As mentioned above, the major risk factor for POAG is elevated IOP, and thus drugs that reduce IOP represent the mainstay treatment for glaucoma at present (Figure 6). Drugs that reduce AH production include ^-adrenoceptor antagonists (e.g., timolol, betaxolol, and levobunolol), a2-adrenoceptor agonists (e.g., brimonidine and apraclonidine), carbonic anhydrase inhibitors (e.g., dorzolamide and brinzolamide), and the rarely used Na/K-ATPase inhibitors (e.g., ouabain). The practice of medicine continues to limit the use of such inflow reducing drugs, as AH is important for the nourishment of the anterior chamber tissues. However, b blockers and carbonic anhydrase inhibitors are often prescribed first, partly because of their relatively lower cost, to begin treatment for ocular hypertension with a subsequent switching to use of drugs that enhance AH efflux. Conventional outflow-promoting drugs include muscarinic cholinergic agonists (e.g., pilocarpine), while uveoscleral outflow promoting drugs are represented by FP-class prostaglandins (e.g., latanoprost, travoprost, bimatoprost, and unoprostone isopropyl ester). Presently, the FP-class prostaglandins are the primary drugs of choice for treating ocular hypertension and glaucoma when cost is not an issue. The latter drugs work by liberating MMPs from the ciliary muscle cells (and perhaps from TM cells) that digest the ECM and help the AH egress via the uveoscleral pathway and, to a small degree, via the TM conventional outflow pathway.

Attempts have been made to combine both inflow- and outflow-enhancing drugs, primarily using timolol and an FP prostaglandin analog, thereby maximizing IOP reduction. However, the FDA has not approved such a combination use of such drugs, even though a combination of latanoprost and timolol is approved for glaucoma treatment in Europe, Canada, and Australia.

The mechanism of action of bimatoprost, the ethyl amide of 17-phenyl-PGF2a, despite the fact that it is structurally related to PGF2a (Figure 6). An uncharacterized so-called 'prostamide receptor',61 through which bimatoprost exerts its IOP-lowering action, is thought to exist.62 Other investigators contend that bimatoprost is simply a pro-drug that is hydrolyzed in the eye to liberate the potent FP-receptor agonist, bimatoprost free acid (17-phenyl-PGF2a), which then activates the classic FP PG receptor to lower IOP.62

Those patients whose IOP is not controlled by drugs become candidates for surgical treatments in order to reduce the IOP and thus slow down their vision loss. Laser trabeculoplasty involves creating holes in the TM to promote AH drainage to lower the IOP. A recent in vitro study demonstrated that femtosecond laser photodisruption of human TM could create holes in the TM without collateral damage.63 Glaucoma filtration surgery is usually the last resort and involves creating a fistula of the scleral tissue to the conjunctiva (the 'bleb') to promote drainage of the AH from the anterior chamber. While such surgery is very effective in lowering IOP, the patency of the bleb is often compromised and limited by the body's healing mechanism, which tends to cover up the drainage hole and eventually leads to elevation of the IOP again. Since the IOP cannot be regulated there is often a danger of anterior segment collapse. Drugs to prevent or slow down the local healing process in the bleb, such as mitomycin C or 5-fluoruracil (Figure 7), and thus keep the drainage pathway open show promise but have a narrow therapeutic index. However, agents that would release MMPs locally to keep the bleb open would be useful adjuncts to the surgical procedures in the future for reducing and maintaining the IOP at an acceptable level.

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