Anti Inflammatory Drugs [Dr. Eddy]

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

The need of anti-inflammatory drugs arises when the inflammatory response is inappropriate, aberrant, sustained, or causes destruction of tissue

Limiting tissue damage

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

Among many mediators, more important mediators are :

● Eicosanoids● Biological oxidants,● Cytokines,● Adhesion factors,● Digestive enzymes (proteases, hyaluronidase,

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 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 eicosanoid production

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 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 primary pulmonary hypertension●Zafirlukast, leucotrien receptor antagonist, use to treat asthma●Zileuton, 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 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 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 more adverse effects than other NSAIDs

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