Anti Inflammatory Drugs

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Antiinflammatory Drugs



Classical Signs of

Inflammation● Redness

● Swelling

● Heat

● Pain

● Loss of function

The actual expression of these signsThe actual expression of these signs

depend on the site of inflammationdepend on the site of inflammation







● Inflammation characterized by orderly process :

–

Initiation – Recruitment & Chemoattraction

– Release of inflammatory mediators

Damage or Kill the invading microbes or tumors

The need of anti-inflammatory drugsThe need of anti-inflammatory drugs

arises when the inflammatory arises when the inflammatory

response is inappropriate, aberrant,response is inappropriate, aberrant,

sustained, or causes destruction of sustained, or causes destruction of

Limiting tissue damage







Only the first three of these are therapeutic

targets for anti-inflammatory drugs

Among many mediators, more important mediatorsAmong many mediators, more important mediators

are :are :

● EicosanoidsEicosanoids● Biological oxidants,Biological oxidants,

● Cytokines,Cytokines,

● Adhesion factors,Adhesion factors,

● Digestive enzymes (proteases, hyaluronidase,Digestive enzymes (proteases, hyaluronidase,

collagenase, and elastase)collagenase, and elastase)



Eicosanoids● Derivation from a 20-carbon unsaturated fatty

acid, arachidonic acid (eicosatetraenoic acid)● Arachidonic acid obtained from membrane

phospholipid & synthesized de novo at the timeof cellular stimulation

● Arachidonic acid may also be derived fromsequential actions of phospholipase C anddiacylglyceryl lipase

● Arachidonic acid

– Cyclooxygenase (COX) pathway

– Lipooxygenase pathway





● COX-1 → constitutive isoform, responsible for the basal production of prostaglandins,

prostacyclins, and thromboxanes

● COX – 2, inducible COX, expression & activityincrease by stimuli of inflammatory cytokines &

other inflammatory stimuli● The final product final product of the COX pathway is tissuetissue

specific specific

●

The production of inflammatory The production of inflammatory eicosanoids is an important target of eicosanoids is an important target of many anti-inflammatory drugs.many anti-inflammatory drugs.

● The side effects of these drugsThe side effects of these drugs

frequently result from their inhibition of frequently result from their inhibition of



Biological Effects of Eicosanoids





Therapeutics Opportunity of

Eicosanoids

● Alprostadil,Alprostadil, PGE1 analog, can be used to maintain patentductus arteriosus (PDA) until surgical correction performed

● MisoprostolMisoprostol, PGE1 analog, use to reduce gastric acidsecretion in patients undergoing treatment with NSAIDs

● Misoprostol, non-FDA-approved use for induction of labor by ripening of cervix and induction of abortion incombination with mifepristone

● DinoprostoneDinoprostone (Prostin E2), a synthetic PGE2, causes uterinecontraction and is used clinically to induce abortion duringthe second trimester and to empty the uterus following fetaldeath, missed abortion, or benign hydatidiform mole.



● CarboprostCarboprost ,PGF2 analogue, can be used toterminate pregnancy or to control refractory

postpartum bleeding by stimulating uterinecontraction

● EpoprostenolEpoprostenol, synthetic prostacyclin, use to treat

primary pulmonary hypertension● ZafirlukastZafirlukast, leucotrien receptor antagonist, use to

treat asthma

●

ZileutonZileuton, inhibit enzyme in lipooxygenase pathway, can be used to treat asthma



NSAIDs● Prostaglandins of the E and F series evoke some of

the local and systemic manifestations of inflammation:

– vasodilation, hyperemia, increased vascular permeability,swelling, pain, and increased leukocyte migration

– Intensify the effects of inflammatory mediators, such ashistamine, bradykinin, and 5-hydroxytryptamine

● NSAIDs ≈ non selectictive COX inhibitors

●

The degree of inhibition vary from drugs to drugs● The spectrum of toxicity produced by each NSAID is

related to its inhibition of specific COX isoforms





Adverse Effects of NSAIDs



Adverse Effects Unequivocally

related to inhibition of PG Synthesis

● Hepatic effectsHepatic effects (hepatitis, hepatic necrosis,cholestatic jaundice, increased serumaminotransferases)

● Dermal effectsDermal effects (photosensitivities, Stevens-Johnsonsyndrome, toxic epidermal necrolysis, onycholysis)

● CNS effectsCNS effects (headaches, dizziness, tinnitus,deafness, drowsiness, confusion, nervousness,increased sweating, aseptic meningitis)

● Ocular effectsOcular effects (toxic amblyopia, retinaldisturbances)



Specific drug of NSAIDs

Aryl and Heteroarylakanoic Acid–Type Drugs

● Prototype : indomethacin & ibuprofen

Oxicam-Type Drugs

● Piroxicam, meloxicam

Fenamate-Type Drugs

●

Mefenamic acid, meclofenamate sodium● The fenamates show no clear superiority in

antiinflammatory activity and may produce moreadverse effects than other NSAIDs





Drugs plotted below the line are more potent inhibitorsDrugs plotted below the line are more potent inhibitors

of COX-2 than drugs plotted above the line. Theof COX-2 than drugs plotted above the line. The

distance to the line is a measure of selectivitydistance to the line is a measure of selectivity









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Anti Inflammatory Drugs