ANTIINFLAMATORY DRUG

PROSTAGLANDIN

OBAT-OBAT ANTIINFLAMASI NONSTEROID

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

ANTI INLAMATORY DRUGSACETAMINOPHEN

ANTI INLAMATORY DRUGS ACETAMINOPHEN

ASPIRIN OTHER NON SELECTIVE NSAID

COX-2 SELECTIVEINHIBITOR

ANALGESIK

ANTIINLAMASI KUAT

ANTIINFLAMASI SEDANG/RINGAN

ANTIINFLAMASI (-)

SALICYLATE(aspirin)

PYRAZOLONE(dipyrone)

INDOL(indomethacine)

PROPIONIC ACID(Ibuprofen)

ANTHRANICIL ACID(Mefenamic acid)ARYLACETIC ACID

(Diclofenac)

ANILINE(Paracetamol)

MECHANISM OF ACTON

DISTURBANCE OF CELL MEMBRANES

PHOSPOLIPIDS

ARACHIDONIC ACID

ENDOPEROXIDASE

PROSTAGLANDIN

ASPIRIN CYCLOOXIGENASE

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 Action1. 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 UsesAnalgesia, 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 EffectsUsual dosage

Gastric upset (intolerance), gastric and duodenal uncers, hepatotoxicity, asthma, rashes, and renal toxicity

Higher dosesSalicylism, 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. RofecoxibFor treatment of rheumatic diseases, osteoarthritis, rheumatoid arthritis, analgesic and antipyretic

5. ValdecoxibA new highly selective cox-2 inhibitorDosage is 20 mg twice dailyNo effect on platelet aggregation or bleeding time

NON SELECTIVE COX INHIBITORS

1. DiclofenacPhenylacetic acid derivateA 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 inflammationA topical gel containing 3 % diclofenac for solar keratosesSuppository form for preemptive analgesis and postoperative nausea

2. DiflunisialDiflunisial is derived from salicylat acidIt undergoes an enterohepatic cycleEffective for cancer painA 2 % diflunisial for pianful oral lession

3. EtodolacAcetic acid derivateMore Cox-2 selective than most other NSAID, with a cox-2:cox1 about 10For post operative painLess gastric toxicity

4. FlurbibiprofenPropionic acid derivateOral : 200-400 mg/d for gout, rheumatoid arthritis, ankylosing spondylitis, osteoarthritisIV: for perioprative analgesia in minor ear, neeck and nose surgeryTopical: intraoperative miosis

5. IbuprofenPhenylpropionat acid derivateDoses: < 240 mg daily for analgesic but anti-inflammatory efficacy400 mg efficacy in postsurgical dental painUsed to treat patent ductus arteriosus Anti-inflammatory effect = aspirinGI irritation and bleeding< aspirin

6. IndomethacinPotent cox inhibitor, inhibit phospholipase A and C, reduce neutrophil migration, decrease T cell and B cell proliferation

Clinical useGout, ankylosing, patent ductus arteriosus, juvenile rheumatoid, nephrotic syndrom, diabetes insipidus, postepisiotomy pain, conjunctival inflammatory, gingival inflammatory

Adverse Effectsabdominal pain, headache, dizziness, confusion, trombocytopenia, aplastic anemia

7. KetoprofenPropionic acid derivate With probenecid elevates ketoprofen level and prolongs its plasma half-lifeThe effectiveness at dosages 100-300 mg/d

8. KetorolacFor systemic use mainly as an analgesicUsed to replace morphineMild to moderate pain

9. Mefenamic acidless effective than aspirinNot be used for longer than 1 weekShould not be given to children

10. NabumetoneAcetic acid derivateProdrug, half-life more than 24 hoursIt may be less damaging to the stomach, SE mirror of other NSAID

11. NaproxenNaphthylpropionic acid derivate effective for the usual rheumatologic indicationsGastrointestinal bleeding is lowRare case of allergic pneumonitis, leukocytoclastic vasculitis and pseudoporphyria

12. OxaprozinPropionic acid derivateVery long half-life (50-60 hours)Can be given once a day

13. PhenylbutazonePyrazolone derivateIts toxicities, particularly the hematologic effect (aplastic anemia)Rarely used today

14. PiroxicamOral: dosages 20 mg/dUsed for the usual rheumatic indicationHigh concentration also inhibits polymorphonuclear leukocyte migration, decrease oxygen radical production and inhibits lymphocyte funtionDosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding

15. SulindacSulfoxide prodrug

IndicationRheumatic diseaseSuppresses familial intestinal polyposis

Adverse effectsReversible 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 painCOX-2 inhibitors are primarily used in anflammatory disordersSelected NSAID are also used to treat other conditions

(dysmenorrhea)

TOXICITY

1. AspirinHypersensitivity,Gastrointestinal disturbance, nepritis, tinitus, vertigo

2. COX-2-selective inhibitorHave reduce risk of gastrointestinal, hypersensitivity

LEARNING TASK1. Jelaskan sintesa prostaglandin dan dimana

obat NSAID bekerja !2. Jelaskan farmakokinetik, farmakodinamik

dan toksisitas dari aspirin !3. Jelaskan farmakokinetik, farmakodinamik

dan toksisitas dari non selective NSAID !4. Jelaskan farmakokinetik, farmakodinamik,

dan toksisitas dari COX-2 selective inhibitors !

5. Jelaskan mekanisme kerja dan toksisitas dari acetaminophen !