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However, chronic PGA use frequently leads to ocular and periocular side effects such as conjunctival hyperemia, eyelash growth, and irreversible iris pigmentation, significantly affecting patient compliance and quality of life. These adverse effects are driven by molecular mechanisms involving receptor-mediated signaling and modulation of the extracellular matrix, with varying severities depending on the specific PGA and the presence of preservatives. Such side effects significantly impact patient compliance and quality of life, necessitating a comprehensive understanding and alternative treatment strategies. This review explores non-PGA alternatives, such as Rho kinase inhibitors, adenosine receptor agonists, and EP2\/EP3 receptor agonists, which offer distinct mechanisms of action and potentially improved tolerability profiles. Future directions highlight the importance of personalized medicine, leveraging genetic insights to tailor treatments and minimize adverse reactions.<\/jats:p>","DOI":"10.4103\/ijo.ijo_2387_25","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T16:00:42Z","timestamp":1772035242000},"page":"344-353","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Prostaglandin analog therapy challenges and innovation in glaucoma therapeutics"],"prefix":"10.4103","volume":"74","author":[{"given":"Madhu","family":"Nath","sequence":"first","affiliation":[{"name":"Ocular Pharmacology and Pharmacy Division, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamare","family":"Alam","sequence":"additional","affiliation":[{"name":"Ocular Pharmacology and Pharmacy Division, Dr. 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