Antiinflammatory Drugs

Classical Signs of Inflammation

Redness Swelling Heat Pain Loss of function

The actual expression of these signs depend 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 Limitingtissuedamage The need of anti-inammatory drugs arises when the inammatory response is inappropriate, aberrant, sustained, or causes destruction of

Among many mediators, more important mediators are :

Eicosanoids Biological oxidants, Cytokines, Adhesion factors, Digestive enzymes (proteases, hyaluronidase, collagenase, and elastase)

Only the first three of these are therapeutic targets for anti-inflammatory drugs

Eicosanoids

Derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid) Arachidonic acid obtained from membrane phospholipid & synthesized de novo at the time of cellular stimulation Arachidonic acid may also be derived from sequential actions of phospholipase C and diacylglyceryl 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 & activity increase by stimuli of inflammatory cytokines & other inflammatory stimuli The final product of the COX pathway is tissue specific The production of inflammatory eicosanoids is an important target of many anti-inflammatory drugs. The side effects of these drugs frequently result from their inhibition of

Biological Effects of Eicosanoids

Therapeutics Opportunity of Eicosanoids

Alprostadil, PGE1 analog, can be used to maintain patent ductus arteriosus (PDA) until surgical correction performed Misoprostol, PGE1 analog, use to reduce gastric acid Misoprostol secretion in patients undergoing treatment with NSAIDs Misoprostol, non-FDA-approved use for induction of labor by ripening of cervix and induction of abortion in combination with mifepristone Dinoprostone (Prostin E2), a synthetic PGE2, causes uterine contraction and is used clinically to induce abortion during the second trimester and to empty the uterus following fetal death, missed abortion, or benign hydatidiform mole.

Carboprost ,PGF2 analogue, can be used to terminate pregnancy or to control refractory postpartum bleeding by stimulating uterine contraction Epoprostenol, synthetic prostacyclin, use to treat Epoprostenol primary pulmonary hypertension Zafirlukast, leucotrien receptor antagonist, use to Zafirlukast treat asthma Zileuton, inhibit enzyme in lipooxygenase Zileuton 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 as histamine, 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 effects (hepatitis, hepatic necrosis, cholestatic jaundice, increased serum aminotransferases) Dermal effects (photosensitivities, Stevens-Johnson syndrome, toxic epidermal necrolysis, onycholysis) CNS effects (headaches, dizziness, tinnitus, deafness, drowsiness, confusion, nervousness, increased sweating, aseptic meningitis) Ocular effects (toxic amblyopia, retinal disturbances)

Specific drug of NSAIDs

Aryl and Heteroarylakanoic AcidType Drugs

Prototype : indomethacin & ibuprofen Piroxicam, meloxicam Mefenamic acid, meclofenamate sodium The fenamates show no clear superiority in antiinflammatory activity and may produce more adverse effects than other NSAIDs

Oxicam-Type Drugs

Fenamate-Type Drugs

Drugs plotted below the line are more potent inhibitors of COX-2 than drugs plotted above the line. The distance to the line is a measure of selectivity