Nepafenac, Ketorolac, Bromfenac

Mechanism

💊 Commercial Names

Nevanac, Acular, Acuvail, Yellox, Bromfenaco Kern, Voltaren Ofta.

🔬 Pharmacological Group

Reversible inhibitors of cyclooxygenase-1 and cyclooxygenase-2 (NSAIDs). Nepafenac (an amide prodrug).

🧪 Standard Formulations

Nepafenac 0.1% and 0.3% (suspension), ketorolac tromethamine 0.5%, bromfenac sodium 0.09%.

Mechanism of Action

Topical NSAIDs act by selectively or nonselectively blocking the active site of the cyclooxygenases:

• Reversible Inhibition of COX-1 and COX-2: They competitively block the access of arachidonic acid to the COX channel, preventing the synthesis of inflammatory prostanoids such as PGE.₂, PGI₂ and thromboxanes.
• Prevention of Intraoperative Miosis: Physical trauma to the iris during cataract surgery causes massive local synthesis of PGE₂ which induces involuntary pupillary constriction (miosis). Topical NSAIDs applied before surgery block this response, keeping mydriasis stable and facilitating the surgical procedure.
• Prevention of Cystoid Macular Edema (Irvine-Gass Syndrome): Inflammation of the anterior segment after surgery releases inflammatory cytokines that diffuse through the vitreous to the posterior pole. NSAIDs, especially prodrugs such as nepafenac (which rapidly penetrates the cornea and is hydrolyzed by hydrolases of the iris, ciliary body and retina to amfenac, an extremely potent COX inhibitor), suppress this inflammatory synthesis in the posterior pole, protecting the tight junctions of the retinal macular capillary endothelium.
• Relief of Eye Pain and Photophobia: It suppresses the sensitization of the free endings of the ophthalmic nerve (trigeminal branch) induced by local prostaglandins.

Pharmacokinetics

Quantitative Ocular and Systemic Pharmacokinetics

Security

Risk of Corneal Keratolysis (Corneal Melting) due to Topical NSAIDs

The uncontrolled application of topical NSAIDs, especially in the presence of previous risk factors (neuropathic keratopathy, severe dry eye, herpetic keratitis or systemic rheumatoid arthritis), can induce a catastrophic ocular dermal complication: corneal keratolysis or corneal melting (perforation and thinning of the cornea). NSAIDs inhibit the synthesis of corneal trophic prostaglandins and decrease dural sensitivity, which drastically delays keratocyte mitosis, simultaneously favoring the local overexpression of matrix metalloproteinases collagenases (MMP-8 and MMP-1) of neutrophils. This causes accelerated self-digestion of the collagen stroma, with the risk of perforation and loss of the eyeball.

Contraindications

• Absolute: Documented hypersensitivity to the salt components of NSAIDs, acetylsalicylic acid or other systemic NSAIDs; personal history of aspirin-induced bronchospasm or asthma triad and nasal polyps.
• Relative: Active extensive corneal epithelial defects; dry eye of moderate to severe course; patients wearing therapeutic silicone hydrogel contact lenses (they may retain preservatives and exacerbate epitheliotoxicity).

Adverse Effects (ADR)

• Ocular Sites: Sensation of stinging and immediate dural burning (associated with osmolarity); diffuse superficial punctate keratitis; delay in re-epithelialization of ulcers; conjunctival hyperemia; pathological corneal thinning and descemetocele in extreme cases of melting.
• Systemic: Mild headaches, dryness of the nasal mucosa. Very low systemic absorption and no gastrointestinal or platelet effect at usual doses.