Advances in Glaucoma Therapy
An overview of contemporary IOP-lowering medications.
LEO SEMES, O.D., F.A.A.O.
Optometric Management is proud to present the second in a series of articles on glaucoma that have been planned in partnership with the Optometric Glaucoma Society (OGS). In 2006, the Society will provide OM with expert authors who will discuss therapies, epidemiology, case studies and other current issues in glaucoma management. For additional information on the Society, contact the OGS through the Web site optometricglaucomasociety.org. The views expressed in this article are the author's and do not necessarily represent the views of the OGS.
Originally, topical glaucoma treatment centered around anti-cholinergic medications. Pilocarpine, and to a much lesser extent, cholinesterase inhibitors, reigned for nearly a century until the introduction of the first topical beta-blocker, timolol maleate (Timoptic, Merck), in the mid-1970's. This represented a revolution in drugs to lower intraocular pressure (IOP). Along the way, adrenergics and alpha-agonists (brimonidine [Alphagan, Allergan] and apraclonidine [Iopdine, Alcon]) as well as two topical carbonic anhydrase inhibitors (dorzolamide [Trusopt, Merck] and brinzolamide, [Azopt, Alcon]) were introduced. The next revolution was FDA-approval of latanoprost (Xalatan, Pfizer) in 1996. Latanoprost is a prostaglandin analogue that offers a great degree of safety and convenience as well as significant IOP-lowering efficacy.
Iris discoloration, though rare, is the most common side-effect of prostaglandin therapy.
A world of options
A recent editorial calculated that using all the concentrations of all medications currently approved in all possible combinations would result in over 50,000 choices. You could virtually never use the same treatment recommendation for any two different patients. When we look a little more closely, clearly a strategy that poses few if any significant side-effects, is convenient for dosing and offers great efficacy is the best choice. With that goal in mind, the prostaglandin analogues go straight to the head of the class.
Initial clinical studies of prostaglandins' ability to reduce IOP were performed using concentrations that produced unacceptable results, either due to limited efficacy or significant side effects. Several candidate molecules have since emerged and subsequently been FDA-approved to lower IOP in patients diagnosed with ocular hypertension or glaucoma. Note that the FDA approves these topical medications for lowering IOP and not for the treatment of glaucoma. Because elevated IOP is the number one risk factor for developing glaucomatous damage, it is the target to reduce that risk. One of the initial hurdles in finding a prostaglandin analogue that lowered IOP without side effects was concentration. Timolol was approved in concentrations of 0.25 and 0.5%. Using prostaglandin analogues at this concentration produced inflammation and increased IOP. Decimating and even further reducing the concentration has resulted in the current range of available prosta-glandin analogues. Since the release of latano- prost, the FDA has also granted approval to bimatoprost (Lumigan, Allergan) and travoprost (Travatan, Alcon).
The effect of these compounds on the management of glaucoma is illustrated by studies that demonstrate a reduction in the number of glaucoma surgeries performed, as well as a very recent favorable comparison of IOP-lowering effect with selective laser trabeculoplasty (SLT). The profound efficacy and dosing convenience of this drug class provides clinicians with a greater likelihood of successfully medically managing patients. When used alone, the prostaglandins have also reduced the number of patients who require combination therapy. All in all, reduction in surgery and decreased frequency of dosing (with increased compliance) has significantly improved outcomes in glaucoma management.
The expected IOP drop from baseline averages about 30% with once-daily dosing. Evening dosing is preferred as the onset of IOP lowering activity for prostaglandin analogues is slow with peak effect at 8 to 12 hours after instillation. Compare this with the two-hour peak efficacy of the beta-blockers, for example.
When we look at diurnal fluctuations in IOP, peaks appear to occur during the sleep (or dark) cycle. This brings up an interesting point: When do you measure IOP? Let's say that you prescribe a prostaglandin analogue for evening administration and find that none of the drugs in that class achieves your desired target pressure. You decide to add a topical beta-blocker after determining that there are no contraindications. Beta-blockers have little if any IOP-lowering effect when dosed at bedtime, so you recommend morning dosing. If you measure the IOP at 9:00a.m., two and 12 hours following the beta-blocker and prostaglandin dosings respectively, it may represent the trough pressure that the patient never experiences! So safety, dosing, efficacy, compliance, and influences on IOP all play a role in glaucoma management.
To paraphrase the late Jerry Garcia, every silver lining has a cloud and the prostaglandins are not without some side-effects. Side-effects appear to be tied to receptor affinity, as is efficacy. This may be the reason for the differing degrees of itching and hyperemia found in the three competing drugs. Hyperemia has been reported to be greatest with bimatoprost and least with latanoprost. But this may also explain the relative equivalence among the three currently available prostaglandin analogues in their efficacy. Significantly lower and consistent IOP was maintained throughout a 12-hour IOP-measuring cycle at the 12-week time point in this study.
The most outwardly noticeable side-effect associated with prostaglandins is permanent darkening of the iris, which was first reported with latanoprost. Patients who seem to be most susceptible are those with two-tone (green-brown) irises. Darkening generally occurs within the first year of treatment but may present as long as 36 months following initiation of treatment. Prevalence is low, ranging from 3 to 8% and there are no reports of melanoma potential in these cases.
The prostaglandin analogues can also potentially increase growth of brow and eyelid hair, as well as periocular pigmentation. The good news regarding side-effects is that this class has little if any systemic absorption, avoiding systemic side-effects. So, there are no potential adverse pulmonary or cardiovascular side-effects that require cautious consideration.
Because prostaglandins are mediators of inflammation, use caution when prescribing for patients with recurrent uveitis, for example. The issue of whether they are causative components in cystoid macular edema has been controversial, however. One study proposes, and offers evidence for, the theory that a breakdown of blood-brain barrier is more likely a side-effect of the preservative benzalkonium chloride (BAK) than the active components of topical drops (comparing timolol and latanoprost). Also, note these drugs are classified as a category C drug for pregnant patients.
The latest buzzword in glaucoma management is adherence. Successful management of any chronic disease process requires patients to adhere to their prescribed treatment regimen. The issue of adherence has been addressed in many other diseases and found to be dreadful. Glaucoma apparently is no exception. Less than one-third of initial glaucoma prescriptions are refilled at one year. Adherence seems to be best with the prostaglandin analogues, yet the adherence rates would still barely reach a passing grade (76% overall for the "big three" prosta-glandins). The once-daily dosing regimen for prostaglandins, ease of use, lack of systemic side-effects and high efficacy are factors that contribute to improved adherence, however good or poor that may be. In fact, increased adherence may offer an explanation for improved efficacy in the so-called "switch trials."
While prostaglandins may offer the easiest and most efficacious treatment options, we cannot totally neglect the beta-blockers. Perhaps their greatest strength lies in the fact that they can be dosed once daily (morning) and are relatively inexpensive in generic form. We must exercise caution, however, due to the potential systemic side-effects, which have been well characterized.
Recent controlled clinical trials have demonstrated a reduction in the risk of glaucoma in more than one setting. The risk of conversion from ocular hypertension to glaucoma is reduced by almost 50% with treatment (OHTS). The early manifest glaucoma trial (EMGT) also shows that progression was retarded in the treatment group. Their quantitative estimate was an IOP reduction of 1mm Hg reduced risk by 10%. Until better means of slowing or halting the progression of glaucoma become available, offering patients risk-reduction recommendations using the prostaglandin analogues remains the treatment of choice.
Another issue regarding compliance is dual medications. Adding a topical CAI, beta-blocker or alpha-agonist will require that the patient remember to dose at least one additional drop. While it has been shown that the topical CAI dosed b.i.d. is perhaps the most effective at further lowering IOP, using a beta-blocker for the morning dose added to the prostaglandin at night may be more convenient and less costly for the patient. In order to limit dosing, several combination medications have been proposed. In fact, two combinations (latanoprost with timolol [Xalacom, Pfizer] and brimonidine plus timolol [Combigan, Allergan]) are available in Europe and Canada. Recently the combination of travoprost and timolol has received an approvable letter from the FDA.
A world away
On the horizon, we will see other means for treating glaucoma and not just lowering IOP. One avenue being explored is enhancing blood flow. The hurdles include selecting a medication that will increase blood flow without side-effects and target the appropriate vascular system.
Still another approach may lie in the area of neuroprotection. The stimulus is ganglion-cell protection, stemming from studies on medication administered following stroke and applications in chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). At the level of the ganglion cells, calcium channel blockade appears to be the mechanism that protects cells from premature death. Human studies are now underway for Memantine, an NMDA-type, open-channel blocker that has shown promise in various models of glaucoma. (Memantine HCl is currently available for the treatment of Alzheimer's disease from Forest Labs under the name Nemanda.)
Finally, to be complete, let's look at complementary and alternative medicine (CAM) for glaucoma treatment. Gingko biloba has been shown to increase blood flow and for patients who choose to self-admin- ister the standardized-extract dosing, it may be beneficial. Caution should be exercised when recommending this regimen, as it is not an FDA-approved treatment strategy.
The future is bright for control of IOP. With newer strategies emerging, patients diagnosed with glaucoma today are in a much more favorable position than those diagnosed 50 years ago. With the increasing life span of the population, our challenge will be to diagnose glaucoma earlier and invoke these more favorable regimens that will keep our patients from developing visual impairment or going blind.
References available upon request.
Dr. Semes is associate professor and director of continuing education at the University of Alabama Birmingham School of Optometry. He has published over 60 articles and was named one of the 2000 Outstanding Intellectuals of the 21st Century.