480 British Journal of Ophthalmology 1996; 80: 480-485 PERSPECTIVE Br J Ophthalmol: first published as 10.1136/bjo.80.5.480 on 1 May 1996. Downloaded from The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology Peter Koay Non-steroidal anti-inflammatory drugs (NSAIDs) are a het- appear in the aqueous after ocular paracentesis, thermal or erogeneous group of compounds which in chemical terms mechanical injury which cause a rise in both intraocular belong to different structural classes. By definition, NSAIDs pressure and protein concentration in the aqueous do not include a steroid nucleus derived biosynthetically humour. The principal source of PGs in the aqueous from cholesterol in their chemical structures. Although the humour is probably derived from the iris-ciliary body. PGs term NSAIDs can be expanded to include other classes of cause miosis, increase in vascular permeability of the compounds such as immunosuppressives and cytokine blood-ocular barriers, and changes in intraocular pressure. modulators,' this discussion will be limited to commercially Furthermore, PGs are known to possess chemokinetic available topical ophthalmic drugs generally regarded as activity and can serve as mediators in both humoral and NSAIDs. Topical ophthalmic drugs under discussion are of cellular phases of the inflammatory response.2 the following chemical classes: indoles, phenylalkanoic The main products of the lipoxygenase (LO) pathway acids, phenylacetic acids, and pyrazolons. The main topical are leukotrienes (LT) such as leukotriene B4 and pepti- ophthalmic drug of the indole chemical class is doleukotrienes. Leukotriene B4 causes aggregation ofpoly- indomethacin. This was the first topically administered morphonuclear cells (PMN), PMN chemotaxis in vivo, NSAID to be used widely in ophthalmic clinical studies. PMN chemokinesis, exudation of plasma, translocation of Phenylalkanoic acids are water soluble and are readily for- calcium, and stimulation of phopholipase A2. Peptido- mulated as topical ophthalmic solutions such as flurbiprofen leukotrienes result in bronchoconstriction, secretion of 003% (Ocufen), ketorolac tromethamine 05% (Acular), mucus, plasma leakage from post capillary venules, vaso- and suprofen 1% (Profenal). The main topical ophthalmic constriction of arterioles, and miosis.2 derivative is diclofenac 1% Inflammation is complex involving a large number of phenylacetic acid (Voltarol) http://bjo.bmj.com/ (Table 1). NSAIDs are also known as cyclo-oxygenase mediators and products. NSAIDs inhibit the cyclo- inhibitors based on their mode of action, and are important oxygenase enzyme (Fig 1) but not the lipoxygenase mediators or modulators of ocular inflammatory reactions.2 enzyme. Thus, NSAIDs inhibit the biosynthesis of PGs but not LTs. Inhibition of PG biosynthesis inhibits intra- operative miosis during cataract surgery, reduces the Arachidonic acid metabolites in ocular vascular permeability of the blood-ocular barrier, and inflammation modifies inflammation. It should be noted, however, that on September 25, 2021 by guest. Protected copyright. Activation of phospholipase A2, following tissue insults, NSAIDs are not capable of inhibiting the actions of PGs breaks down cell membrane phospholipids to arachidonic once formed.3 acid. This forms the substrate for further reactions mainly Glucocorticoids inhibit the phospholipase A2 enzyme by the cyclo-oxygenase and the lipoxygenase pathways (Fig (Fig 1) , thus inhibiting the biosynthesis ofarachidonic acid 1). Other pathways, such as the cytochrome P450 pathway, itself. This results in the inhibition of the biosynthesis of are also involved in the production of biologically active both PGs and LTs. Other effects of glucocorticoids not lipids. The resulting arachidonic acid metabolites, along directly involved in the arachidonic pathway include: with other chemical mediators, interact to cause inflamma- effects on white cells (inhibit migration of macrophages, tion. Although arachidonic acid metabolites are associated neutropenia, lymphocytopenia, eosinopenia, monocyto- with pro-inflammatory actions, there are a few studies to penia, neutrophilic leucocytosis); inhibition of degranula- suggest that some of these metabolites also have anti- tion of neutrophils, mast cells, basophils; lysosome inflammatory actions.2 stabilisation; suppression oflymphokines; reduction of cap- The main products of the cyclo-oxygenase (CO) path- illary permeability; and suppression ofvasodilatation.4 way are prostaglandins (PGs). In the rabbit model, PGs Table 1 Commercially available topical ophthalmic non-steroidal Ocular penetration and distribution oftopical anti-inflammatory drugs ophthalmic NSAIDs Chemical class Generic name Trade name (Manufacturer) Indomethacin is soluble in alcohol but not in water and was initially formulated for ophthalmic clinical studies Indoles Indomethacin Indomethacin 0 5% and 1% in castor oil eyedrops (Moorfields using a sesame oil vehicle which proved to be irritating. An Eye Hospital) aqueous suspension of indomethacin 1% is now available Indocid ophthalmic suspension (Merck, Sharp & Dohme) and shaking the bottle is recommended.5 Indomethacin Phenylalkanoic acids Flurbiprofen Ocufen (Allergan) has been shown to significantly decrease levels of Ketorolac Acular (Allergan) Suprofen Profenal (Alcon) prostaglandin E2 in the human cornea.6 In an animal Phenylacetic acids Diclofenac Voltaren/Voltarol (Ciba Vision model, topical 1% indomethacin suspension resulted in Ophthalmics) Pyrazolons Oxyphenbutazone Tanderil 10% (Geigy) high concentrations in the cornea, but low concentrations in the iris, the ciliary body, the lens, and the choroid.7 Emerging roles oftopical non-steroidal anti-inflammatory agents in ophthalmology 481 Membrane phospholipids Br J Ophthalmol: first published as 10.1136/bjo.80.5.480 on 1 May 1996. Downloaded from Phospholipase A2 (A) Epoxygenases Cyclo-oxygenase pathway Epoxides Cyclo-oxygenase (prostaglandin synthetase) ILipoxygenase pathway| Arachinonic acid /(B) lipoxygenases Cyclic endoperoxidases Hydroperoxy- prostaglandin G2 eicosatetraenoic acid (PGG2) (HPETE) Prostaglandin (B) _ hydroperoxidase Peroxidase ILeukotriene A4 Hydroxyeicosatetraenoic acid (HETE) PGH2 Leukotrienes Prostaglandins Prostacyclin Thromboxane A2 (PG) P2) TrmoaeA D2, E2, F2a (T XA2) Figure 1 A simplified schematic representation ofthe enzymatic pathways ofarachidonic acid metabolism. Site ofaction ofglucocorticoids (A) and NSAIDs (B). Topical administration of indomethacin appears to retard the formation of fibrinous coagulum, cellular infil- http://bjo.bmj.com/ produce better penetration into the eye than oral admini- tration, and fibroblastic repair.'9 Srinivasan, in a series of stration.8 experiments involving mechanical corneal injury, demon- Commercially available topical NSAIDs generally have strated in a rabbit model that corticosteroids (prednisolone good ocular penetration. Topical use of flurbiprofen or acetate 1%, dexamethasone 0-1%, and fluorometholone ketorolac will result in the distribution ofthe drug through- 1%) appear to inhibit re-epithelialisation by mainly con- out the conjunctiva, cornea, aqueous, sclera, iris, ciliary junctival epithelial cells following complete epithelial body, and choroid-retina in rabbits.9 10 Diclofenac applied denudation. These corticosteroids do not inhibit re- on September 25, 2021 by guest. Protected copyright. topically readily penetrates the cornea and into the epithelialisation by mainly corneal epithelial cells after aqueous.1' Systemic absorption of topical NSAIDs is partial epithelial denudation. NSAIDs (indomethacin minimal as demonstrated by the plasma levels of 0.5% and flurbiprofen 0-01%) in contrast, do not inhibit diclofenac following ocular instillation (two drops of the re-epithelialisation by either corneal or conjunctival diclofenac to each eye) being below the limit of quantifica- epithelial cells.20 Topical diclofenac sodium 0- 10% does not tion (10 ng/ml) over a 4 hour period.12 delay re-epithelialisation following excimer laser treatment in rabbit corneas.21 However, Hersh et al in their study of epithelial scrape wound healing in rabbits demonstrated a Potential advantages oftopical NSAIDs over delay in epithelial healing for the first 3 days when NSAIDs corticosteroids (flurbiprofen sodium 0O03%, diclofenac sodium 0.10o) or The main advantage of topical NSAIDs is that the steroids (prednisolone acetate 1%) were used compared undesirable effects of topical corticosteroids are avoided. with placebo vehicle.22 These include decreased immunological response to infec- Corticosteroids can result in decreased stromal corneal tion,'3 cataract formation,'4 and steroid-induced raised wound healing.23 One rabbit study involving full thick- intraocular pressure (IOP).15 A study of steroid responsive ness corneal wounds demonstrated that treatment with patients revealed that flurbiprofen has no effect upon the flurbiprofen sodium or diclofenac sodium actually elevation ofIOP compared with dexamethasone. 16 Topical resulted in stronger scars than untreated controls. diclofenac 0 1% had no significant effect on IOP following Corneal wounds treated with prednisolone acetate cataract surgery compared with placebo.17 Furthermore, resulted in the weakest scar.24 In another rabbit study, the use of NSAIDs such as flurbiprofen sodium or the effects of equipotent anti-inflammatory doses of diclofenac sodium does not exacerbate acute herpetic flurbiprofen and prednisolone on the wound