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Prostaglandins may benefit glaucoma patients as first-line medication
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Currently, the initial therapy for open-angle glaucoma is based upon reducing the intraocular pressure (IOP) with medication to obtain a target or goal pressure. A medication is initiated and its efficacy and side effect profile is evaluated in the first weeks to months of therapy. If it is successful in lowering the IOP and free of major side effects, the medication is continued.
For many years, topical beta-blockers were the initial class of drugs used to treat primary open-angle glaucoma (POAG). When evaluating a drug by considering different parameters, topical beta-blockers came out on or near the top when compared to the alternatives, even though their systemic side effect profile left something to be desired. New medications have become available since beta-blockers were introduced — topical carbonic anhydrase inhibitors, alpha agonists — but beta-blockers have remained at or near the top of most clinicians’ lists of first-line glaucoma medications.
The therapeutic landscape changed recently as several prostaglandin or prostaglandin-type medications became available that offer advantages compared to beta-blockers and other glaucoma medications, both in regards to their efficacy as well as in their side effect profile.
Prostanoid receptors
Prostaglandins are naturally occurring fatty acids that activate prostanoid receptors. When activated, these receptors enhance uveoscleral outflow by remodeling the extracellular matrix in and around the ciliary muscle. This allows aqueous to exit via the uveal tissue and sclera.
Latanoprost, the first prostaglandin available, is categorized as an eicosanoid and stimulates the PGF2 receptors. There are now three additional prostaglandin or prostaglandin-type drugs: unoprostone isopropyl, travoprost and bimatoprost.
Unoprostone isopropyl is categorized as a docosanoid, as it begins from docosahexaenoic acid. Its analog appears to be a partial agonist of the FP receptor. Travoprost is similar to latanoprost as a full agonist of the FP receptor, while bimatoprost is described as a prostamide with the exact receptor stimulated unknown, though it does not appear to stimulate the FP receptor.
Prostamides: a new class?
One question is whether prostamides are a new class of medications or a subgroup of prostaglandins. Currently, many people view them as a type of prostaglandin because their efficacy, mechanism and side effect profile are similar to prostaglandin drugs. If prostamides are a new class of drugs, then bimatoprost should be additive to other prostaglandins, which would allow even greater flexibility in our management of open-angle glaucoma. Still, there is little information at this time apart from drug company data to validate whether bimatoprost is part of a new category of medications.
Latanoprost, as the original of the prostaglandin class of medications, became available in 1996 and quickly marched to the front of glaucoma therapy. Along the way, it changed our perception of what a glaucoma drug can do. PGF2a is the prostaglandin receptor stimulated by latanoprost, travoprost and — to a lesser extent — unoprostone isopropyl that leads to an enhancement of uveoscleral outflow. In contrast, bimatoprost does not appear to activate the PGF2a receptor, though it does enhance both uveoscleral and trabecular meshwork outflow. Whether each mode of outflow is affected equally or one greater than the other still needs to be determined.
Unoprostone isopropyl, like bimatoprost, also increases both trabecular and uveoscleral outflow. It would not be surprising if, in the near future, both latanoprost and travoprost are also found to enhance trabecular meshwork outflow, at least to some degree. Finally, latanoprost and travoprost are pro-drugs, as they are converted to the biologically active component after penetrating the cornea. Both are effective in much lower concentrations than the other prostaglandin and prostaglandin-type medications (concentration of unoprostone isopropyl is 0.15%, bimatoprost 0.03%, latanoprost 0.005% and travoprost 0.004%).
Determining whether bimatoprost and unoprostone isopropyl have a different side effect profile, either locally or systemically because they are not pro-drugs or due to their higher concentration, will require independent studies as well as careful observation to recognize and understand.
Evaluating new agents
What criteria should be used to evaluate new medications? The obvious criteria are efficacy, safety, ease of use and cost. All the prostaglandins except for unoprostone isopropyl appear to consistently reduce IOP by 30% or more with a low non-responder rate. There is little efficacy information available on travoprost and bimatoprost, being the newest of the prostaglandin agents, apart from data submitted to the Food and Drug Administration by the individual companies.
The FDA data are impressive, with both drugs showing a 30% to 38% IOP reduction. One unique feature of travoprost is its enhanced efficacy in African Americans, which is both unusual and a welcome bonus. In Caucasians, the data between the two new drugs appear similar, though it will take independent studies to validate this.
Subgroup analysis has been part of the FDA approval process for new medications for 13 years, but few medications of any type have shown either race or gender differences. For travoprost, this difference is approximately a 1-mm Hg additional IOP reduction. From the FDA data, both bimatoprost and travoprost appear to offer slightly greater efficacy than latanoprost, but independent studies are needed for validation.
Side effect profile
The side effect profile of all the prostaglandins is excellent, with hyperemia as the most common problem. Incidents of anterior uveitis, eyelash growth, cystoid macula edema or iris color change are occasionally seen. While the hyperemia can be significant initially, especially with the newer prostaglandins, it tends to subside over the first weeks of use. If patients are counseled that hyperemia may occur, they may better deal with and accept this often transient problem. Hyperemia that does not decrease over the first weeks of therapy or is accompanied by symptoms may be due to some other cause, such as anterior uveitis, and must be evaluated further. Both of the newest prostaglandins appear to have a greater incidence of hyperemia than latanoprost, though in most individuals it does not lead to discontinuation of the medication.
Eyelash growth is another common side effect that is more of a cosmetic concern than a significant problem. It is best visualized by looking at the patient in profile and is most obviously noted when taking tonometry and the lashes get in the way.
The only data currently available comparing incidence of side effects come from material submitted as part of the FDA approval process and is printed on the package inserts of the individual drugs. The incidence of ocular dryness was 1% to 4% for travoprost and latanoprost and 10% for bimatoprost, while the incidence of pruritus was 5% to 10% for travoprost, 5% to 15% for latanoprost and 15% for bimatoprost. Determining if there are significant differences will require our use for a period of time as well as independent studies.
Ease of use
Regarding ease of use, latanoprost, bimatoprost and travoprost have once-daily dosing; unoprostone isopropyl requires a twice-daily schedule. While latanoprost, bimatoprost and travoprost are recommended to be used before bedtime, this is in part so that hyperemia, when it is greatest, occurs during sleep.
Data from different latanoprost studies provide contrasting information concerning which time of the day dosing leads to the best IOP reduction. And between the studies, the differences are small. For bimatoprost and travoprost, there was no difference in IOP reduction if the drug was instilled in the morning or at bedtime, though the package insert recommends bedtime use. In individuals who often miss their nighttime dosage, it may be easier to use the medication upon awakening. Also in contrast to latanoprost, neither of the newer drugs requires refrigeration before opening, which will be helpful for some individuals.
Indications for prostaglandins
The indications for the prostaglandins as seen on the package insert are the following: “reduction of elevation in IOP in patients with open angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication.”
From this set of indications, it appears that the placement of prostaglandins in the therapeutic regimen is fixed and is relegated to secondary status. In reality, the indications of a particular drug can be modified if the doctor feels it is in the patient’s best interest. This has occurred quite often in the use of prostaglandins, as many doctors recognize their advantages and have recommended them as the initial drug. Recent data suggest that approximately 35% of all prescriptions for latanoprost are as the initial glaucoma drug. In regard to cost, there appears to be no major differentiation between the prostaglandins, as all are priced similarly.
Additional benefits
Finally, there have been reports that several of the new drugs may have additional therapeutic benefits beyond reducing IOP. Animal data have shown unoprostone isopropyl to inhibit endothelin-1, with the anticipated effect of less blood vessel constriction and greater blood flow to the back of the eye. In addition, work with unoprostone as well as with other topical drugs (betaxolol, travoprost) has shown that, in its topical form, significant amounts reach the back of the eye, including the optic nerve head.
Also, unoprostone, due to its active ingredient, has been shown to have neuroprotective properties in rats. Similarly, travoprost has been seen to improve blood flow to the optic nerve head in rabbits.
Challenges of studies
Still, work with animal models is not easily translated to humans. And even work in humans does not always translate to changes in how we manage glaucoma. Measurements of the clinical impact of blood flow and neuroprotection are extremely difficult to document. Long-term studies using either perimetry or optic nerve imaging and comparing one group against a control is difficult, tedious and expensive.
A decade ago, work done by Drance, Brach and Flammer showed that betaxolol used over a 2- to 3-year period appeared to positively affect visual field preservation as compared to timolol. Still, for a host of reasons, this work never translated to a change in how we practice, and IOP reduction continued to be the Holy Grail. Now, with medications that lower the IOP better than anything previously seen, secondary factors such as blood flow may be relegated again to the periphery because of the difficulty in validating any claim that a specific drug has an impact on these factors. Only time and additional studies will tell how significant the new drugs are in these other areas.
Need for more prostaglandins?
Do we need more than one prostaglandin agent? Latanoprost has been with us for several years. While successful a great deal of the time, most clinicians periodically have patients who either do not respond, show reduced efficacy over time or develop an allergy or side effects, such that latanoprost must be discontinued. With topical beta-blockers, conventional wisdom was that if a person developed tolerance or allergy to one drug from this class, it was best to move on to a different category of drugs. Is this true with the prostaglandins?
While no studies are available at this time, anecdotal evidence indicates that patients who were non-responders or developed tolerance to latanoprost may show a positive response with either travoprost or bimatoprost. Individuals who showed side effects such as uveitis or cystoid macular edema would in most cases show similar responses to any of the newer drugs, and caution should be exercised if these drugs are initiated. If bimatoprost as a prostamide is in a different class of drugs from the prostaglandins, it should show synergy with either travoprost or latanoprost. Studies are needed to address these questions.
Prostaglandins as a class of drugs are an improvement over beta-blockers, alpha agonists, topical carbonic anhydrase inhibitors or other drugs with regard to their ability to lower IOP while considering side effects, complications and ease of use. They are safe and effective. Initially, caution was urged due to the fear of unknown complications. We now have several years of experience with this class of drugs and understand them in better detail. Because of their advantages, most patients would benefit from their use as the primary medication in the therapy of glaucoma, though, as with any drug, caution is needed.