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 body’s 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

Cyclogenase pathway• Cox-1 gene cox-2 gene translocation translocation

mrNA Membrane phphl

C0X1 COX2 - Arachidonic - acid

Prostaglandin NSAIDs Prostaglandin

mrNA

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 blood-

brain 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 water- soluble 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 aggregation3.Respiratory depression and uncompensatory

respiratory and metabolic acidosis

4.Hypertthermia in toxic quantity5.Hypersensivity6.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-lifeAdverse 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 anti-inflamatory 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 Reye’s 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,Anti-inflamatory Drugs in Lippincott’s Illustrated Pharmacology 3rd edition,2006.,495-507Reviews