Prostaglandin analogs in ophthalmology
A detailed search of databases was done including Pubmed, Medical Subject Headings (MeSH) Cochrane library, and Google Scholar. The search was conducted with the following keywords: prostaglandins, PGAs in glaucoma, latanoprost, bimatoprost, travoprost, antiglaucoma medications, newer antiglaucoma medications, prostaglandin receptors, and nitric oxide (NO)–donating prostaglandins.   Prostaglandins were discovered in human semen in 1935 by the Swedish physiologist Ulf von Euler, who named them, believing that they were secreted by the prostate gland. Ambache et al . made the first observation of effects of PG in the eye. They isolated a substance from iris extracts capable of contracting the cat iris, which was a mixture of PGs, mainly prostaglandin F2α (PGF2α) and prostaglandin E (PGE). Prostaglandins constitute a group of naturally occurring hydroxylated fatty acids found in small concentrations in mammalian tissues and produced enzymatically from fatty acids. The first report on the ocular effects of topically applied PGF2α in volunteers was published in 1985. There are nine prostaglandin receptors: PGE receptor (EP 1–4), PGD receptor (DP 1–2), PGIP receptor, PGFP receptor, and thromboxane A2 receptor (TP). Among these, two receptors are found in the eyes predominantly. FP is seen in corneal and ciliary epithelium, circular portion of ciliary muscle, iris stroma, and smooth muscle cells. EP is present in trabecular meshwork, choroid, and retina. The clinically used PGF2α derivatives are latanoprost, bimatoprost, travoprost, and tafluprost, and they all act as agonists of the PGF2α receptor. The mechanism by which prostaglandins increase conventional and unconventional outflow is not yet fully understood. Several studies suggest that their ocular hypotensive effect is carried out mainly by FP and EP receptors. Latanoprost and tafluprost bind to FP, EP1, and EP3 receptors with significant affinity, while travoprost binds to FP receptor with the highest affinity among the PGAs, and with minimal affinity for DP, EP1, EP3, EP4, and TP receptors. Bimatoprost has a high affinity and agonist activity for EP1 and EP3 receptors, in addition to its FP receptor activity. Pharmacology Prostaglandins and their related compounds prostacyclins, thromboxanes, leukotrienes, and lipoxins are collectively known as eicosanoids. Most of them are metabolic products of arachidonic acid and they all contain 20 carbon atoms. Since prostaglandins are derivatives of 20-carbon fatty acids (prostanoic acid), they are called prostanoids. Prostaglandins are fatty acids which structurally carry a negatively charged carboxyl group (COOH), while prostamides are fatty acid amides that do not carry the negative charge. Mechanism of action PGAs increase the uveoscleral outflow of aqueous humor. PGAs trigger a cascade of tissue remodeling enzymes like matrix metalloproteinases, which remodels the extracellular matrix of ciliary muscle and sclera and also causes widening of the connective tissue spaces, thereby increasing the uveoscleral outflow . Studies have shown that PGAs also increase the conventional outflow by relaxation of the trabecular meshwork(TM). IOP-lowering effect of PGAs ranges from 28% to 31%. Washout period ranges from 4 to 6 weeks. Indications PGAs have a wide variety of indications. They are used as a first-line drug in most of the forms of glaucoma and OHT. Indications of PGAs are listed in . Contraindications Absolute contraindications include active uveitis and macular edema. The role of prostaglandins as mediators of inflammation is a well-known fact, and hence, the use of PGAs in the long term stimulates the release of arachidonic acid by activating phospholipase II. Arachidonic acid, in turn, promotes an increase in eicosanoids as well as other proinflammatory mediators, thus damaging the blood–aqueous barrier. Therefore, PGAs should be avoided or used cautiously in patients with active/recurrent history of uveitis, macular edema, and herpetic keratitis. Relative contraindications include eyes at risk of(CME) cystoid macular edema (aphakic or pseudophakic with posterior capsule rupture), old history of macular edema, history of herpetic keratitis, pregnant and nursing mothers, and recent intraocular surgery. Side effects Excellent safety profile with regard to systemic side effects is one of the factors for the PGAs to become the first line of drug in glaucoma management. Adverse events of PGAs are mainly ocular, whereas systemic adverse effects are uncommon. Some of the local side effects are only of cosmetic significance, whereas others are much less common but represent potentially sight-threatening side effects. The ocular and systemic side effects of PGAs are presented in . Available medications PGAs: Latanoprost (0.005%) Travoprost (0.004%) Tafluprost (0.0015%) Prostamides : Bimatoprost (0.03% and 0.01%) Eicosanoids : Unoprostone (0.15%). Latanoprost Latanoprost is the first PGA approved by the United States Food and Drug Administration (US FDA). It was approved in the year 1996. It is an isopropyl ester prodrug analog of PGF2α, with high selectivity for the FP subtype of prostanoid receptors. It is hydrolyzed by esterases to acid form in the cornea to become biologically active. It is more lipophilic, and therefore, it has a better ability to penetrate the cornea. In human aqueous humor, a peak concentration is reached approximately 1–2 h after topical application. The IOP-lowering effect of latanoprost lasts for 20–24 h after a single dose, which allows a single daily dosage regimen. Unopened vials of latanoprost should be refrigerated between 2°C and 8°C, whereas opened bottles can be stored at room temperature for up to 6 weeks. However, refrigeration-free vials of latanoprost are also available in the market. A meta-analysis of 11 randomized controlled trials showed significant reduction in IOP with latanoprost when compared to timolol in patients with open-angle glaucoma (OAG) and OHT. A systematic review including eight unique randomized controlled trials compared the efficacy of PGAs with dorzolamide and brimonidine for IOP reduction in OAG and OHT patients. Latanoprost group showed a significant reduction in mean IOP compared to the dorzolamide group but not to the brimonidine group. In a meta-analysis including a total of 17 studies, the safety and efficacy of latanoprost monotherapy were evaluated systematically in patients with primary angle-closure glaucoma and chronic angle closure glaucoma. The study concluded that latanoprost reduced the mean IOP by 7.9 mmHg (32.4%) in patients with angle-closure glaucoma and adverse reactions associated with latanoprost were mainly ocular in nature. A prospective, randomized, double-masked, 12-week, multicenter study compared the efficacy and safety of latanoprost versus timolol that included 137 subjects aged ≥18 years with pediatric glaucoma. The study concluded that latanoprost 0.005% was not inferior to timolol and produced clinically relevant IOP reduction across pediatric patients with and without primary congenital glaucoma (PCG). Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial. In another prospective study comparing preserved and preservative-free latanoprost in patients with POAG and OHT, the authors reported that preservative-free latanoprost exhibited the same efficacy as preserved latanoprost, but found a better tolerance with preservative-free drops. A study by Mochizuki et al . suggested that after opening the vial, if latanoprost is stored at 30°C for 4 weeks, it remains effective and as safe as latanoprost stored under cold chain conditions (4°C). Travoprost Travoprost was approved by the US FDA in the year 2001; it is a PGF2α analog. Unlike other drugs in its group, it has a 100% agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.004% and has a once-daily dosage. It can be safely stored between 2°C and 25°C for up to 6 weeks. This drug offers an excellent stabilization of diurnal variation. The international travoprost study group found that mean IOP reductions from baseline were significantly greater with travoprost 0.004% (8.0–8.9 mmHg) than with timolol 0.5% (6.3–7.9 mmHg). Based on intent-to-treat data, the travoprost study group found a statistically significant mean IOP change from baseline for travoprost 0.004% (−6.5 to −7.1 mmHg) than for timolol 0.5% twice daily (BID; −5.2 to −6.8 mmHg) in patients with OAG and OHT. A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared to timolol found that travoprost was not inferior to timolol in lowering IOP in patients with pediatric glaucoma or OHT. Travoprost was well tolerated, and no treatment-related systemic adverse events were reported. Gandolfi et al . investigated the efficacy and safety of travoprost preserved with either polyquaternium-1 or benzalkonium chloride (BAK) in a multicenter, randomized, noninferiority study which included 371 patients suffering from either OAG or OHT. The study concluded that travoprost BAK-free safely and effectively lowered IOP in eyes with OAG or OHT. This BAK-free formulation had comparable safety, efficacy, and duration of IOP-lowering effect with those of travoprost preserved with BAK. BAK-free travoprost is an effective option for IOP reduction while avoiding BAK exposure. Tafluprost Tafluprost was approved by the US FDA in the year 2008. The mechanism of action is similar to latanoprost and travoprost, and it has a partial agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.0015% and is used once daily at bedtime. Unopened foil pouches have to be refrigerated and can be stored at room temperature after opening. It is the first preservative-free prostaglandin approved by the US FDA to treat OAG and OHT. A multicenter prospective study, the VISIONARY trial, concluded that the fixed dose combination (FDC) of preservative-free tafluprost with timolol provided significant IOP reduction over 6 months and was well tolerated among OAG/OHT patients showing poor response to latanoprost or b-blocker monotherapy. A meta-analysis of five randomized controlled trials comparing tafluprost and latanoprost concluded that tafluprost 0.0015% eye drops (BAK 0.1 mg/mL) and latanoprost 0.005% eye drops (BAK 0.2 mg/mL) were comparable in lowering IOP in OAG and OHT. There were no differences in the incidence of foreign body sensation, eye irritation, eye pain, iris hyperpigmentation, dry eye, and eye pruritus, but tafluprost showed less ocular tolerability because of higher incidence of conjunctival hyperemia. Bimatoprost Bimatoprost was approved by the US FDA in the year 2001. Unlike the PGF2α analogs, bimatoprost is a fatty acid with an ethyl amide, rather than an isopropyl ester, at the C-1 carbon of the α-chain. It has a dual action mechanism, which involves an increase of uveoscleral outflow like other PGAs and also acting on the prostamide receptors present in the trabecular meshwork, thus increasing the conventional outflow. It is the most efficient drug in reducing IOP because of its dual action but has more adverse drug reactions. It is available in two strengths, 0.03% and 0.01%, and has a once-daily dosage. It can be stored at temperatures between 15°C and 25°C. A prospective, randomized, double-masked, multicenter clinical trial in patients with OHT, POAG, chronic angle-closure glaucoma with patent iridotomy or iridectomy, pseudoexfoliation glaucoma (PXFG), or pigmentary glaucoma concluded that bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering IOP throughout 12 months of treatment and demonstrated improved tolerability, including less-frequent conjunctival hyperemia. Another randomized multicenter clinical trial suggested that bimatoprost 0.03% once daily demonstrated superior efficacy compared to timolol 0.5% BID in patients with glaucoma and OHT. Hyperemia is the most common side effect observed more with bimatoprost compared to other prostaglandins. A double-masked, prospective, randomized study in patients with POAG, pigmentary glaucoma, PXFG, or OHT found that bimatoprost 0.03% lowered IOP to a statistically similar amount as timolol maleate 0.5% and dorzolamide 2% FDC. In another randomized, double-masked, parallel group, 3-month follow-up study, the efficacy and safety of preservative-free bimatoprost 0.03% ( n = 302) were compared to those of BAK-preserved bimatoprost 0.03% formulation ( n = 295) in patients with POAG, chronic-angle closure glaucoma with patent iridotomy/iridectomy, PXFG, pigmentary glaucoma, or OHT and it was found that preservative-free bimatoprost was noninferior and equivalent to BAK preserved bimatoprost in its ability to reduce IOP, with a safety profile similar to that of preserved bimatoprost. Apart from the treatment of glaucoma, bimatoprost (0.03%) is indicated to treat hypotrichosis and chemotherapy-induced madarosis. shows the studies comparing PGAs with other antiglaucoma medications. Studies comparing PG analogs shows the studies comparing the PG analogs. A meta-analysis of 28 trials involving 6953 participants for the trough and 6841 participants for the peak of IOP in patients with POAG and OHT concluded that latanoprost reduced IOP by 28%–31% from baseline, travoprost by 29%–31%, and bimatoprost by 28%–33%. A randomized, parallel-group study in patients with OAG and OHT demonstrated that latanoprost, bimatoprost, and travoprost are equally potent in lowering IOP, and also found that latanoprost exhibited greater ocular tolerability. A meta-analysis of 13 trials involving 2222 patients with OHT and glaucoma, with a mean follow-up of 4.1 months, evaluated the development of conjunctival hyperemia after the use of latanoprost versus travoprost and bimatoprost. The study concluded that latanoprost (16.5%) was associated with a lower incidence of conjunctival hyperemia when compared to travoprost (33%) and bimatoprost (40.2%). Systemic side effects were found to be rare with these medications. Conjunctival hyperemia reached its peak by 15 days and started to decrease 1 month after initiation of the therapy. It showed a clear tendency for a time-dependent decrease of severity. Therefore, discontinuation of successful treatment with a PGA because of conjunctival hyperemia in the early days or weeks of the treatment is not recommended. A 6-month randomized controlled trial in patients with OAG and OHT concluded that conjunctival hyperemia and eyelash growth were significantly more common in patients treated with bimatoprost than with latanoprost. PRESSURE study, a multicenter, randomized study conducted in patients with OAG and OHT, concluded that the appearance of eyelid pigmentation was found to be 3.3% with latanoprost, 15.4% with Travoprost, and 25.9% with bimatoprost. On the other hand, the appearance of changes in eyelashes was found to be 30.7% with travoprost, 36.7% with latanoprost, and 48.1% with bimatoprost. A prospective, comparative study revealed a significant deepening of upper eyelid sulcus (DUES ) and periocular hyperpigmentation after bimatoprost use than after latanoprost use in patients with POAG/OHT. Aihara et al . studied the incidence of DUES after the use of bimatoprost. Twenty-five OAG Japanese patients treated with latanoprost in both eyes for 6 months or longer and needing further IOP reduction were enrolled prospectively. The study concluded that at 1, 3, and 6 months after the switchover to bimatoprost, 44% (11/25), 60% (15/25), and 60% (15/25) of the patients, respectively, had DUES. At 3 months, the IOP reductions from baseline in the non-DUES group and the DUES group were 0.5 ± 1.8 and 1.5 ± 1.6 mmHg, respectively, and the incidence of DUES was not related to the additional IOP reduction by bimatoprost. Iris pigmentation appears to be irreversible, whereas changes in eyelash and periocular skin pigmentation are reversible within a few months after stopping the drug. Also, discontinuation of the medication results in partial or complete reversal of DUES in 3–6 months. A meta-analysis of six studies comparing original and generics concluded that they did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials included in this analysis was suboptimal. Fixed combinations FDCs simplify the dosing regimen and increase convenience and can, therefore, potentially increase both compliance and patients’ quality of life. FDCs avoid the potential washout effect and also reduce exposure to excess preservatives. Finally, the cost of FDCs is less than the combined cost of the component medications. PGAs have an additive effect when combined with other classes of antiglaucoma agents like β-blockers and carbonic anhydrase inhibitors. In a systematic review, Quaranta et al . concluded that PGAs administered in combination with β-blockers (FDC) are more efficacious in lowering IOP than their individual components (monotherapy) for OAG. FDCs lead to a lower hyperemia risk than unfixed combinations and their respective PGA monotherapy. FDCs of timolol and all the three main prostaglandins are available.They are usually given as a once-daily dose in the bedtime, similar to PGAs. BID dosage can cause loss of FP receptor (downregulation) or change in the FP receptor (sub-sensitivity), leading to a reduction of efficiency of the drug. The FDC of latanoprost 0.005% with netarsudil 0.02% was approved by the US FDA in 2019 and it is available under the trade name Rocklatan ™ (PG324, Aerie Pharmaceuticals). A pooled analysis of the MERCURY I and II trials showed that this FDC lowered IOP significantly more than either of the individual components, with an acceptable safety profile, in patients with OAG and OHT. Newer PGAs NO-donating prostaglandins Latanoprostene bunod (LBN; Vyzulta) is a NO-donating PGF2 analog, which was approved by the US FDA in November 2017. It releases NO, which is thought to relax the trabecular meshwork to increase drainage of aqueous humor and improve aqueous humor outflow. Interestingly, there have been genetic and laboratory studies suggesting that NO may play a role in glaucoma through its effects on blood flow to the optic nerve, and thus the mechanism of Vyzulta may go beyond simply lowering the eye pressure. The VOYAGER study (NCT01223378), a Phase II, parallel-group, dose-ranging study, compared the efficacy and safety of LBN 0.006%, 0.012%, 0.024%, and 0.040% versus latanoprost 0.005% in 413 patients with OAG or OHT and concluded that LBN 0.024% dosed once daily was the most effective of the concentrations evaluated, with significantly greater IOP-lowering effect and comparable side effects relative to latanoprost 0.005%. The APOLLO study was a Phase III, randomized, multicenter, double-masked, parallel-group clinical study comparing LBN 0.024% once daily versus timolol 0.5% BID in a cohort of 420 OAG or OHT subjects and consisted of a 3-month efficacy phase and a 9-month safety extension phase. The study concluded that LBN 0.024% demonstrated significantly greater IOP-lowering effect than timolol 0.5% BID throughout the day over 3 months of treatment. LBN 0.024% was effective and safe in these adults with OAG or OHT. NCX 470 is an NO-donating PGF2 analog similar to Vyzulta. NCX 470 is metabolized into prostamide bimatoprost, which is further metabolized into bimatoprost acid and 6-(nitrooxy) hexanoic acid. Bimatoprost acid is a PGF2α agonist, while 6-(nitrooxy) hexanoic acid is an NO-donating moiety. It is currently in Phase III clinical trial named Mont Blanc. The Dolomites study, a randomized controlled comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and latanoprost 0.005% in patients with OAG or OHT, concluded that NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy. Selective EP receptor agonists A number of novel EP receptor agonists are currently at different stages of development. Omidenepag isopropyl, OMDI (DE-117), is a selective EP2 receptor agonist produced by Santen (Osaka, Japan). It is the world’s first commercially available EP2 receptor agonist approved for medical use in Japan in 2018 and in the USA in September 2022. It is sold under the brand name Eybelis for the treatment of glaucoma and OHT. It also has dual action like bimatoprost. It not only increases the uveoscleral outflow, but also reduces collagen deposition in TM and improves the contractility of trabecular cells. This results in improved aqueous drainage. Currently, OMDI is also approved in Singapore and Thailand. Moreover, India has pending reviews by its local regulatory agencies. Three randomized, controlled, multicenter studies (two in the USA and one in Japan) using different concentrations of OMDI ranging from 0.0003% to 0.003% performed in 338 OAG and OHT patients concluded that OMDI 0.002% was the optimal dose with regard to both efficacy and safety. In another Phase 3 AYAME study, OMDI 0.002% was found to be noninferior to latanoprost 0.005% in reducing IOP in patients with OHT or POAG and was well tolerated. Taprenepag isopropyl (PF-04217329), a prostaglandin EP2 receptor agonist, is under Phase II clinical trials and has shown efficacy in lowering IOP in humans. A Phase 2, randomized, dose–response trial of taprenepag isopropyl showed significantly reduction of IOP in POAG and OHT. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. The study also concluded that the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications. Aganepag isopropyl (AGN-210961) is a selective EP2 receptor agonist. In the clinical trial NCT01001195, the safety and efficacy of three formulations of aganepag isopropyl ophthalmic solution were compared with bimatoprost ophthalmic solution in 165 patients with OAG or OHT. At the end of 1 month, conjunctival hyperemia was observed in 53.85% of the subjects using aganepag isopropyl 0.1% and in 60.98% of participants using bimatoprost. Other adverse events detected were punctate keratitis, photophobia, eye pain, anterior chamber cells, and eye irritation. Sepetaprost (previously named ONO-9054; Ono Pharmaceutical, Osaka, Japan) and DE-126 (Santen, Osaka, Japan) are in Phase II trial. They are prostaglandin EP3 receptor and prostaglandin F2α receptor agonist, and hence reduce the IOP by targeting two receptors simultaneously. A 28-day, double-masked, randomized study in patients with OAG and OHT concluded that those who treated with ONO-9054 were more likely to achieve a greater percent reduction in IOP and were more likely to achieve target IOP than those receiving latanoprost. The effects of ONO-9054 in reducing IOP appear to persist longer than those of latanoprost. Other selective prostaglandin receptor agonists in clinical development are JV-GL1 (PGN-9856 isopropyl) (EP2 receptor agonist) and sulprostone (prostaglandin E2 receptor agonist), which have shown IOP-lowering effects in rabbits, and butaprost/dinoprost (naturally occurring PGE2 agonist), which has been shown to lower IOP in monkeys. Other uses of PGAs Latanoprost improves optic nerve head perfusion. Lab experiments using latanoprost demonstrated increased optic nerve head blood circulation in rabbits, monkeys, and normal humans, apart from IOP-reducing effect. A randomized controlled trial comparing latanoprost and bimatoprost found that both prostaglandins demonstrated significant IOP reduction, but latanoprost was associated with improved ocular perfusion pressure, whereas bimatoprost did not show this effect. Bimatoprost is used as an eyelash growth serum (Latisse) for cosmesis and chemo-induced madarosis. Unoprostone causes long-term maintenance of salvageable visual function and has been shown to improve central retinal sensitivity in retinitis pigmentosa (Phase II clinical trials).   Prostaglandins and their related compounds prostacyclins, thromboxanes, leukotrienes, and lipoxins are collectively known as eicosanoids. Most of them are metabolic products of arachidonic acid and they all contain 20 carbon atoms. Since prostaglandins are derivatives of 20-carbon fatty acids (prostanoic acid), they are called prostanoids. Prostaglandins are fatty acids which structurally carry a negatively charged carboxyl group (COOH), while prostamides are fatty acid amides that do not carry the negative charge.   PGAs increase the uveoscleral outflow of aqueous humor. PGAs trigger a cascade of tissue remodeling enzymes like matrix metalloproteinases, which remodels the extracellular matrix of ciliary muscle and sclera and also causes widening of the connective tissue spaces, thereby increasing the uveoscleral outflow . Studies have shown that PGAs also increase the conventional outflow by relaxation of the trabecular meshwork(TM). IOP-lowering effect of PGAs ranges from 28% to 31%. Washout period ranges from 4 to 6 weeks.   PGAs have a wide variety of indications. They are used as a first-line drug in most of the forms of glaucoma and OHT. Indications of PGAs are listed in .   Absolute contraindications include active uveitis and macular edema. The role of prostaglandins as mediators of inflammation is a well-known fact, and hence, the use of PGAs in the long term stimulates the release of arachidonic acid by activating phospholipase II. Arachidonic acid, in turn, promotes an increase in eicosanoids as well as other proinflammatory mediators, thus damaging the blood–aqueous barrier. Therefore, PGAs should be avoided or used cautiously in patients with active/recurrent history of uveitis, macular edema, and herpetic keratitis. Relative contraindications include eyes at risk of(CME) cystoid macular edema (aphakic or pseudophakic with posterior capsule rupture), old history of macular edema, history of herpetic keratitis, pregnant and nursing mothers, and recent intraocular surgery.   Excellent safety profile with regard to systemic side effects is one of the factors for the PGAs to become the first line of drug in glaucoma management. Adverse events of PGAs are mainly ocular, whereas systemic adverse effects are uncommon. Some of the local side effects are only of cosmetic significance, whereas others are much less common but represent potentially sight-threatening side effects. The ocular and systemic side effects of PGAs are presented in .   PGAs: Latanoprost (0.005%) Travoprost (0.004%) Tafluprost (0.0015%) Prostamides : Bimatoprost (0.03% and 0.01%) Eicosanoids : Unoprostone (0.15%). Latanoprost Latanoprost is the first PGA approved by the United States Food and Drug Administration (US FDA). It was approved in the year 1996. It is an isopropyl ester prodrug analog of PGF2α, with high selectivity for the FP subtype of prostanoid receptors. It is hydrolyzed by esterases to acid form in the cornea to become biologically active. It is more lipophilic, and therefore, it has a better ability to penetrate the cornea. In human aqueous humor, a peak concentration is reached approximately 1–2 h after topical application. The IOP-lowering effect of latanoprost lasts for 20–24 h after a single dose, which allows a single daily dosage regimen. Unopened vials of latanoprost should be refrigerated between 2°C and 8°C, whereas opened bottles can be stored at room temperature for up to 6 weeks. However, refrigeration-free vials of latanoprost are also available in the market. A meta-analysis of 11 randomized controlled trials showed significant reduction in IOP with latanoprost when compared to timolol in patients with open-angle glaucoma (OAG) and OHT. A systematic review including eight unique randomized controlled trials compared the efficacy of PGAs with dorzolamide and brimonidine for IOP reduction in OAG and OHT patients. Latanoprost group showed a significant reduction in mean IOP compared to the dorzolamide group but not to the brimonidine group. In a meta-analysis including a total of 17 studies, the safety and efficacy of latanoprost monotherapy were evaluated systematically in patients with primary angle-closure glaucoma and chronic angle closure glaucoma. The study concluded that latanoprost reduced the mean IOP by 7.9 mmHg (32.4%) in patients with angle-closure glaucoma and adverse reactions associated with latanoprost were mainly ocular in nature. A prospective, randomized, double-masked, 12-week, multicenter study compared the efficacy and safety of latanoprost versus timolol that included 137 subjects aged ≥18 years with pediatric glaucoma. The study concluded that latanoprost 0.005% was not inferior to timolol and produced clinically relevant IOP reduction across pediatric patients with and without primary congenital glaucoma (PCG). Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial. In another prospective study comparing preserved and preservative-free latanoprost in patients with POAG and OHT, the authors reported that preservative-free latanoprost exhibited the same efficacy as preserved latanoprost, but found a better tolerance with preservative-free drops. A study by Mochizuki et al . suggested that after opening the vial, if latanoprost is stored at 30°C for 4 weeks, it remains effective and as safe as latanoprost stored under cold chain conditions (4°C). Travoprost Travoprost was approved by the US FDA in the year 2001; it is a PGF2α analog. Unlike other drugs in its group, it has a 100% agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.004% and has a once-daily dosage. It can be safely stored between 2°C and 25°C for up to 6 weeks. This drug offers an excellent stabilization of diurnal variation. The international travoprost study group found that mean IOP reductions from baseline were significantly greater with travoprost 0.004% (8.0–8.9 mmHg) than with timolol 0.5% (6.3–7.9 mmHg). Based on intent-to-treat data, the travoprost study group found a statistically significant mean IOP change from baseline for travoprost 0.004% (−6.5 to −7.1 mmHg) than for timolol 0.5% twice daily (BID; −5.2 to −6.8 mmHg) in patients with OAG and OHT. A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared to timolol found that travoprost was not inferior to timolol in lowering IOP in patients with pediatric glaucoma or OHT. Travoprost was well tolerated, and no treatment-related systemic adverse events were reported. Gandolfi et al . investigated the efficacy and safety of travoprost preserved with either polyquaternium-1 or benzalkonium chloride (BAK) in a multicenter, randomized, noninferiority study which included 371 patients suffering from either OAG or OHT. The study concluded that travoprost BAK-free safely and effectively lowered IOP in eyes with OAG or OHT. This BAK-free formulation had comparable safety, efficacy, and duration of IOP-lowering effect with those of travoprost preserved with BAK. BAK-free travoprost is an effective option for IOP reduction while avoiding BAK exposure. Tafluprost Tafluprost was approved by the US FDA in the year 2008. The mechanism of action is similar to latanoprost and travoprost, and it has a partial agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.0015% and is used once daily at bedtime. Unopened foil pouches have to be refrigerated and can be stored at room temperature after opening. It is the first preservative-free prostaglandin approved by the US FDA to treat OAG and OHT. A multicenter prospective study, the VISIONARY trial, concluded that the fixed dose combination (FDC) of preservative-free tafluprost with timolol provided significant IOP reduction over 6 months and was well tolerated among OAG/OHT patients showing poor response to latanoprost or b-blocker monotherapy. A meta-analysis of five randomized controlled trials comparing tafluprost and latanoprost concluded that tafluprost 0.0015% eye drops (BAK 0.1 mg/mL) and latanoprost 0.005% eye drops (BAK 0.2 mg/mL) were comparable in lowering IOP in OAG and OHT. There were no differences in the incidence of foreign body sensation, eye irritation, eye pain, iris hyperpigmentation, dry eye, and eye pruritus, but tafluprost showed less ocular tolerability because of higher incidence of conjunctival hyperemia. Bimatoprost Bimatoprost was approved by the US FDA in the year 2001. Unlike the PGF2α analogs, bimatoprost is a fatty acid with an ethyl amide, rather than an isopropyl ester, at the C-1 carbon of the α-chain. It has a dual action mechanism, which involves an increase of uveoscleral outflow like other PGAs and also acting on the prostamide receptors present in the trabecular meshwork, thus increasing the conventional outflow. It is the most efficient drug in reducing IOP because of its dual action but has more adverse drug reactions. It is available in two strengths, 0.03% and 0.01%, and has a once-daily dosage. It can be stored at temperatures between 15°C and 25°C. A prospective, randomized, double-masked, multicenter clinical trial in patients with OHT, POAG, chronic angle-closure glaucoma with patent iridotomy or iridectomy, pseudoexfoliation glaucoma (PXFG), or pigmentary glaucoma concluded that bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering IOP throughout 12 months of treatment and demonstrated improved tolerability, including less-frequent conjunctival hyperemia. Another randomized multicenter clinical trial suggested that bimatoprost 0.03% once daily demonstrated superior efficacy compared to timolol 0.5% BID in patients with glaucoma and OHT. Hyperemia is the most common side effect observed more with bimatoprost compared to other prostaglandins. A double-masked, prospective, randomized study in patients with POAG, pigmentary glaucoma, PXFG, or OHT found that bimatoprost 0.03% lowered IOP to a statistically similar amount as timolol maleate 0.5% and dorzolamide 2% FDC. In another randomized, double-masked, parallel group, 3-month follow-up study, the efficacy and safety of preservative-free bimatoprost 0.03% ( n = 302) were compared to those of BAK-preserved bimatoprost 0.03% formulation ( n = 295) in patients with POAG, chronic-angle closure glaucoma with patent iridotomy/iridectomy, PXFG, pigmentary glaucoma, or OHT and it was found that preservative-free bimatoprost was noninferior and equivalent to BAK preserved bimatoprost in its ability to reduce IOP, with a safety profile similar to that of preserved bimatoprost. Apart from the treatment of glaucoma, bimatoprost (0.03%) is indicated to treat hypotrichosis and chemotherapy-induced madarosis. shows the studies comparing PGAs with other antiglaucoma medications.   Latanoprost (0.005%) Travoprost (0.004%) Tafluprost (0.0015%) Prostamides : Bimatoprost (0.03% and 0.01%) Eicosanoids : Unoprostone (0.15%).   Latanoprost is the first PGA approved by the United States Food and Drug Administration (US FDA). It was approved in the year 1996. It is an isopropyl ester prodrug analog of PGF2α, with high selectivity for the FP subtype of prostanoid receptors. It is hydrolyzed by esterases to acid form in the cornea to become biologically active. It is more lipophilic, and therefore, it has a better ability to penetrate the cornea. In human aqueous humor, a peak concentration is reached approximately 1–2 h after topical application. The IOP-lowering effect of latanoprost lasts for 20–24 h after a single dose, which allows a single daily dosage regimen. Unopened vials of latanoprost should be refrigerated between 2°C and 8°C, whereas opened bottles can be stored at room temperature for up to 6 weeks. However, refrigeration-free vials of latanoprost are also available in the market. A meta-analysis of 11 randomized controlled trials showed significant reduction in IOP with latanoprost when compared to timolol in patients with open-angle glaucoma (OAG) and OHT. A systematic review including eight unique randomized controlled trials compared the efficacy of PGAs with dorzolamide and brimonidine for IOP reduction in OAG and OHT patients. Latanoprost group showed a significant reduction in mean IOP compared to the dorzolamide group but not to the brimonidine group. In a meta-analysis including a total of 17 studies, the safety and efficacy of latanoprost monotherapy were evaluated systematically in patients with primary angle-closure glaucoma and chronic angle closure glaucoma. The study concluded that latanoprost reduced the mean IOP by 7.9 mmHg (32.4%) in patients with angle-closure glaucoma and adverse reactions associated with latanoprost were mainly ocular in nature. A prospective, randomized, double-masked, 12-week, multicenter study compared the efficacy and safety of latanoprost versus timolol that included 137 subjects aged ≥18 years with pediatric glaucoma. The study concluded that latanoprost 0.005% was not inferior to timolol and produced clinically relevant IOP reduction across pediatric patients with and without primary congenital glaucoma (PCG). Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial. In another prospective study comparing preserved and preservative-free latanoprost in patients with POAG and OHT, the authors reported that preservative-free latanoprost exhibited the same efficacy as preserved latanoprost, but found a better tolerance with preservative-free drops. A study by Mochizuki et al . suggested that after opening the vial, if latanoprost is stored at 30°C for 4 weeks, it remains effective and as safe as latanoprost stored under cold chain conditions (4°C).   Travoprost was approved by the US FDA in the year 2001; it is a PGF2α analog. Unlike other drugs in its group, it has a 100% agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.004% and has a once-daily dosage. It can be safely stored between 2°C and 25°C for up to 6 weeks. This drug offers an excellent stabilization of diurnal variation. The international travoprost study group found that mean IOP reductions from baseline were significantly greater with travoprost 0.004% (8.0–8.9 mmHg) than with timolol 0.5% (6.3–7.9 mmHg). Based on intent-to-treat data, the travoprost study group found a statistically significant mean IOP change from baseline for travoprost 0.004% (−6.5 to −7.1 mmHg) than for timolol 0.5% twice daily (BID; −5.2 to −6.8 mmHg) in patients with OAG and OHT. A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared to timolol found that travoprost was not inferior to timolol in lowering IOP in patients with pediatric glaucoma or OHT. Travoprost was well tolerated, and no treatment-related systemic adverse events were reported. Gandolfi et al . investigated the efficacy and safety of travoprost preserved with either polyquaternium-1 or benzalkonium chloride (BAK) in a multicenter, randomized, noninferiority study which included 371 patients suffering from either OAG or OHT. The study concluded that travoprost BAK-free safely and effectively lowered IOP in eyes with OAG or OHT. This BAK-free formulation had comparable safety, efficacy, and duration of IOP-lowering effect with those of travoprost preserved with BAK. BAK-free travoprost is an effective option for IOP reduction while avoiding BAK exposure.   Tafluprost was approved by the US FDA in the year 2008. The mechanism of action is similar to latanoprost and travoprost, and it has a partial agonistic action at the prostaglandin FP receptor site. It is available in the strength of 0.0015% and is used once daily at bedtime. Unopened foil pouches have to be refrigerated and can be stored at room temperature after opening. It is the first preservative-free prostaglandin approved by the US FDA to treat OAG and OHT. A multicenter prospective study, the VISIONARY trial, concluded that the fixed dose combination (FDC) of preservative-free tafluprost with timolol provided significant IOP reduction over 6 months and was well tolerated among OAG/OHT patients showing poor response to latanoprost or b-blocker monotherapy. A meta-analysis of five randomized controlled trials comparing tafluprost and latanoprost concluded that tafluprost 0.0015% eye drops (BAK 0.1 mg/mL) and latanoprost 0.005% eye drops (BAK 0.2 mg/mL) were comparable in lowering IOP in OAG and OHT. There were no differences in the incidence of foreign body sensation, eye irritation, eye pain, iris hyperpigmentation, dry eye, and eye pruritus, but tafluprost showed less ocular tolerability because of higher incidence of conjunctival hyperemia.   Bimatoprost was approved by the US FDA in the year 2001. Unlike the PGF2α analogs, bimatoprost is a fatty acid with an ethyl amide, rather than an isopropyl ester, at the C-1 carbon of the α-chain. It has a dual action mechanism, which involves an increase of uveoscleral outflow like other PGAs and also acting on the prostamide receptors present in the trabecular meshwork, thus increasing the conventional outflow. It is the most efficient drug in reducing IOP because of its dual action but has more adverse drug reactions. It is available in two strengths, 0.03% and 0.01%, and has a once-daily dosage. It can be stored at temperatures between 15°C and 25°C. A prospective, randomized, double-masked, multicenter clinical trial in patients with OHT, POAG, chronic angle-closure glaucoma with patent iridotomy or iridectomy, pseudoexfoliation glaucoma (PXFG), or pigmentary glaucoma concluded that bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering IOP throughout 12 months of treatment and demonstrated improved tolerability, including less-frequent conjunctival hyperemia. Another randomized multicenter clinical trial suggested that bimatoprost 0.03% once daily demonstrated superior efficacy compared to timolol 0.5% BID in patients with glaucoma and OHT. Hyperemia is the most common side effect observed more with bimatoprost compared to other prostaglandins. A double-masked, prospective, randomized study in patients with POAG, pigmentary glaucoma, PXFG, or OHT found that bimatoprost 0.03% lowered IOP to a statistically similar amount as timolol maleate 0.5% and dorzolamide 2% FDC. In another randomized, double-masked, parallel group, 3-month follow-up study, the efficacy and safety of preservative-free bimatoprost 0.03% ( n = 302) were compared to those of BAK-preserved bimatoprost 0.03% formulation ( n = 295) in patients with POAG, chronic-angle closure glaucoma with patent iridotomy/iridectomy, PXFG, pigmentary glaucoma, or OHT and it was found that preservative-free bimatoprost was noninferior and equivalent to BAK preserved bimatoprost in its ability to reduce IOP, with a safety profile similar to that of preserved bimatoprost. Apart from the treatment of glaucoma, bimatoprost (0.03%) is indicated to treat hypotrichosis and chemotherapy-induced madarosis. shows the studies comparing PGAs with other antiglaucoma medications.   shows the studies comparing the PG analogs. A meta-analysis of 28 trials involving 6953 participants for the trough and 6841 participants for the peak of IOP in patients with POAG and OHT concluded that latanoprost reduced IOP by 28%–31% from baseline, travoprost by 29%–31%, and bimatoprost by 28%–33%. A randomized, parallel-group study in patients with OAG and OHT demonstrated that latanoprost, bimatoprost, and travoprost are equally potent in lowering IOP, and also found that latanoprost exhibited greater ocular tolerability. A meta-analysis of 13 trials involving 2222 patients with OHT and glaucoma, with a mean follow-up of 4.1 months, evaluated the development of conjunctival hyperemia after the use of latanoprost versus travoprost and bimatoprost. The study concluded that latanoprost (16.5%) was associated with a lower incidence of conjunctival hyperemia when compared to travoprost (33%) and bimatoprost (40.2%). Systemic side effects were found to be rare with these medications. Conjunctival hyperemia reached its peak by 15 days and started to decrease 1 month after initiation of the therapy. It showed a clear tendency for a time-dependent decrease of severity. Therefore, discontinuation of successful treatment with a PGA because of conjunctival hyperemia in the early days or weeks of the treatment is not recommended. A 6-month randomized controlled trial in patients with OAG and OHT concluded that conjunctival hyperemia and eyelash growth were significantly more common in patients treated with bimatoprost than with latanoprost. PRESSURE study, a multicenter, randomized study conducted in patients with OAG and OHT, concluded that the appearance of eyelid pigmentation was found to be 3.3% with latanoprost, 15.4% with Travoprost, and 25.9% with bimatoprost. On the other hand, the appearance of changes in eyelashes was found to be 30.7% with travoprost, 36.7% with latanoprost, and 48.1% with bimatoprost. A prospective, comparative study revealed a significant deepening of upper eyelid sulcus (DUES ) and periocular hyperpigmentation after bimatoprost use than after latanoprost use in patients with POAG/OHT. Aihara et al . studied the incidence of DUES after the use of bimatoprost. Twenty-five OAG Japanese patients treated with latanoprost in both eyes for 6 months or longer and needing further IOP reduction were enrolled prospectively. The study concluded that at 1, 3, and 6 months after the switchover to bimatoprost, 44% (11/25), 60% (15/25), and 60% (15/25) of the patients, respectively, had DUES. At 3 months, the IOP reductions from baseline in the non-DUES group and the DUES group were 0.5 ± 1.8 and 1.5 ± 1.6 mmHg, respectively, and the incidence of DUES was not related to the additional IOP reduction by bimatoprost. Iris pigmentation appears to be irreversible, whereas changes in eyelash and periocular skin pigmentation are reversible within a few months after stopping the drug. Also, discontinuation of the medication results in partial or complete reversal of DUES in 3–6 months. A meta-analysis of six studies comparing original and generics concluded that they did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials included in this analysis was suboptimal.   FDCs simplify the dosing regimen and increase convenience and can, therefore, potentially increase both compliance and patients’ quality of life. FDCs avoid the potential washout effect and also reduce exposure to excess preservatives. Finally, the cost of FDCs is less than the combined cost of the component medications. PGAs have an additive effect when combined with other classes of antiglaucoma agents like β-blockers and carbonic anhydrase inhibitors. In a systematic review, Quaranta et al . concluded that PGAs administered in combination with β-blockers (FDC) are more efficacious in lowering IOP than their individual components (monotherapy) for OAG. FDCs lead to a lower hyperemia risk than unfixed combinations and their respective PGA monotherapy. FDCs of timolol and all the three main prostaglandins are available.They are usually given as a once-daily dose in the bedtime, similar to PGAs. BID dosage can cause loss of FP receptor (downregulation) or change in the FP receptor (sub-sensitivity), leading to a reduction of efficiency of the drug. The FDC of latanoprost 0.005% with netarsudil 0.02% was approved by the US FDA in 2019 and it is available under the trade name Rocklatan ™ (PG324, Aerie Pharmaceuticals). A pooled analysis of the MERCURY I and II trials showed that this FDC lowered IOP significantly more than either of the individual components, with an acceptable safety profile, in patients with OAG and OHT.   NO-donating prostaglandins Latanoprostene bunod (LBN; Vyzulta) is a NO-donating PGF2 analog, which was approved by the US FDA in November 2017. It releases NO, which is thought to relax the trabecular meshwork to increase drainage of aqueous humor and improve aqueous humor outflow. Interestingly, there have been genetic and laboratory studies suggesting that NO may play a role in glaucoma through its effects on blood flow to the optic nerve, and thus the mechanism of Vyzulta may go beyond simply lowering the eye pressure. The VOYAGER study (NCT01223378), a Phase II, parallel-group, dose-ranging study, compared the efficacy and safety of LBN 0.006%, 0.012%, 0.024%, and 0.040% versus latanoprost 0.005% in 413 patients with OAG or OHT and concluded that LBN 0.024% dosed once daily was the most effective of the concentrations evaluated, with significantly greater IOP-lowering effect and comparable side effects relative to latanoprost 0.005%. The APOLLO study was a Phase III, randomized, multicenter, double-masked, parallel-group clinical study comparing LBN 0.024% once daily versus timolol 0.5% BID in a cohort of 420 OAG or OHT subjects and consisted of a 3-month efficacy phase and a 9-month safety extension phase. The study concluded that LBN 0.024% demonstrated significantly greater IOP-lowering effect than timolol 0.5% BID throughout the day over 3 months of treatment. LBN 0.024% was effective and safe in these adults with OAG or OHT. NCX 470 is an NO-donating PGF2 analog similar to Vyzulta. NCX 470 is metabolized into prostamide bimatoprost, which is further metabolized into bimatoprost acid and 6-(nitrooxy) hexanoic acid. Bimatoprost acid is a PGF2α agonist, while 6-(nitrooxy) hexanoic acid is an NO-donating moiety. It is currently in Phase III clinical trial named Mont Blanc. The Dolomites study, a randomized controlled comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and latanoprost 0.005% in patients with OAG or OHT, concluded that NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy. Selective EP receptor agonists A number of novel EP receptor agonists are currently at different stages of development. Omidenepag isopropyl, OMDI (DE-117), is a selective EP2 receptor agonist produced by Santen (Osaka, Japan). It is the world’s first commercially available EP2 receptor agonist approved for medical use in Japan in 2018 and in the USA in September 2022. It is sold under the brand name Eybelis for the treatment of glaucoma and OHT. It also has dual action like bimatoprost. It not only increases the uveoscleral outflow, but also reduces collagen deposition in TM and improves the contractility of trabecular cells. This results in improved aqueous drainage. Currently, OMDI is also approved in Singapore and Thailand. Moreover, India has pending reviews by its local regulatory agencies. Three randomized, controlled, multicenter studies (two in the USA and one in Japan) using different concentrations of OMDI ranging from 0.0003% to 0.003% performed in 338 OAG and OHT patients concluded that OMDI 0.002% was the optimal dose with regard to both efficacy and safety. In another Phase 3 AYAME study, OMDI 0.002% was found to be noninferior to latanoprost 0.005% in reducing IOP in patients with OHT or POAG and was well tolerated. Taprenepag isopropyl (PF-04217329), a prostaglandin EP2 receptor agonist, is under Phase II clinical trials and has shown efficacy in lowering IOP in humans. A Phase 2, randomized, dose–response trial of taprenepag isopropyl showed significantly reduction of IOP in POAG and OHT. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. The study also concluded that the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications. Aganepag isopropyl (AGN-210961) is a selective EP2 receptor agonist. In the clinical trial NCT01001195, the safety and efficacy of three formulations of aganepag isopropyl ophthalmic solution were compared with bimatoprost ophthalmic solution in 165 patients with OAG or OHT. At the end of 1 month, conjunctival hyperemia was observed in 53.85% of the subjects using aganepag isopropyl 0.1% and in 60.98% of participants using bimatoprost. Other adverse events detected were punctate keratitis, photophobia, eye pain, anterior chamber cells, and eye irritation. Sepetaprost (previously named ONO-9054; Ono Pharmaceutical, Osaka, Japan) and DE-126 (Santen, Osaka, Japan) are in Phase II trial. They are prostaglandin EP3 receptor and prostaglandin F2α receptor agonist, and hence reduce the IOP by targeting two receptors simultaneously. A 28-day, double-masked, randomized study in patients with OAG and OHT concluded that those who treated with ONO-9054 were more likely to achieve a greater percent reduction in IOP and were more likely to achieve target IOP than those receiving latanoprost. The effects of ONO-9054 in reducing IOP appear to persist longer than those of latanoprost. Other selective prostaglandin receptor agonists in clinical development are JV-GL1 (PGN-9856 isopropyl) (EP2 receptor agonist) and sulprostone (prostaglandin E2 receptor agonist), which have shown IOP-lowering effects in rabbits, and butaprost/dinoprost (naturally occurring PGE2 agonist), which has been shown to lower IOP in monkeys.   Latanoprostene bunod (LBN; Vyzulta) is a NO-donating PGF2 analog, which was approved by the US FDA in November 2017. It releases NO, which is thought to relax the trabecular meshwork to increase drainage of aqueous humor and improve aqueous humor outflow. Interestingly, there have been genetic and laboratory studies suggesting that NO may play a role in glaucoma through its effects on blood flow to the optic nerve, and thus the mechanism of Vyzulta may go beyond simply lowering the eye pressure. The VOYAGER study (NCT01223378), a Phase II, parallel-group, dose-ranging study, compared the efficacy and safety of LBN 0.006%, 0.012%, 0.024%, and 0.040% versus latanoprost 0.005% in 413 patients with OAG or OHT and concluded that LBN 0.024% dosed once daily was the most effective of the concentrations evaluated, with significantly greater IOP-lowering effect and comparable side effects relative to latanoprost 0.005%. The APOLLO study was a Phase III, randomized, multicenter, double-masked, parallel-group clinical study comparing LBN 0.024% once daily versus timolol 0.5% BID in a cohort of 420 OAG or OHT subjects and consisted of a 3-month efficacy phase and a 9-month safety extension phase. The study concluded that LBN 0.024% demonstrated significantly greater IOP-lowering effect than timolol 0.5% BID throughout the day over 3 months of treatment. LBN 0.024% was effective and safe in these adults with OAG or OHT. NCX 470 is an NO-donating PGF2 analog similar to Vyzulta. NCX 470 is metabolized into prostamide bimatoprost, which is further metabolized into bimatoprost acid and 6-(nitrooxy) hexanoic acid. Bimatoprost acid is a PGF2α agonist, while 6-(nitrooxy) hexanoic acid is an NO-donating moiety. It is currently in Phase III clinical trial named Mont Blanc. The Dolomites study, a randomized controlled comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and latanoprost 0.005% in patients with OAG or OHT, concluded that NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy.   A number of novel EP receptor agonists are currently at different stages of development. Omidenepag isopropyl, OMDI (DE-117), is a selective EP2 receptor agonist produced by Santen (Osaka, Japan). It is the world’s first commercially available EP2 receptor agonist approved for medical use in Japan in 2018 and in the USA in September 2022. It is sold under the brand name Eybelis for the treatment of glaucoma and OHT. It also has dual action like bimatoprost. It not only increases the uveoscleral outflow, but also reduces collagen deposition in TM and improves the contractility of trabecular cells. This results in improved aqueous drainage. Currently, OMDI is also approved in Singapore and Thailand. Moreover, India has pending reviews by its local regulatory agencies. Three randomized, controlled, multicenter studies (two in the USA and one in Japan) using different concentrations of OMDI ranging from 0.0003% to 0.003% performed in 338 OAG and OHT patients concluded that OMDI 0.002% was the optimal dose with regard to both efficacy and safety. In another Phase 3 AYAME study, OMDI 0.002% was found to be noninferior to latanoprost 0.005% in reducing IOP in patients with OHT or POAG and was well tolerated. Taprenepag isopropyl (PF-04217329), a prostaglandin EP2 receptor agonist, is under Phase II clinical trials and has shown efficacy in lowering IOP in humans. A Phase 2, randomized, dose–response trial of taprenepag isopropyl showed significantly reduction of IOP in POAG and OHT. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. The study also concluded that the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications. Aganepag isopropyl (AGN-210961) is a selective EP2 receptor agonist. In the clinical trial NCT01001195, the safety and efficacy of three formulations of aganepag isopropyl ophthalmic solution were compared with bimatoprost ophthalmic solution in 165 patients with OAG or OHT. At the end of 1 month, conjunctival hyperemia was observed in 53.85% of the subjects using aganepag isopropyl 0.1% and in 60.98% of participants using bimatoprost. Other adverse events detected were punctate keratitis, photophobia, eye pain, anterior chamber cells, and eye irritation. Sepetaprost (previously named ONO-9054; Ono Pharmaceutical, Osaka, Japan) and DE-126 (Santen, Osaka, Japan) are in Phase II trial. They are prostaglandin EP3 receptor and prostaglandin F2α receptor agonist, and hence reduce the IOP by targeting two receptors simultaneously. A 28-day, double-masked, randomized study in patients with OAG and OHT concluded that those who treated with ONO-9054 were more likely to achieve a greater percent reduction in IOP and were more likely to achieve target IOP than those receiving latanoprost. The effects of ONO-9054 in reducing IOP appear to persist longer than those of latanoprost. Other selective prostaglandin receptor agonists in clinical development are JV-GL1 (PGN-9856 isopropyl) (EP2 receptor agonist) and sulprostone (prostaglandin E2 receptor agonist), which have shown IOP-lowering effects in rabbits, and butaprost/dinoprost (naturally occurring PGE2 agonist), which has been shown to lower IOP in monkeys.   Latanoprost improves optic nerve head perfusion. Lab experiments using latanoprost demonstrated increased optic nerve head blood circulation in rabbits, monkeys, and normal humans, apart from IOP-reducing effect. A randomized controlled trial comparing latanoprost and bimatoprost found that both prostaglandins demonstrated significant IOP reduction, but latanoprost was associated with improved ocular perfusion pressure, whereas bimatoprost did not show this effect. Bimatoprost is used as an eyelash growth serum (Latisse) for cosmesis and chemo-induced madarosis. Unoprostone causes long-term maintenance of salvageable visual function and has been shown to improve central retinal sensitivity in retinitis pigmentosa (Phase II clinical trials).   Currently, lowering of IOP remains the only modifiable risk factor in the management of glaucoma. PGAs have revolutionized the management of glaucoma and have progressively replaced β-blockers as a first-line therapy in majority of the glaucomas because of their once-daily dosing benefit, effective IOP reduction, and lesser systemic side effects. With the available evidence, latanoprost seems to be more patient friendly, it is better tolerated with lesser incidence of conjunctival hyperemia, DUES, and periorbital pigmentation. Bimatoprost offers maximum pressure reduction with possible additional 1 mmHg IOP reduction compared to other available PGAs, but at the cost of increased ocular side effects. Travoprost scores over the other PGAs in stabilizing the diurnal fluctuations. Patients might differ in their response to PGAs, and they can be switched from one PGA to another in case of poor response. Furthermore, FDCs of PGAs and timolol are helpful in reducing exposure to BAK. The novel NO-donating PGAs like LBN and NCX 470 provide robust IOP-reducing activity by concomitantly activating conventional and uveoscleral pathways. Furthermore, these new compounds hold great promise as they may also target mechanisms other than IOP reduction that are thought to play important roles in the pathogenesis of glaucoma. Newer drugs acting specifically on the EP receptors have also widened the choice of prostaglandins. Many clinical studies focusing on PGAs with more targeted action and safety profile are ongoing. Recently launched new PGAs or those still in the pipeline offer new opportunities and future challenges. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.   Nil.   There are no conflicts of interest.   