Prostaglandin Analogs


Prostaglandin (PG) analogs, originally introduced for glaucoma therapy in the United States with latanoprost in 1996, have rapidly become the most commonly used ocular hypotensive agents. As a class, PG analogs are the most effective topical agents currently available for lowering intraocular pressure (IOP).1-4 Four PG analogs are available for clinical use: latanoprost (Xalatan 0.005%, Pfizer, New York, NY), travoprost (Travatan 0.004%, Alcon, Fort Worth, Tex.), bimatoprost (Lumigan 0.03%, Allergan, Irvine, Calif.), and unoprostone (Rescula 0.15%, Novartis Ophthalmics, Basel, Switzerland). All have similar structures and are prodrugs of prostaglandin F2a (PGF2a) analogs. The structures of these drugs are compared in figure 2.1. Latanoprost, travoprost, and unoprostone are ester prodrugs that are hydrolyzed by corneal esterases to become biologically active. Latanoprost and travoprost are selective agonists for the F2a prostaglandin (FP) prostanoid receptor. Bimatoprost has been described as a prostamide, although the structure is similar to that of the other two PG analogs. It has been shown to be an amide prodrug.5 The free acid of bimatoprost has a structure almost identical to the free acid of latanoprost, is a potent FP receptor agonist, and appears to be the active form of this drug.5-7 Unoprostone is an analog of a pulmonary metabolite of PGF2a, and the affinity of unoprostone for the FP receptor is 100-fold less than that of latanoprost. It has been demonstrated to be less effective than the other three analogs in clinical trials.8,9 Unoprostone was withdrawn from the U.S. market in 2004; however, it continues to be commercially available in Japan and in some other countries.

The first study to demonstrate a reduction in IOP after topical application of PGs was published in 1977.10 This study demonstrated that the dose is an important factor influencing the effect in rabbits, since other early studies on the ocular effects

Figure 2.1. Chemical structures of the prostaglandin analogs.

of PGs consistently showed that very high doses of topical or intracameral PGs raised IOP. Studies over the next two decades led to the development of a PG analog that was effective and well tolerated, and the development of other PG analogs followed.

Because their mechanism of action is different from most other glaucoma medications, PGs can produce a substantial additional reduction in IOP when added to treatment regimens consisting of other topical and/or systemic ocular hypotensive agents.

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