Nepafenac ophthalmic suspension is a topical non-steroidal anti-inflammatory drug (NSAID) approved in the US and Europe for prevention and treatment of post-operative pain and inflammation associated with cataract surgery, and recently approved in Europe for reduction in risk of post-operative macular oedema associated with cataract surgery in diabetic patients. Unlike conventional NSAIDs, nepafenac is a prodrug that is uncharged and this results in great corneal permeability. Experimental studies on nepafenac demonstrated enhanced permeability compared with other NSAIDs, and rapid bioactivation to amfenac by intraocular hydrolases within ocular tissues including ciliary body epithelium, retina, choroid and cornea, which results in targeted delivery of active drug to anterior and posterior segments. Furthermore, these study results have been confirmed in clinical trials. Nepafenac may have prolonged activity in vascularised tissues of the eye because bioconversion is targeted to the iris/ciliary body, and to a greater extent the retina and choroid. Nepafenac and amfenac are potent inhibitors of cyclo-oxygenase (COX) enzyme isoforms, COX-1 and COX-2. Topical nepafenac penetrated into the posterior segment in a rabbit model of concanavalin-A induced retinal inflammation, where it diminished vitreous protein and prostaglandin E2 concentrations and reduced breakdown of the blood–retinal barrier. Other NSAIDs, including ketorolac, failed to reduce the increase of these inflammatory markers in the same study. A randomised clinical study showed that based on retinal thickening and vision, treatment with nepafenac beginning pre-surgery and used for up to 90 days post-cataract surgery is effective in preventing macular oedema and associated loss of visual acuity in diabetic patients.
Non-steroidal anti-inflammatory drugs (NSAIDs), cataract surgery, pain, inflammation, nepafenac, prodrug, permeability
During ophthalmic surgery, surgical trauma causes activation of cyclo-oxygenase (COX) COX-1 and COX-2, which metabolise arachidonic acid to prostaglandins (PGs). PGs are mediators of the inflammatory response, and increased production of these molecules can result in discomfort, pain and ocular inflammation. As inhibitors of PGs, non-steroidal anti-inflammatory drugs (NSAIDs) are often employed by ophthalmic surgeons to provide anti-inflammatory control post-surgery and work synergistically with steroid therapy to minimise pain and inflammation following ocular surgery,1,2 albeit by different mechanisms. NSAIDS primarily act on cyclo-oxygenase-1 (COX-1) and COX-2 to minimise PG formation,3 and while steroids also reduce PG synthesis, this is due to the inhibition of phospholipase A2.4
Moreover, NSAID treatment has been demonstrated to have a beneficial effect on visual outcomes,5 preventing macular oedema after cataract surgery, however, it is essential to attain therapeutic concentrations in the posterior chamber to obtain the effect of NSAID treatment on the target retina tissue. Thus, for maximum therapeutic benefit, the ideal NSAID is one that reaches therapeutic levels in both the aqueous humour and in the posterior segment tissues. Nepafenac is a NSAID with a unique prodrug structure that has superior corneal permeability to other currently available NSAIDs.6 This review aims to consider the properties, existing efficacy and safety data, other possible indications of nepafenac in inflammation treatment and the advantages it provides over existing NSAIDs in cataract surgery.
Mode of Action of Nepafenac
Nepafenac has a unique prodrug structure and is converted to a potent cyclo-oxygenase inhibitor, amfenac, by intraocular hydrolases (see Figure 1).6,7 Upon ocular dosing, nepafenac permeates the cornea, is metabolised by intraocular tissues8 and is converted into amfenac for optimal efficacy. The prodrug mechanism of action maximises bioactivation to amfenac in the iris, ciliary body, retina, choroid and cornea to a lesser extent, making nepafenac a target-specific NSAID.9 xperimental studies on nepafenac demonstrated properties of enhanced permeability and rapid bioactivation to amfenac, to inhibit PG synthesis in the anterior and posterior eye segments.7
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Marco Nardi has participated in the European registration study of nepafenac and has given presentations on this for which he has received honoraria.
Marco Nardi, Ophthalmology Unit, Neuroscience Department, University of Pisa, Via Roma 56, IT-56100 Pisa, Italy. E: firstname.lastname@example.org
The publication of this article was funded by Alcon. The views and opinions expressed are those of the author and not necessarily those of Alcon.