ANTI-INFLAMATORY DRUGS

M.Djamaludin,dr.,SpFK.,M.Kes

I.Overview
Inflamatory is a normal process Protective respon to tissue injury with some caueses: Trauma,noxious chemicals,or microbiologic agents Inflamatory is the bodys effort to inactive or to destroy invading organism Inflamatory is a subside process

 The defense reactionsl themselves may cause progressive tissue injury, and antiinflamatory or immunosuppressive drugs maye required to modulate the inflamatory process.

II.Classification
A.Based on steroid Steroid Non-steroids (NSAIDs) B. Based narcotic Narcotics Non-narcotis

C.Based on cheimical stucture 1.Salicylic acid 2.Para aminophenol 3.Acetic acid 4.Enolic acid 5.Others

III.PROSTAGLANDINS
All of NSAIDs act by inhibiting the synthesis of prostaglandind. A.Role of prostaglandins B.Synthesis of prostaglandins C..Action of prostaglandins D.Functions in the boddy

IV.NON-STEROIDAL ANTI INFLAMATORY DRUGS

The NSAIDs are a group of chemically dissimlar agents that differ in their antipyretic analgesic, and antiinflamatory activites. The act primary by inhiting cyclogenase enzyme that catalyze the first step in prostanoid biosynthesis

Aspirin and other salysilates

Aspirin is the prototype of traditional NSAIDs Commonly used and compare with other antiinflamatory agents. Fifteeen percent of patients show intolerance

it is may benefit some of newer NSAIDs NSAIDs superior to aspirin because: have greater anti-inflamatory activity less gatrointestinal irritation can be taken less frequently more expensive and more toxic

Mehanism of action

 Cox-1 gene translocation

Cyclogenase pathway
cox-2 gene translocation

mrNA

Membrane phphl

mrNA

C0X1 Arachidonic acid NSAIDs -

COX2

Prostaglandin

Prostaglandin

Lipoxygenase pathway
Membrane phosppholipids

Arachidonic acid 5-Lipoxygenase Leukotrienes

Action
Anti-inflamatory Analgesia antipyrexia

 Anti-inflamatory Aspirin inhibit ctclogenase activity Disminished prostaglandins formation

 Analgesic action Decreasing PGE2 synthesis Aspirin and other NSAIDs repress sensation of pain

Antipyretic action Impending PGE2 synthrsis and release Respiratory action Hyperventilation

Gastrointestinal effects
Normally prostacyclin (PGI2) inhibits gastric ,whereas PGE2 and PGF2 stimulatr acid secretion synthesis of protectiive mucus in both stomach and small intestine.In the persence of aspirin these prosranoids are not formed,resulting in increased gastric secretion and disminished mucus protection

Effects on platelet
TXA2 enhance platelet aggregation whereas PGI2 decreases. Low dose of aspirin&60-80 mg) irreversibly can inhibits tromboxane production in the endothelial blood vessel TXA2 decreased .......platelet aggregation is reduced,........anticoagulant effect with a prolong bleeding time

Action the kidney

Cyclogenase inhibitions prevent the synthesis of PGE2 and PGI2 thjat are responsive for maintaining renal blood flow,Decreased of prostaglandin can result in retention of sodium and water and cause edema and hyperkalemia

Therapeutic uses
1.Antipyretics and Analgesics 2.External application 3.Cardiovsculat application 4.Colon cancer

PHARMACOKINETICS
AFE (ABSORPTION,FATE,AND EXRETION) Salysilates can admistrated per orl,topical Absorptionb occurs from stomach,small intestine and intact skin Rectal application and absorption ia slow and unrealible it is useful for vomiting children Salysilates except difunisal cross both bloodbrain and placental barrier.

Dosage
For analgesic and antipyretics:325 mg/tablet for 3-5 days 160-325 mg is effective to prevent myocardial infarction:

Fate
Aspirin is hidrolyzed to s salysilate and acetic acid by esterase in tissues and blood. Salysilates is converted by the liver to watersoluble conyugatates that ar rapidly cleared by the kidney in elemination Half life 3-5 hours

Adverse effects

1. Epigastric distrss,nausea,and vomiting Must take wityh food and large volume of fluid to disminiished git distress

2.Reduce level of platelet TXA2 resulting inhibition of platelet aggregation 3.Respiratory depression and uncompensatory respiratory and metabolic acidosis

4.Hypertthermia in toxic quantity 5.Hypersensivity 6.Reye syndrome:Aspirin given during viral infection has been associated with this syndrome which is often fatal,fulminating hepatitis with cerebral edema especially in children

Toxicity
Toxicity may be mild or sewvere.The mild form is called salysilism and is characterized by Nausea,vomiting,mark hyperventilation,headache,mental confusion,dizziness,and tinnitus (ringing or roaring in the ears)

PROPINIC AND DERIVATRS

Ibuprofen Naproxenb Lenoprofen Ketoprofen Flurbiprofen Oxaprozin

All these drugs possess anti inflamatory,nalgesic and antipyretic activity These drugs indicated to RA,osteoarthritis because their gastrontestinal effects are generally less intense than that of aspirin. These drugs are reversible inhibitors of cyclogenase

 Oxazepin has longest half-life and administred once daily. The most common adverse effects are GI,ranging from dyspepsi to bleeding Side effect involving CNS such as headache,tinnitus.

Dosage
Adult dose :200-400 mg 3 times dayly Children 20 mg/kgBW Children < 30 kg maximal dose 500 mg dayly

ACETIC ACID DERIVATES

Indomethazcin Sulindac Etodolac All have anti-inflamatory,analgesic and antipyretic activity

Sulindac is an inactive prodrug less potent than indomethacin It is useful for RA,Ankylosing spondylitis osteoarthritis

Dosage
Indomethacin:1-2 times 25 mg/tablet Maximal dose 75 mg/caps

OXICAM DERIVATES
Piroxicam Meloxicam They have long half-life Adverse effect GI disturbances in 20 % of patients Piroxicam excreted via urine Meloxicam excreted from urine and faces.

Dosage
Piroxicam: 1-2 X 10 mg/cap/dayly 1-2 X 20 mg/cap/dayly Meloxicam: 1-2 x 7.5 mg/cap/dayly 1-2 X 15 mg/dayly

FENAMATES
Mefenamic acid and meclofenamate have no advantages over other NSADIsas antiinflamatory agents.

DICLOFENAC
Diclofenac Ketorolac Toimetin Nabumetone Diffunisal

COX-2 SELECTIVE NSAIDs

Cyclogenase-1 COX-1 is reponsible for the physiologic production of prostanoids whereas cyclogenase-2 (COX-2) causes the elevated production of prostanoids that occurs in the site of disaese and inflamation

 COX-1 is described as house-keeping enzyme regukate normal cellular processs,such as gastric cytoprotection,vascular homeostasis,platelet aggregation and kidney function

 COX-2 is constitutively expressed in some tissues,such as brain.kidney,and bone It expression at other sites is increased during states of inflamation

OTHER ANALGESICS
Acetaminophen Mechanism of action: Acetaminophen inhibits prostaglandine in CNS and have less effect to cyclogenase at periferal tissues.which accounts for its weak anti-inflamatory activity. Acetaminophen does not affect function or increase blood clothing time,but it does havemany of the side effects of aspirin.

 THERAPEUTICAL USES: Substitues for the and antipyretic effects of aspirin CONTRAINDICATION: 1.Gastric complaints 2.Prologation of bleeding time 3.Who do not require the anti-inflamatory action of aspirin

4.Children with viral infection or chickenpox(aspirin increases the risk of Reyes syndrome). FARMAKOKINETICS Well and rapidly absorbed fromGI tract These drugs are first metabolized in intestine and in hepatocytes The drugs are exreted in the urine

 ADVERSE EFFECTS Relatively free of significant adverse effects 1.Skin rash and minor allergic reactions occur infrequently 2.Renal tubular necrosis,hypoglycemic ,and hepatic necrosis are rare except prolonged and large doses

REFFERENCES
Richard D.Howland,Marry J.Mycek,Antiinflamatory Drugs in Lippincotts Illustrated Pharmacology 3rd edition,2006.,495507Reviews