxicam half-life 12-24 hours

NONSELECTIVE COX INHIBITOR

Used for the treatment of mild to moderate pain COX-2 inhibitors are primarily used in anflammatory disorders Selected NSAID are also used to treat other conditions (dysmenorrhea)

TOXICITY
1. Aspirin Hypersensitivity,Gastrointestinal disturbance, nepritis, tinitus, vertigo 2. COX-2-selective inhibitor Have reduce risk of gastrointestinal, hypersensitivity

LEARNING TASK
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Jelaskan sintesa prostaglandin dan dimana obat NSAID bekerja ! Jelaskan farmakokinetik, farmakodinamik dan toksisitas dari aspirin ! Jelaskan farmakokinetik, farmakodinamik dan toksisitas dari non selective NSAID ! Jelaskan farmakokinetik, farmakodinamik, dan toksisitas dari COX-2 selective inhibitors ! Jelaskan mekanisme kerja dan toksisitas dari acetaminophen !