Prostaglandin derivates as ocular hypotensive agents

Low doses of naturally occurring prostaglandins reduce the intraocular pressure (IOP) in many species. Species differences do occur both in terms of efficiency and mechanism of action, and also among the different prostaglandins. Among the prostaglandins mainly PGF2 alpha has been tested in human eyes. Although it is an effective ocular hypotensive drug it is not clinically useful due to pronounced ocular side-effects, mainly conjunctival hyperemia and irritation, at doses that produce a maximal effect on IOP. Modification of the drug has resulted in two analogues that are now in clinical use, latanoprost and unoprostone. In long-term studies latanoprost, when applied as a once-daily dose of a 0.005% concentration, reduces IOP at least as effectively as adrenergic beta-receptor blockers. The reduction of IOP is due to increased outflow. This takes place mainly, or exclusively, through the uveoscleral routes, thus introducing a new pharmacological principle for the treatment of glaucoma. The drug reaches systemic concentrations that are below the level expected to stimulate FP-receptors outside the eye and it is rapidly eliminated with a half-life in plasma of 17 minutes, which explains why the clinical trials have not revealed any systemic side-effects with latanoprost. The most frequent side-effect observed with latanoprost is an increased pigmentation of the iris mainly in eyes with irides that are already partly brown. This effect is seen with several naturally occurring prostaglandins and is due to stimulation of melanin production in the melanocytes of the iridial stroma. No structural changes of the melanocytes have been observed in studies performed both in vivo and in vitro. The mechanism of action for unoprostone is the same as for latanoprost. No effect on iris colour has been reported for unoprostone but so far there is limited experience with the drug in eyes with a mixed iris colour.