iridial melanocytes that is required to reach the genetic maximum

level of pigmentation in an individual.221 This observation has been confirmed in rabbits with both unoprostone and latanoprost.228,229

Prostaglandins apparently stimulate the formation of extra melanin granules in the individual iris stromal melanocytes. There is no increase in the number of melanocytes and no effect at all on the iris epithelial melanocytes or melanin. The increased melanin

granules remain in the melanocytes without any evidence of shedding into the anterior chamber or trabecular meshwork.224,230 The

mechanism (at least in monkeys) may be related to an increase in tyrosinase transcription associated with latanoprost administration (at least); this increased transcription may be the cause of the increased melanogenesis.231 Evidence in tissue culture suggests that fibroblasts may play some role in the process.232

A large-scale, multicenter histopathologic study of iridectomy specimens from patients with and without a history of latanoprost treatment found an increase in iris freckles and fibroblasts in those with a history of latanoprost treatment compared to those without.233 The mean number of melanocytes was statistically similar between the two groups. No evidence of malignant or pre­ malignant changes were noted. Pfeiffer and co-workers randomly assigned a small number of patients awaiting trabeculectomy to 3 months of treatment with latanoprost or other antiglaucoma agents. They found no differences in cellularity at the end of the 3-month period between the two treatment groups.234 The same investigators performed a similar study only randomly assigning one eye to latanoprost for 6 months prior to trabeculectomy and immediate trabeculectomy in the fellow eye.At the end of 6 months, no histo­ pathologic differences were found between the two sets of eyes. Yet another histopathologic study compared iridectomy specimens from one eye which had been treated with latanoprost and had iris darkening with the iridectomy from the fellow eye unexposed to latanoprost treatment.235 This study failed to show any difference in numbers of melanocytes or numbers of melanin granules in the melanocytes between the latanoprost-treated and untreated eyes. The only difference was that the latanoprost-treated irides had larger melanin granules. The same group looked at concomitant trabecular pigmentation and found that, although trabecular pigmentation increases with age and with duration of primary open-angle glaucoma, no increase of trabecular pigmentation was

associated with latanoprost use even in eyes that had demonstrable darkening of the iris.236

Despite increased melanin in the melanocytes of the iris, there is no evidence that the condition leads to increased pigment shedding; the anterior chamber angle (especially the trabecular meshwork color) appears to remain stable over at least a 3-year follow-up.237 Because the iris melanocyte melanin granules are approximately onetenth the size of those in the epithelial melanocytes, they are easy to identify if they are shed. No effect of topical prostaglandin treatment has been detected on nevi, iris freckles, uveal melanocytes, melanocytes of the conjunctiva, or melanocytes of the skin of the eyelid.238 Because little is known about the effect of this increased iris melanocyte melanin over a period of decades, it seems prudent to monitor young patients as carefully as is practical when considering topical prostaglandin therapy, especially with those whose irides are at risk for color change or when single eye use is being considered.

Aside from headache, no systemic side effects of latanoprost, travoprost, bimatoprost, or unoprostone were reported in any of the phase III trials. However, a few patients report joint or muscle pains, dry mouth, backache, bitter taste, and allergic skin reactions.The prostaglandins are well tolerated by patients with asthma, although wheezing, and in rare cases asthma, has been reported in the post-market surveillance.239 Urge incontinence has been seen and confirmed with re-challenge.240 The reported side effects are summarized in Table 23-2.

Suggestions for use

The prostanoids as a group are very effective ocular hypotensive agents.They lower IOP in most patients with primary and secondary open-angle glaucoma. They are particularly effective compared to other classes of medications in reducing IOP in patients with normal-pressure glaucoma. The effectiveness of these agents is not affected by episcleral venous pressure, so they can be used in the glaucomas that are associated with elevated episcleral venous pressure such as dysthyroid ophthalmopathy and Sturge-Weber syndrome. They are also useful in the residual glaucoma following iridotomy in angle-closure glaucoma.

The prostanoids have become the primary medical treatment for both open-angle glaucoma and angle closure (after iridotomy if

due to papillary block), because of their relative potency compared to other classes of medications, once-daily dosing, general tolerability, and lack of serious systemic side effects. Except for unoprostone, they are all once-per-day medications which is helpful as for compliance. In fact the adherence with these agents far exceeds

that of other agents, although at about 70% at 1 year, there is room to improve this facet of therapy.241,242 Patients should certainly be

warned about the possibility of permanent iris color change and be monitored for it.

The hypotensive lipids theoretically should not work well in either primary or secondary angle-closure glaucoma (e.g., neovascular, iridocorneal endothelial syndrome) with extensive synechiae since aqueous does not seem to have access to the ciliary body band and thus the uveoscleral outflow route. However, experience has proven otherwise with good results in such conditions. In fact, in masked, randomized studies of patients with chronic angleclosure glaucoma, both latanoprost and bimatoprost lowered IOP

better than timolol and as well as might be expected in open-angle glaucoma.243–246 Furthermore, the degree of angle closure seems

not to affect the pressure-lowering ability of these agents.247

The prostaglandin-like agents are not additive to each other.248 However, all of these agents are additive to all other antiglaucoma medications available today. Other medications can be added to it in a regimen, or it can be added to pre-existing medications. The

most synergistic effect seems to be with the topical carbonic anhydrase inhibitors.249,250 However, one study, at least, shows equivalent

effect from adding either brimonidine or dorzolamide to latanoprost.251 Often, only 1–2 mmHg is gained by adding -blockers to prostanoid therapy which is roughly the average difference in IOP between latanoprost and bimatoprost; in fact, bimatoprost alone as monotherapy seems to have the same IOP effect as combined latanoprost and timolol treatment with fewer respiratory side effects.252 Timolol has been added to latanoprost (as well as travoprost) in a fixed combination (Xalcom™); the fixed combination is as effective as the drops given separately. Although efficacy is not improved over the non-fixed concomitant drops, it is hoped that the oncedaily dosage of the fixed combination would improve adherence/ compliance compared to the separate use.253–255 A travoprost/timolol

combination has shown clinically significant improvement in IOP over travoprost alone.256,257 The prostaglandin agents are additive to

brimonidine and vice-versa. Little additional effect on IOP can be expected when adding cholinergics to a regimen that already contains latanoprost – although in desperate situations it may be worth a try. Adding latanoprost to a regimen that already contains cholinergic agents may produce a significant further reduction in IOP.

While two randomized, masked, prospective studies in general glaucoma patients showed little practical differences among latanoprost, travoprost, and bimatoprost, most studies have shown a slight

average advantage in IOP lowering with travoprost and bimatoprost (in both blacks and other groups).122,123,125,141,258 The Kaiser

Permanente Medical Group, California’s largest health maintenance organization, switched patients from latanoprost to bimatoprost for

cost reasons; the switch was well tolerated by 85% of the patients and there was a slightly lower IOP with bimatoprost compared to latanoprost.259 In a prospective study, greater than 95% of patients tolerated a switch from latanoprost to travoprost without significant side effects or change in efficacy.260 Two studies have shown

some advantage of using bimatoprost in patients not controlled on latanoprost.119,126 A recent retrospective study of a large health

plan database showed that patients are more likely to need adjunctive medication with latanoprost than with either bimatoprost or travoprost.261 Other evidence suggests a greater cost-effectiveness

in reaching target pressure with bimatoprost compared to latanoprost.262,263 The Ocular Hypertension Treatment Study was unable

to show any difference in effectiveness of the prostaglandin analogs based on race.264 In separate studies, both travoprost and bimatoprost have been shown to be slightly superior to latanoprost in exfoliative glaucoma patients.265

In all studies, the incidence of hyperemia is higher with both travoprost and bimatoprost than latanoprost. Therefore, on average, there may be little to choose between the agents. However, based on the above, when all other things are equal (e.g., cost, accessability, acceptability of side effects), latanoprost is a good agent to try first as monotherapy in newly diagnosed glaucoma, but if it does not adequately lower the IOP, then bimatoprost or travoprost should be tried before resorting to multiple agent therapy. Travoprost may be the best agent if adherence to the treatment regimen is in question since it seems to be more forgiving to occasional forgotten doses.

Some evidence suggests that concomitant use of non-steroidal anti-inflammatory agents, either topical or oral, may reduce the pressure-lowering effect of latanoprost.266

Because of their propensity to exacerbate (or possibly cause) uveitis, prostanoids should be used with extreme caution in those patients with active uveitis or a recent history thereof. Patients with a remote history of uveitis should be monitored closely in the first few months of treatment. In addition, latanoprost should be used with great caution in those with active or recent cystoid macular edema or high risk factors for it (e.g., aphakia, recent cataract surgery, vitrectomy or discission, retinitis pigmentosa, active diabetic retinopathy). If any of these agents are used, both the patient and the doctor should monitor vision closely, and the fundus should be carefully perused periodically for signs of macular edema. Ocular coherence tomography is a useful adjunct in this monitoring. At the first sign of vision decrease that could be ascribed to cystoid macular edema or anatomic evidence of macular edema, the prostanoid should be discontinued.

The three major agents, latanoprost, travoprost, and bimatoprost, are best used as a once-daily dose given in the evening. Latanoprost seems to be more effective when given in the evening than when given in the morning over the first 6 months of treatment.63 After 6 months of evening dosing, 69% of the patients had IOPs less than 17 mmHg, whereas only 34% of those with morning dosing had IOPs under 17 mmHg. Subsequent data suggest that after 3 months of treatment, morning and evening dosing produces the same results. Presumably (but not proven), the same could be said for bimatoprost; however, travoprost seems to perform slightly better when administered at night (see above). If the medication is to be used over a long period of time and compliance is a problem, consideration should be given to morning dosing. For all of these agents (except unoprostone), twice-daily dosing is probably less effective than once daily, possibly because of the development of receptor tolerance.56 If the evening dosing is chosen, within 1 or 2 months after initiating therapy, IOP should be checked late in the day to see if the effect holds over the full 24 hours. If it does not,

consideration should be given to switching to travoprost which seems to have a somewhat longer duration of action.267 Similarly, if morning dosing is chosen, IOP should be checked early in the morning before instilling the drop.

Patients should be counseled that the bottle in which latanoprost is sold is made of a soft plastic unlike that of other eyedrop preparations with which he or she may be familiar.The bottle is designed to deliver one drop by simple gravity when held upside down or by gently tapping on the bottom; squeezing the bottle will produce a rivulet of medication on the cheek – an expensive waste. If a patient has arthritis or otherwise has difficulty maneuvering the bottle properly, Pfizer has available a trigger-operated dispenser that some of these patients find quite useful in delivering just one drop (XalEase™). Other companies have similar aids for drop delivery. Different manufacturers’ bottles may require slight modification of instillation for most efficient use.268

The latanoprost (Xalatan™) bottle should be refrigerated if it will be open for longer than 6 weeks. This is usually not a problem unless the solution is used unilaterally or the patient maintains more than one open bottle at a time. Latanoprost is subject to deterioration when exposed to heat over 100°F for longer than 8 days (Xalatan package insert, Pfizer, NY). The other prostanoids seem to be somewhat more stable at temperatures likely to be found in most natural settings. All agents may deteriorate at an accelerated pace when exposed to direct sunlight.

Isopropyl unoprostone (Rescula™) is significantly less potent than latanoprost. It must be used twice daily. It may be somewhat better tolerated, with fewer and milder side effects, but this has not been tested in a side-by-side comparison. Because of its relatively low potency, unoprostone is not used much in the United States although it may be useful if pressure reduction goals are modest.The indications and cautions for the other agents apply to unoprostone as well.

The fixed combinations of a prostanoid and timolol do not seem to offer much additional pressure lowering over the prostanoids themselves except in an occasional patient. In fact, one study showed bimatoprost to be at least as good as the fixed combination of latanoprost and timolol.269 When adjunctive therapy is needed, better clinical results seem to be had using either a carbonic anhydrase inhibitor or brimonidine concomitantly with the prostaglandins rather than a -blocker.270 Not all studies agree that timolol adds relatively little to the pressure-lowering effect of the prosta­ glandins;271 therefore, after bimatoprost has been tried and is still not controlling the IOP, one of the prostaglandin/timolol combinations may be tried, especially if the patient would benefit from the convenience and adherence-enhancing effect of a single drop.

Hyperemia is a frequent side effect but often lessens after a few weeks. Patients should be notified about this so that they do not become alarmed. If the patient is warned, the hyperemia rarely is a cause for discontinuation of the medication. Iris color should be monitored by patient and doctor. Baseline photographic documentation may be helpful to detect early changes. Patients with graybrown, blue-brown, hazel, or green-brown irides should be warned about iris color change and its permanence. If cosmesis is a concern to the patient, consideration should be given to alternative medications if possible. Similarly, patients should be warned that their eyelashes may grow longer and darker and may proliferate. Most patients will not mind this at all, but, again, if it may be a problem, consideration should be given to an alternative. Occasionally, patients may have to trim their lashes in order to prevent rubbing on the inside of spectacles. Because an increase of eyelid hair and