The prostaglandins burst on the clinical scene in the 1990s and have become one of the mainstays of glaucoma treatment around the world. As a class, they are very potent intraocular pressure (IOP) lowering agents with a unique mechanism of action ( Fig. 23-1 ). Prostaglandins are hormones that are produced, released, and effective locally; such agents are called autocoids. The prostaglandins are members of a family of substances called eicosanoids, which also include, among others, prostacyclin, thromboxane, and leukotrienes. Prostaglandin was first identified in seminal fluid in the 1930s. In 1955, Ambache identified a substance in iris tissue that he called irin and that seemed to mediate the ocular response to irritation. This extract induced miosis when injected into the anterior chamber and probably contained prostaglandins, as well as other substances. This was the first non-reproductive system source for this family of local hormones that are now known to be present throughout the body.
MECHANISM OF ACTION
Prostaglandins were first thought to mediate inflammation in both the eye and other tissues. High doses injected into the anterior chamber of rabbits produced signs of inflammation such as hyperemia, breakdown of the blood–aqueous barrier, and increased IOP. It soon became clear that the prostaglandins were synthesized by trabecular endothelial cells and by ciliary muscle cells from membrane phospholipids and arachidonic acid and released by several different ocular tissues during inflammation. Ocular tissues produce not only the prostaglandins E and F but also other eicosanoids.
Many of the initial observations regarding the inflammation-mimicking effect of prostaglandins may have been due to the experimental techniques themselves (e.g., intraocular cannulation), the use of the very sensitive rabbit eye as the experimental model, and the rather high doses of injected prostaglandins used. Other mediators such as neuropeptides, interleukins, and platelet-activating factor appear to play a more significant role in the actual inflammatory process. Current thought relegates prostaglandins to ‘a minor, mostly regulatory, role’ in ocular inflammation in primates. In fact, prostaglandins may have some anti-inflammatory action because they may downregulate some aspects of the inflammatory response. Furthermore, because at least some prostaglandins improve uveoscleral outflow, these agents, when released during inflammation, may provide an alternate pathway for clearing the anterior chamber and uvea of inflammatory products.
Because of the experimental observation that topical prostaglandins produced first an increase, but later a profound decrease, in IOP, and because of the clinical observation that intraocular inflammation was often accompanied by low IOPs, work began to determine if one or more of the prostaglandins might be of value in glaucoma. Initial studies in rabbits showed that low doses of topical prostaglandins could reduce IOP in rabbits for as much as 20 hours. Using a relatively high topical dose of prostaglandin F 2 (PGF 2 ), Camras and Bito produced a reduction in IOP in monkey eyes lasting for up to 3 days. This reduction seemed to be due to an increase in outflow facility without significant effect on aqueous formation, trabecular outflow facility, or episcleral venous pressure. In low doses, PGF 2 and other analogs were found to produce a very potent hypotensive response – capable of lowering IOP in monkey eyes to 5 mmHg without the initial hypertensive phase and without effects on refraction or pupil size.
Considerable species differences exist in the magnitude of response to prostaglandins and, perhaps, even the mechanism of the pressure lowering and the role of prostaglandins in inducing inflammatory signs. Some prostaglandins even raise IOP in some species. Like the situation with adrenergic agents, several different prostaglandin receptor types exist. For example, five different human prostaglandin receptor types have been positively identified; DP, EP, FP, IP, and TP. Additionally, several subtypes of EP are now known. The same ocular tissues in different species may have different receptors, and the receptors may mediate different functions. Prostaglandins A, D, E, and F have been studied for their pressure-lowering effect. It appears that, in primates, the agents that affect the EP 3 and FP receptor types (i.e., those responsive to prostaglandins E and F) seem to be the most effective in lowering IOP. In addition, primates are much less likely than rabbits and cats to show a breakdown of the blood–aqueous barrier in response to prostaglandin application. EP and FP receptors have been found in the ciliary body and in the trabecular meshwork of primates. All of the currently available clinical agents have shown agonist activity at a cloned human FP receptor.
Further studies show that the increase in outflow facility produced by prostaglandins, at least in primates, is due to increasing the flow through the uveoscleral pathway. The increased uveoscleral outflow was confirmed with the use of tracer substances in primate eyes. Studies in humans are confirmatory.
Prostaglandins appear to alter not only the function of the uveoscleral pathway(s) but also the structure. Lütjen-Drecoll and co-workers have shown that prostaglandins produce extracellular matrix remodeling, widening of intermuscular spaces along the longitudinal ciliary muscle bundles, and dissolution of collagen types I and III. Another study using cultured human trabecular cells showed extensive remodeling of the extracellular matrix around these cells; specifically, there was reduction in both the density and the branching of type IV collagen and laminin, as well as a reduction in the density of type III collagen. Other studies have shown an increase in the space between ciliary body muscle bundles induced by all the currently available clinical agents in this class. The loss of extracellular matrix in the uveal tract may be related to the increase in production of metalloproteinases associated with administration of the appropriate prostaglandins. Latanoprost induces matrix metalloproteinase I activity in the non-pigmented epithelium of the ciliary body; this upregulation may account for its action on the uveoscleral outflow system. The observed ulstrastructural changes are most likely the anatomic counterpart to the functional improvement in uveoscleral outflow associated with the clinical use of the prosta-glandins. While improvement in uveoscleral outflow may be the most obvious mechanism by which these agents work, studies at the cellular level suggest that some other intracellular metabolic changes may also contribute to the overall effect.
All prostaglandin and prostaglandin-like agents seem to be changed as they traverse the cornea. For some like latanoprost, it is the acid ester that is created during the transit across the cornea that becomes the active ingredient. For others, it is not clear whether it is the molecule itself or a metabolic product that does the job. Evidence does point to the fact that these agents can definitely get across the sclera directly and perhaps even facilitate this pathway.
There are two other agents whose potency and clinical activity seem to suggest similar prostaglandin activity. Travoprost seems to work directly on the FP receptors just as latanoprost does. However, controversy exists as to the exact mechanism of action of bimatoprost. While clinically it seems to work in the same way, evidence suggests that there may be some differences in the way it acts. Bimatoprost by itself seems to have little effect on prostaglandin receptors. The manufacturer of bimatoprost has significant evidence that it is derived, at least in part, from and mimics the action of a seemingly parallel group of autocoids called prostamides. These hypotensive lipids are derived from the endocannabinoid family. Bimatoprost also seems to inhibit enzymes that metabolize prostaglandins. Further evidence to support the theory that bimatoprost may not act exactly the same as latanoprost stems from the fact that, whereas latanoprost and travoprost seem to work mainly by increasing outflow via the uveoscleral outflow pathway, bimatoprost also seems to increase outflow through the pressure-sensitive (i.e., trabecular) pathway. On the other hand, research from a rival company’s laboratories suggested that all of the currently available agents are direct prostaglandin FP agonists in tissue cultures of human trabecular meshwork cells. Furthermore, investigators affiliated with yet another rival company found enough free acid of bimatoprost in the anterior chamber of patients undergoing cataract surgery to explain its IOP-lowering effects. Finally, an independent study showed that cornea, sclera and other ocular tissues do hydrolyze bimatoprost to its free acid which is a potent FP2a receptor agonist and that enough hydrolysis occurs to explain its action. Because of the lack of clarity as to the mechanism of action of bimatoprost and perhaps unoprostone, the terms ‘prostanoids’ and ‘hypotensive lipids’ have been used to designate the entire group. Whether these terms are more accurate than the simpler ‘prostaglandins’ remains to be determined. Clearly, the solution of this controversy awaits some definitive studies to determine if bimatoprost is: 1) a compound that acts on a different set of receptors (e.g. prostamides) than the other prostaglandin-like agents; 2) a prodrug which is metabolized by the cornea into its free acid which is a potent FP receptor and, therefore, acts like the other agents, or 3) some combination of these. For the time being, this text will assume that they all have some common pathway since this does fit the clinical observations. The term ‘prostanoid’ will be used to designate the group of agents that have prostaglandin agonist-like activity.
Isopropyl unoprostone, a weaker chemical cousin with some unique properties, seems to also work by increasing cellular metalloproteinases and improving uveoscleral outflow via the extracellular, interciliary body muscular bundles. Similar anatomical findings occur after chronic treatment with any of these agents. Unoprostone has been placed in the class of agents called docosanoids.
DRUGS IN CLINICAL USE
Although the pressure-lowering effects of the prostaglandins have been known for almost two decades, it took almost that long to find analogs that were both effective and tolerable as far as side effects are concerned. The first prostaglandin analog to be tried in humans was prostaglandin F 2 -tromethamine salt (PGF 2 -TS). Although this agent lowered IOP, significant conjunctival hyperemia, stinging, foreign body sensation, and headache occurred in over one-third of patients.
The first usable prostaglandin was developed in Japan. Isopropyl unoprostone (Rescula) is a prodrug that is derived from a pulmonary metabolite of PGF 2 , lowers IOP in a dose-dependent fashion with twice daily dosing, and is well tolerated.
Major progress was made with the development of a 17-phenyl-substituted PGF 2 -isopropylester (PHXA34), which is considerably more potent than the PGF 2 without the phenyl substitution. A single dose of this agent lowered IOP by up to 5 mmHg in normal patients, and by about 40% in ocular hypertensive patients, for over 24 hours with very few side effects. Furthermore, the pressure lowering was maintained for at least a week with acceptable side effect levels. PHXA34 is an epimeric mixture. The 15-R epimer is ten times more potent than the 15-S epimer and two times more potent than the mixture. PHXA41 (latanoprost) has the same chemical structure as PHXA34 but is a solution of only the R epimer. One would expect it to be more potent, and it is!
LATANOPROST (XALATAN, PHXA41)
Latanoprost (Xalatan™ Pfizer, New Jersey) is a very potent IOP-lowering medication and has become one of the most useful antiglaucoma agents. In initial trials, latanoprost 0.005% reduced IOP by 25–35% with a single daily dose. The 0.005% dose seems to be the most efficient with the best balance of efficacy versus side effects. Furthermore, unlike most drugs, more is not better; once-daily dosage appears to be superior to twice daily. At least during the first few months of use, an evening dose seems to be slightly superior in lowering morning IOP than a morning dose.
Several multicenter, controlled, randomized clinical trials in Scandinavia, the United States, the United Kingdom, and Japan showed topical latanoprost 0.005% once daily to compare favorably with timolol maleate 0.5% twice daily. In the Scandinavian study, latanoprost once daily was equal to timolol twice daily in general pressure-lowering activity if the dose of latanoprost was given in the morning. If the dose was given in the evening, then latanoprost was more effective in lowering the IOP than timolol. In the other studies, latanoprost produced a sustained decrease of 25–30% in IOP and was slightly more potent in reducing IOP than timolol, especially after 4 months of treatment. Latanoprost produced a higher incidence of conjunctival hyperemia than timolol, but the hyper-emia was mild in all cases. No patients developed miosis or signs of intraocular inflammation. Latanoprost had no effect on heart rate or blood pressure, whereas timolol did slow the pulse an average of 2–3 beats per minute. After 1 year, latanoprost maintained good IOP control in patients switched from timolol with return of heart rate to pre-timolol baseline. Latanoprost is superior in pressure lowering to once-daily timolol gel throughout the day from 8 am to 12 midnight. Latanoprost has also been shown to be superior in diurnal IOP control to brimonidine. In a study comparing latanoprost with timolol, betaxalol and brimonidine, latanoprost had the best IOP-lowering effect, the least systemic side effects, and very few significant local side effects. Latanoprost has been shown to have no adverse effect on the respiratory system, even in patients with significant, steroid-dependent asthma.
In addition, the latanoprost-induced pressure drop and increase in uveoscleral outflow persist over 24 hours, unlike the timolol-induced decrease in aqueous formation, which is lost at night. Latanoprost effectively flattens the diurnal curve and is effective throughout the night in contrast to timolol which is not. Like all other known ocular medications reducing IOP, latanoprost has no effect on the increase in IOP occurring when assuming the supine position. When the phase III trials from the United States, Scandinavia, and the United Kingdom were combined and the patients followed for 1 year, not only was the effectiveness of latanoprost maintained with little evidence of drift, but the pressure control was not affected by race, eye color, sex, or age. Even over a 2-year period, there is no evidence of tachyphylaxis. Recent evidence suggests that all antiglaucoma medications may be inhibited in their action by thicker corneas. True non-responders to latanoprost are unusual, occurring about 4–10% of the time; however, the number of non-responders among Japanese patients with normal-tension glaucoma is as high as 20%.
Latanoprost is rapidly converted by the cornea into its acid which appears to be the active ingredient. Therefore, latanoprost should be considered a prodrug. It reaches a maximum concentration in the aqueous humor 1–2 hours after topical application with a half-life of 2–3 hours. It reaches maximum concentration in the bloodstream in 5 minutes with a half-life of 17 minutes. Even in chronic users, the plasma levels are often undetectable. The acid is oxidized outside the eye; it is mostly excreted via the urine with a small amount eliminated in feces.
Several studies have shown that latanoprost has no effect on the blood–aqueous barrier as measured by flare meters and by fluorescein leakage into the anterior chamber after systemic administration. Even after long-term use, no effect on the blood–aqueous barrier could be found. In fact, timolol seemed to produce a higher concentration of protein in the anterior chamber than latanoprost. However, one study was able to show an adverse effect on the blood–aqueous barrier. Latanoprost seemed to be unaffected by concurrent oral administration of non-steroidal anti-inflammatory agents in one study; however, further studies have suggested that concurrent administration of either an oral or topical non-steroidal anti-inflammatory agent may produce a slight but definite reduction or increase in the effectiveness of latanoprost. Either the effect on latanoprost of this class of drugs is agent specific or there are as yet unkown factors affecting the relationship. No effect of latanoprost (or timolol) on bloodflow velocity was noted using color Doppler imaging of the retrobulbar blood vessels. Conversely, in normal patients, latanoprost did increase the pulsatile blood flow whereas timolol had no effect. The same clinic reported in another study that glaucoma patients show an increase in pulsatile blood flow and also retinal microcirculation with latanoprost. In yet another study of normal-pressure glaucoma patients, once-daily latanoprost 0.005% was shown to significantly lower the IOP and increase the ocular perfusion pressure, whereas timolol did not significantly change the ocular perfusion. In this report, once-daily latanoprost 0.005% appears to be the most potent ocular hypotensive agent for patients with normal-pressure glaucoma among the β-blockers, α agonists and carbonic anhydrase inhibitors. The drug is also effective in pigmentary glaucoma despite its propensity to increase pigment granules in the iris (see below). Furthermore, it is effective in steroid-induced glaucoma. While latanoprost may be very effective in some pediatric patients, it seems to be effective in fewer pediatric patients than in adults, although the nature of some pediatric glaucomas may be more the problem than the age of the patients.
Because latanoprost (and the other PGF 2 analogs) works by significantly increasing the outflow of aqueous through the uveoscleral pathways, its effects on IOP should be additive to any agent that decreases aqueous formation. PGF 2 -isopropylester is additive to β-blocker therapy, causing a further decrease in IOP of 17% compared with timolol alone. In a subsequent study of patients whose conditions were uncontrolled with timolol, the addition of PGF 2 -isopropylester reduced IOP an additional 6–9 mmHg below the level produced by timolol alone. Similar results were obtained in studies with latanoprost producing a 13–17% reduction in IOP compared with timolol alone. In patients whose IOP was not controlled under 25 mmHg with timolol, adding latanoprost reduced the IOP by 28–37% over 3 months. However, not all patients respond to latanoprost; as many as 25% will demonstrate little or no reduction of IOP. A similar lack of response in some patients is seen with most other antiglaucoma agents. A fixed combination of latanoprost and timolol has been tested and found to be marginally better than latanoprost alone and significantly more effective in lowering IOP than timolol alone.
Latanoprost is also additive with carbonic anhydrase inhibitors. In a double-masked study, adding topical latanoprost to the regimen of patients already taking 250 mg of oral acetazolamide twice daily produced a 21% drop in IOP. Latanoprost is also additive to topical carbonic anhydrase inhibitors. Latanoprost is also additive with topical adrenergic agonists. Two studies, one in England and one in Sweden, showed that latanoprost added to dipivefrin therapy reduced IOP about 28–32% and, conversely, that adding dipivefrin to latanoprost therapy produced a further reduction in IOP of 15–35%. Studies on the additivity of latanoprost with the α-adrenergic agonists have not been reported; however, the authors’ experience strongly suggests that they are additive to each other.
Adding a prostaglandin analog to topical cholinergic therapy may be more problematic, at least theoretically. Cholinergic agents reduce IOP by direct stimulation of the ciliary muscle whose contraction opens the trabecular meshwork and improves trabecular outflow. At the same time, cholinergic stimulation reduces uveoscleral outflow, possibly by reducing the spaces between the muscle fibers. Therefore pilocarpine or other cholinergic agonists could inhibit the action of prostaglandins on the uveoscleral outflow system. Several studies suggest that this is not a problem clinically. In the first, a single-dose study, one drop of latanoprost added to a 3-day regimen of pilocarpine produced a further mean reduction of IOP of 3.3 mmHg. In another study, latanoprost was more potent as an ocular hypotensive agent than pilocarpine 2%. In this same study, adding latanoprost to pilocarpine treatment produced a further reduction in IOP of 2.7 mmHg, whereas adding pilocarpine to latanoprost produced only an average additional pressure reduction of 1.5 mmHg. In a study of normal volunteers, adding latanoprost to the potent cholinergic agonist physostigmine produced additional lowering of pressure in normal volunteers. Toris and co-workers found that pilocarpine did not inhibit the uveoscleral outflow improvement associated with latanoprost. However, in monkey eyes, the combination of miotics and at least one prostaglandin did reduce the effect on the uveoscleral outflow.
A generic latanoprost is available in India and should be in the US by 2011. A study of the generic agent available in India indicated that it did not exhibit equivalent pressure-lowering activity as the branded latanoprost (Xalatan®). Whether or not this observation will be generalizable to other generic agents has yet to be demonstrated.
In summary, topical latanoprost was the first of the potent prostaglandin ocular hypotensive agents. It has been shown to be better than any of the other classes of drugs in terms of monotherapy, with additivity to most, if not all, of the other types of ocular hypotensive agents.
Bimatoprost (Lumigan™ Allergan Inc., Irvine, CA) is a relatively new prostaglandin F2α analog where the carboxylic acid is replaced by a neutral ethylamide; the agent has little direct effect on prostaglandin F2α receptors. Numerous studies have shown its effectiveness in lowering IOP and its superiority in maintaining 24-hour control compared to timolol and dorzolamide. Like its chemical cousin, bimatoprost as monotherapy seems to be superior in flattening the diurnal curve to timolol alone and to timolol combined with dorzolamide.
Most published studies to date have shown that when compared to latanoprost, bimatoprost seems to offer slightly improved pressure control or works in a greater percentage of patients. In addition, bimatoprost seems to have a slight edge in IOP control over travoprost. Furthermore, bimatoprost seems to have a slight advantage in those of African heritage although both travoprost and bimatoprost are effective in lowering IOP in that group. In a head-to-head randomized comparison of all three major prostanoid agents used for 6 months, Noecker and co-workers found a statistically significant but clinically small advantage for bimatoprost over both latanoprost and travoprost. A meta-analysis of four controlled comparative studies revealed that bimatoprost seemed to improve pressure control by about 1–1.5 mmHg over latanoprost.
In contrast, another head-to-head comparison for 3 months failed to confirm any significant difference in IOP control between the three agents. A study by one of the authors of this book in patients uncontrolled on latanoprost showed about one-third were brought back under control when bimatoprost was substituted for latanoprost. Several studies support the fact that bimatoprost may be the most cost-effective agent since it has the greatest chance of reaching target pressure without needing adjunctive agents.
The preponderance of studies do seem to support a slight IOP advantage of bimatoprost over latanoprost. Most likely, in the average patient, this is not a clinically significant difference. However, in many, it might make enough of a difference to warrant a trial of bimatoprost if latanoprost is not as effective as desired. All of the above studies do agree that there is a higher incidence of hyperemia with bimatoprost and travoprost than latanoprost; it also appears that a somewhat larger percentage of patients have troublesome local side effects with bimatoprost compared to latanoprost.
In summary, bimatoprost, whatever its exact mechanism of action, seems to be, by a slight margin, the most potent of these agents but with a concomitant increase in local side effects.
Travoprost (Travatan™, Alcon Laboratories, Ft Worth, TX) is the isopropyl ester of a potent prostaglandin F2α agonist. It is hydrolyzed into the active agonist by the cornea and sclera and thus, like its cousins, is a prodrug. Travaprost is a highly selective FP receptor agonist. Like latanoprost, it is a very effective agent when used once daily for lowering IOP in most species including human; unlike latanoprost, it is more effective when used twice daily compared to once daily but, of course, side effects, especially conjunctival hyper-emia, increase proportionately when that happens. Like latanoprost, travoprost works by improving outflow facility; it is not clear how much of this is via trabecular and how much is via uveoscleral outflow. It seems to make little difference if the once-daily dosage is applied in the morning or evening although there is a slightly greater effectiveness when the dose is given at night, both in controlling the daytime IOP and limiting the fluctuation of IOP.
The obligatory studies comparing travoprost to timolol showed that both the 0.0015% and 0.004% solutions were superior in pressure-lowering activity by about 2 mmHg over 9 months versus timolol. In this study of over 500 patients, travoprost did produce more hyperemia, itching, eye pain, and iris color change than timolol, but by and large the complications were tolerable. Similar results were obtained from a second prospective, randomized, masked study in the US. In both studies, timolol slowed the pulse and reduced the blood pressure whereas travoprost had no effect on either. There were no other statistically significant differences between the two agents.
Compared to latanoprost, travoprost shows similar IOP levels over a 24-hour period but may have a greater duration of action – over 40 hours from a single dose. If a dose is missed, the effect on IOP is attenuated during the day but seems to be sustained during the nocturnal period when the pressure may be the highest. As with bimatoprost, some patients uncontrolled with latanoprost may get improved control when switched to travoprost. In a prospective randomized controlled study, Netland and co-workers found travoprost to be at least equal to (and perhaps slightly superior to) latanoprost and superior to timolol. In a retrospective analysis of these data, they concluded that travoprost was superior to both latanoprost and timolol in black patients. The same authors did a retrospective meta-analysis of two large studies and came to the same conclusion. A prospective, controlled and masked study in black patients took this concept one step further; it found that travoprost not only was superior to both timolol and latanprost in reducing IOP, but it was less likely to result in visual field progression in these patients. This difference in response between black and white patients has been seen with other autonomic-related topical agents. A similar analysis of bimatoprost data concluded that bimatoprost was equally effective in black and white patients and slightly more potent in that group than travoprost.
As of this writing, travoprost is the only prostaglandin-like agent that is available with a different preservative than benzalkonium chloride (BAK) (Travatan Z™). The BAK-free travoprost may be particularly useful in those patients who are showing evidence of BAK toxicity and in those on multiple medications with ocular surface disease whose condition may be exacerbated by large doses of BAK. Like the other prostaglandin and prostaglandin-like agents, travoprost works well with timolol and other topical antiglaucoma medications. In summary, travoprost is an effective and relatively safe prostanoid.
ISOPROPYL UNOPROSTONE (UF-021, RESCULA™)
As noted previously, isopropyl unoprostone (Rescula™, Ciba Vision Care/Novartis, Duluth, GA) is a prodrug derived from a pulmonary metabolite of PGF 2 . It reduces IOP in normal volunteers without significant side effects for at least a 2-week period. In a large trial of patients with elevated IOP, twice-daily unoprostone given over a 12-week period reduced IOP by about 5 mmHg from baseline at 4 hours post dosing; this was equivalent to the effect produced by timolol twice daily. Although there was no effect on blood pressure in the unoprostone-treated group, 4% of patients developed mild conjunctival hyperemia. The timolol group showed significant episodes of decreased blood pressure. In a 1-year study by the same multicenter group, patients with glaucoma or ocular hypertension were randomly assigned to either 0.06% or 0.12% of unoprostone twice daily. Both groups showed a rather high 32–46% dropout rate – many for inadequate IOP control. Of those still in the study at 1 year, those in the 0.06% group had an average IOP drop from baseline of 3.4 mmHg, and those in the 0.12% group had an average IOP drop of 4.5 mmHg. All of these studies measured IOP 2–6 hours after dosing and did not measure the crucial ‘trough’ pressure before the next dose was due. In a randomized, masked study, unoprostone isopropyl 0.15% used twice daily reduced IOP in open-angle glaucoma patients but not quite as much as either timolol or betaxolol. Several studies have shown unoprostone to be weaker than latanoprost. Furthermore, adding unoprostone to latanoprost does not augment the effect of latanoprost while, as might be expected with a more potent agent, adding latanoprost to unoprostone produces the maximum effect expected from latanoprost alone.
Side effects included a dose-dependent conjunctival hyperemia, corneal epithelial defect, and headache. Increased iris pigmentation occurs but at lower frequency than latanoprost. Some side effects may have been related to the preservative rather than unoprostone. The higher dose was also associated with two cases each of dry mouth and paresthesia. On the basis of these studies, isopropyl unoprostone was approved for use as an antiglaucoma agent in Japan and was, in fact, the first prostanoid approved for clinical use in the world.
Like the other prostanoids, unoprostone appears to work by improving the outflow facility through the uveoscleral outflow system. Unoprostone also prevented IOP spikes following laser trabeculoplasty in rabbits.
In normal volunteers, a single drop of unoprostone in one eye had no effect on IOP, blood pressure, heart rate, or pulsatile ocular blood flow. On the other hand, timolol reduced IOP in both eyes (more in the treated eye) but also reduced pulsatile ocular blood flow, blood pressure, and heart rate. In patients with glaucoma, unoprostone 0.15% twice daily also seems to increase pulsatile blood flow although not as much as latanoprost 0.005% once daily. What pulsatile blood flow as measured by today’s technology means and what its implications are for the care of glaucoma have not been elucidated.
FIXED COMBINATION AGENTS
All three major prostaglandin analogues have been combined in a single bottle with timolol. In all three cases, the combination does as well or even slightly better than when the two drugs are administered separately but concomitantly. As of this writing, only the travatan/timolol combination (DuoTrav®, Alcon, Ft Worth, TX) has been approved by the US Food and Drug Administration (FDA) because it is the only one that met the FDA criterion of at least 1.5 mmHg improvement over the base prostaglandin analogue alone. The travoprost/timolol combination may have a slightly longer duration of action than the latanoprost/timolol fixed combination. The bimatoprost/timolol fixed combination seems, in one study anyway, to have slightly better IOP-lowering effect than the fixed latanoprost/timolol combination. Evening dosing with the fixed combinations seems to be slightly better than morning dosing. The fixed combinations do combine the side effect potential of both agents so care must be taken to remember that β-blockers are contraindicated in patients with asthma, among other conditions, and to watch for the dizziness, low blood pressure, slow pulse, and other systemic side effects of these agents.
Generally speaking, the prostanoids as a group are very well tolerated with side effects being relatively mild and local; serious side effects are infrequent and systemic ones rare. The most common side effects in the three multicenter, international, comparative studies after 6 months of latanoprost treatment were conjunctival hyperemia, foreign body sensation, eye irritation, and superficial punctate keratopathy, all of which were more common with latanoprost than with timolol ( Table 23-1 ). Other irritative and subjective symptoms such as burning, stinging, itching, eye pain, and tearing were similar for the two medications. The side effects for travoprost, bimatoprost, and unoprostone are roughly the same with bimatoprost having the most frequent conjunctival hyperemia, travoprost in the middle, and unoprostone the least. The incidence of conjunctival hyperemia ranges from 5% for latanoprost and unoprostone to 50% for travoprost and bimatoprost. However, the hyperemia is often transient lasting only 1–2 weeks after which it usually settles down to a tolerable level. The hyperemia is superficial and histopathologic study fails to show any pathological changes compared to untreated controls. Only 6–9% of patients withdrew from any of these studies because of side effects, defaulting, or ineffectiveness. The withdrawal rates were similar for both timolol and latanoprost. The withdrawal rate from studies is definitely higher for bimatoprost although, as noted above, target pressures are more frequently reached with bimatoprost than with the other agents.