Lecture: Update on Glaucoma Medical Therapy: A Global Perspective

>> Dr. Louis Cantor: Good morning, everyone. Or good afternoon, wherever you may be, good evening. It’s a pleasure to share time for the next few minutes to talk about a topic that on its surface perhaps seems somewhat straightforward. But which I think is incredibly complex. And something I have been involved in for many years, including in the development of many of the drugs that we’ll talk about today. And in speaking about glaucoma medical from a global perspective, I think it’s challenging, at best, to talk about what goes on in every part of the world and every drug that’s available. But I think there are some global principles that pertain to medical therapy that I would like to discuss.
Here are my disclosures. I do consult and work with a number of our industry partners in scientific advisory board capacities. So, as with everything, things evolve with time. We live in an ever-changing world. It’s often said that the only constant is change. And certainly we’ve seen that in the world of glaucoma medical therapy. I would like to do a little stroll through time if we may. We’ve had a long history in the development of our various classes of drugs. And I would like to walk through this in a bit more detail. And in particular, we’ll talk a little bit about mechanism of action of some of these drugs in a few minutes and how that may be important and something we maybe don’t think about enough. If we go back in time, it was the late 1800s when Eserine, a cholinergic agonist was introduced, derived from the West African Calabar bean. What was noticed with oral use of these beans was that it caused miosis and therefore was useful in iridectomy in break angle-closure. And pilocarpine was introduced, and then the first indirect acting drug later, 60 to 75 years before we had an indirect acting cholinergic drug followed about a decade later by phospholine iodide which you may know or be familiar with. The myotics, pilocarpine, there were a lot of side effects, dosing four times a day. There were different ways to deliver the drug through gel and extended release to reduce side effects in dosing. But many of those didn’t persist and aren’t available today. It wasn’t until the 1950s that we had a carbonic anhydrase inhibitor developed, acetazolamide. There were agents used for short-term pleasure lowering over many decades. In the 1940s, we had adrenergic antagonists that were noted to reduce interocular pressures. Intravenous dibenamine was one of those, but they were limited by severe adverse reactions such as sere orthostatic hypotension. Then we had the introduction of adrenergic agonists, just the opposite. And that was epinephrine. And it led to some topical and systemic side effects. But was found to be also useful in lowering interocular pleasure. It wasn’t until the late ’70s that we finally had another class of medications, the beta blockers. Timolol was introduced. It’s a beta-adrenergic antagonists. We’re using beta-adrenergic antagonists and agonists to lower pressure which highlights, I think, some of the complexities of the physiology of the eye. That we can work on both sides of the equation for the desired effect of lowering pressure. There were some side effects, of course, noted with these — this class of drugs that was eventually overcome and Timolol was introduced. We then had an alpha-adrenergic agonist, apraclonidine, and another one in 1996, brimonidine. A lot of pharmacology during this time. We continued to evolve with different formulations and molecules of adrenergic drugs, dipivefrin, we had the topical anhydrase inhibitors, brinzolamide/dorzolamide, and then in 1996, the prostaglandins with the introduction of latanoprost. This was a new era. And five years later, others, bimatoprost and travoprost that were introduced and were effective and became the first-line gold standard drugs for treatment of glaucoma. Others continued to be developed in the family of prostaglandins with tafluprost, latanoprostene bunod, latanoprost emulsion, and bimatoprost, and now another class, the Rho kinase inhibitors with the introduction of netarsudil. We’ve also had the evolution of a number of fixed combination drugs. In the US, these are the common ones used, dorzolamide/timolol, brimonidine/timolol and brinzolamide/brimonidine to enhance patient compliance. There are a number of other — and I did — I looked at some of the global literature can there are fix the combinations available globally that have two, three, or even four medications in a single bottle. But I think it’s important to keep in mind that fixed combinations are really
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S in many ways. We can’t extrapolate how a drug necessarily does by itself in combination with another drug separately to what they would do when they’re put together in the same bottle. Drug formulations are rather complex. To get the optimal penetration of the drug and the optimal efficacy, the formulation has to be of a specific nature. The pH has to be of a specific nature for that particular molecule. And when you mix another molecule in there, it’s sweet spot, if you will, for penetration and efficacy may be slightly different. So, these formulations, trying to match those up as best they can. But they’re often not ideal. But from a patient use perspective and for making it simpler for patients, they certainly make sense. But we have to realize that they’re not the panacea for many patients that we would hope for them to be. And many of these fixed combinations, for example, in the US with some drugs that may be approved in other parts of the world, I’ll give you an example of the prostaglandin Timolol fixed combination drugs which were never approved in the US because they didn’t quite meet the bar for efficacy that our FDA sought. So, but used separately, they can be very effective. So, I think we have to realize that while there are some definite benefits to the fixed combination products for patients, we may be sacrificing something at the same time.
Just to go through the classes a little bit and talk about mechanism of action. In the cholinergic class, we have really two ways of approaching it. The cholinergic drugs, the parasympathetic memetics, they worked a increasing the effect of acetylcholine at the post-synaptic junction as shown in the cartoon on the upper left of the side. What a direct-acting drug does, is it acts like acetylcholine and can bind to the receptor and activate it. That’s a direct-acting cholinergic or parasympathetic drug. An indirect-acting drug enhances the acetylcholine at the receptor by blocking the breakdown of acetylcholine and therefore it hangs around longer and has more effect. In the ends, they both work by enhancing acetylcholine effect at the post-synaptic junction. Our beta blockers, although they have been around since the late 1970s for glaucoma, the mechanism by which they work is still a bit of a mystery, at least to me. They work through cyclic AMP, it appears, and have an effect on the ciliary epithelium and therefore aqueous production. But I think there’s still work to be done to understand how these drugs reduce aqueous production.
The carbonic anhydrase inhibitors — the carbonic anhydrase is an enzyme that catalyzes this reaction of reversible hydration of carbon dioxide. And that’s used in the ciliary body to cause fluid flow and production of aqueous. So, as shown on the bottom on the left, that’s the normal physiological process that’s happening in the non-pigmented epithelium that’s leading to fluid flow into the anterior chamber as the aqueous humor and if you block that reaction by a carbonic anhydrase inhibition, you block that process of fluid flow and movement of water molecules into the aqueous.
By the way, in order to do this, the carbonic anhydrase inhibitors have to inhibit carbonic anhydrase activity in the eye by approximately 99.9%. So, it almost completely blocks carbonic anhydrase activity, nearly 100%, with both the topical and the oral agents similarly. The only reason why the oral agents at times seem to work a little better than the topical agents is because on top of the carbonic anhydrase inhibition with a systemic drug like acetazolamide, you also get a metabolic acidosis, because of the systemic effects, which is a diuretic effect, which also has an effect on the eye. Our alpha-2 adrenergic agonists, most commonly represented by brimonidine, they have complex effects on inflow and outflow. And it’s — it’s, as I said, it’s alpha-2 adrenergic. The alpha-1 effects, alpha-1 adrenergic agonist effects probably aren’t beneficial in ocular therapy, it’s vasoconstriction and dilation. Alpha-2, we get ILP reduction, you get a little pupillary miosis. The pupil constricts with these drugs which is sometimes used for that purpose in certain circumstances. There may also be a potential for neuroprotective effects because of alpha-2 that have been postulated. And then the prostaglandins, there’s a whole host of prostaglandins as I mentioned now. And this list will continue to expand. They have a very complex mechanism of action through remodeling of the extracellular matrix in tissue through matrix activity, and TNF-alpha, it remodels what goes on in the trabecula and the other systems. What’s frequently overlooked with the prostaglandins, it’s said that they are uveoscleral outflow drugs, they have effect on the system, but the uveoscleral outflow 20%, the majority of the outflow is through the trabecular meshwork. What I like to point out is even if the drug is having the majority of its effect on the uveoscleral outflow, it’s having it on the smaller percentage of total outflow. So, in my little attempt at math here. So, if 80% of the outflow is through the trabecular meshwork, and the prostaglandin only has 20%, that’s very conceptual. And there’s the uveoscleral outflow, it’s still 16. The number 16 isn’t important. What’s important is that these drugs, on average, probably have about an equal impact on outflow, trabecular and uveoscleral, even though the majority of the effect is on the uveoscleral outflow pathway through the remottling of the extracellular matrix in the ciliary body. And most recently, these Rho kinase inhibitors, this newest class of drugs which have also very complex mechanisms of action that works on actin fibers. And it’s — it’s probably best illustrated in the slide on the right. Where you see on top the normal composition of the trabecular meshwork there and the dark blue with the TM and the bar across it. That’s the normal trabecular meshwork, above it, where it says SC, that’s Schlemm’s canal. And after the work, it’s the bottom slide, it becomes much more spongy. There’s a great increase in the intracellular beams, between the trabecular beams. And you can just see how that could just lead to much easier outflow. In addition to outflow, there may be some inflow effects, but there’s also been this new sort of novel observation that it — that these drugs affect episcleral venous pressure. And because of how the eye works, every millimeter decrease in episcleral venous pressure leads to approximately a millimeter drop in intraocular pressure. So, and this has been verified now clinically and in various studies that this — that this class of medications can affect episcleral venous pressure. And that may in part be contributing to its pressure-lowering effect. I’m not gonna spend a whole lot of time on drug side effects in this talk because of all the different classes. But because we have this new class Rho kinase, I want to point out things I see fairly commonly. One is the cornea verticillata, you goat did in the cornea, usually asymptomatic and no discomfort, but occasionally it can. I get some patients with more pro found changes in the depth of the cornea where it bothers them and you have to stop the drug. You have to look for it. And you get this fine, lacey buildup of drug in the superficial cornea.
You also tend to get these little subconjunctival petechial hemorrhages. And I see these fairly commonly. It’s somewhat related to the episcleral venous plexus and lowering the pressure. But these are very common to see and seem to be of no particular symptom other than patients sometimes notice it. And sometimes these get a little bit bigger and cause small, larger subconjunctival hemorrhages. Again, I mixed the fixed combinations that we have today. And those options continue to expand. We also have a lot of generics. In the US and around the world. And I’m gonna talk specifically about generics a little bit more towards the end of the talk. But in the US alone for just latanoprost, we have eight generics and increasing. And look at classes of medicines and the combinations of one, two, three, four, even up to five because we have five classes. It’s a lot of options. And look at various brand names and the various generic options within each of those classes, the number of options for glaucoma medical therapy quickly gets into the thousands. So, it becomes a very complex environment in which to work. And what do we choose for who?
In the US we commonly ask our patients about the color of the cap of their bottles. And that’s how we can often tell what they’re on. But these aren’t consistent and certainly generics don’t always have to follow these. Even the brand name manufacturers follow the cap color design only voluntarily, it’s not required. So, with all of these options, with these different mechanisms of action, we have drugs that work on the trabecular meshwork, the uveoscleral pathway, aqueous humor inflow, and episcleral venous pressure. So, those are — we have got five classes that cover these four different ways of getting at lowering of intraocular pressure.
I think one of the things that I always like to do is when I think about medical therapy typically today if we’re gonna start medical therapy, we’re still gonna start with a prostaglandin. As our baseline foundational drug as long as there’s no contraindications and the patient tolerates it. Since the majority of patients with glaucoma can not be controlled with one drug, or maybe if they are, they can’t be controlled on one drug indefinitely and we have to add something else, where do you go next? And I think it’s worthwhile to think of drugs by these mechanism of action. That’s why I went through that. I think that in most cases, for example, if a patient is on a beta-blocker, on Timolol that decreases aqueous humor production, aqueous humor inflow, does it make sense to add another aqueous humor drug to that? Or to go to a different mechanism? I think in general we get better results and keep patients on fewer medicines if we mix mechanisms of action. So, if we’re on a uveoscleral drug, maybe we go with an aqueous humor outflow or inflow drug as our next choice. Maybe we want to add that episcleral venous pressure mechanism to the mix on top of it. And look at mechanisms of action and think about the drugs and think about that in a way a bit. Often we pick it randomly or what’s available. But maybe give it a little bit more thought and think what have a drug that the patient is on work? And if I’m gonna add something to it, can I pick something that works slightly different so that they’re more likely to be complementary?
And here is a case in point. So, the — this is a picture I took with my phone of this patient’s medicines who came in to see me. This was the parent of somebody who works here in Indianapolis and their parent was visiting from overseas. Because none of these formulations of medicines do we have available in the US. I forget exactly where they came from, to be honest. But these are the bottles that they pulled out of their pocket. They were seeing me for consult because the family here in the US and their parent came over to visit, you know, they were complaining about their eye drops and their vision and didn’t think they were doing very well and wanted another opinion. So, the first medicine there is brinzolamide. The second medicine is dorzolamide/timolol, the third is brimonidine/timolol and the fourth is Timolol/pilocarpine. And the patient is instructed to use these three or four times a day. We have four different bottles, three are fixed combinations, one is a single agent. And we’ve got multiple dosing regimens. Plus the patient says to me that every — every week or two they have to hold their drugs. And they don’t use their drops for a day or two because their eyes get very irritated and the vision gets very blurry. And if they stay off the drug for a day or two, all the drops, things get better, then they’ll start up again. And they have been doing this for quite a while. So, then I asked, well, so, how are you using these drops? And like I said, they were all to be given three to four times daily. And they proceed to tell me — they start off with the brinzolamide drop, put it in. An hour later they put in a second drop that have and an hour after that, a third drop of that. So, that’s their three times for that. And the two in the middle they were also using three times a day. And so, then they would start doing that same thing. So, they were doing what they were told, but in a completely wrong way. The timolol/pilocarpine was used four times a day, and that was the last, they would put it in at 5, 6, 7 and 8:00 at night, it wasn’t spaced properly, of course. Plus you have another problem of all the overlap between these drugs. We’ve got seven medications between all these drops that cover just four classes. So, the brinzolamide overlaps with the dorzolamide, they were way overdosed with timolol, and I was glad they weren’t having cardiac side effects, but there was a risk for that. And they were doing it wrong. There was a lot of opportunity to simplify this regimen. To be on these four classes of drugs would probably only require two bottles. And could have gotten rid of a lot of potential for side effects, misunderstanding, and ocular tolerability issues.
So, I got a lot of challenges in medical treatment. We’ve got all these old medicines, new medicines. Do we use them over or under-utilized? You know, there are a whole host of challenges with compliance. There’s the availability in different regions of the world. Certainly cost is an issue. Compliance tolerability. This is from the American Academy of Ophthalmology. You know, one of the very simple, straight-forward algorithms for treating pressure. Start with prostaglandin monotherapy. Is the pressure good or bad? Go from there. But in reality, it’s more like this. It’s a lot more complicated. And not only is it medicines, but what about laser? What about surgery? If medications, which one? How many medications do you use before moving on to surgery? Or laser? When is laser surgery appropriate as first line therapy? So, you know, medical therapy is mixed up in all this, of course. But it’s a very much more complicated process of working between the patient, you as the physician/provider in the healthcare system, whatever that is, that you work within as to what’s available and what the treatment norms and practice patterns are. So, that we can really control patients and prevent vision loss.
Now, let me quickly switch gears for a minute. I want to talk about something that we probably don’t talk about enough. It’s a problem in the US and a probably globally, and that’s ocular surface disease in glaucoma. What we know, there’s a lot of ocular surface disease goon glaucoma patients, dry eye, trachoma and other factors that affect the general population also affect glaucoma patients. And there’s a high prevalence of ocular surface disease among treated glaucoma patients. And using a medication is associated with a significant increase in ocular surface disease symptoms as shown here in the glaucoma treatment. If they’re on one med, two meds. If you’re on two meds or more, nearly two-thirds of patients are going to have some ocular surface complaints. And preservatives in a lot of our drugs do disrupt tear film stability in the ocular surface. They cause morphologic changes that I won’t go into detail in both the tear film and the cornea. The higher the preservative concentrations, the worse all this gets. And all of this ultimately then affects patient compliance. Patients who have irritated dry eyes, like the example of the patient I gave you who was having such tolerability that they would go on a drug holiday every week or two for a day or two just to let their eyes recover. speaks to some of the issues that we create with our medications. And not only is it associated with these symptoms, but there have been studies that show that ocular side effects accelerate disease progression. Probably because patients can’t be as adherent to their therapy and their disease progressions — progresses more rapidly. So, there’s a lot of non-adherence among glaucoma patients to their therapy and we tend to grossly, as providers and physicians, we tend to grossly overestimate how compliant patients are really being. And if you could really measure it we’d be surprised of how often they miss their medications either because we make the regimens too complicated, patients don’t understand what they’re doing, or because of side effects that drives them towards stopping their therapy or not using it as prescribed and would be optimal. So, you know, easily 50 to 60% of all glaucoma patients will suffer from some form of ocular surface and dry eye disease. And they experience side effects from therapy more often and they experience greater disease progression because of that. So, that gets into, you know, preservative free therapies when possible, laser or surgery. Or even other approaches. There’s a — here’s some references for all of that. There’s a lot of systems being developed that try to get around some of this without preservatives. And to take some of the burden off patients. This is a punctal plug delivery system which has drug in it. You put it in one of the tear ducts and it releases drug over time. No preservatives, slow release of drug. Here’s another approach to this from ocular therapeutics with a travoprost-containing plug. And low rates of hyperemia. With Allergan, they have their anterior chamber approach to delivering a pelt of drug, slowly releases the drug. Patients have to put in a drop. But they’re getting constant and sustained release of medication. And it releases it over several months. And interestingly, one of the things that’s been recently noted is that the IOP lowering may be sustained, even after all the drug is eluted out of the pellet that’s put in the anterior chamber to last much longer for reasons that are still being investigated.
Here is another device with a ring that had drug in it. I don’t think we’re ever gonna see this commercially. The studies kind of stalled. There’s contact lens solutions. And most recently we have the iDose TR from Glaukos. This is a trabecular device that’s into the trabecular meshwork that is released slowly over time. There’s a lot of new approaches to therapy. I want to show you a little bit about what may be coming in the future, some of which is available now, to get around some of the issues of complex medical therapy, reducing the burden on patients, and reducing ocular side effects. And here is from the clinical trials with the iDose TR, has an effect non-inferior to Timolol. Reducing the pressures. And I know that globally generics are — and even in the US now — generics are the majority. It’s 80% of the medications that patients get. But I think we have to understand what generics are and what they aren’t. Because the assumption is often made that they’re just the same as everything else. But there are some studies that show that perhaps that’s not always the case. Obviously, there’s only one true benefit to generics, and that’s cost. They tend to be much cheaper than brand medicines, even with insurance. But they do have some disadvantages. There have been some efficacy and safety issues, and that’s from a branded to a generic or from a generic to another generic. We can’t always assume they’re always the same. And there’s possible reasons to explain all of this. And as I mentioned, drug formulations, eye drops, are actually more complicated to design and manufacturer than a pill that somebody takes. To get a drug into an eye drop that has the proper consistency and properties and pH and the — and will stay on the eye long enough to release drug that can get through the cornea and be — be available to the receptors in the eye where it needs to work is a very complicated process. So, how these drugs are formulated and some of the — the fine minutiae of drug design play an important role. In the US, you know, these drugs have a, you know, less rigorous approval process. We just have to show that they have had the same active and inactive ingredients as the innervater drug. But there’s FDA guidance, and identical in strength and be bioequivalent. Again, look the same on paper, but never required to be tested against the brand drug. So, we just have to take it on faith that on paper if it looks the same, it should work the same. Does that always happen? Maybe, maybe not. There’s another issue as well and that’s in the bottles. Generic bottles are not — there’s a lot of effort that companies spend on their bottles. This is just one example of a bottle that’s a generic Timolol. Looks fairly standard, timolol 0.5%, there’s no hole in the tip of the bottle. In the middle picture there, you can see the cap has a little pointy thing in the middle of it. What the patient has to do when they get their drop, screw that thing down really tight and push it. When it pushes, it makes a little hole in the top of the tip that now the drop can actually be delivered. Problem is, patients sometimes make a little hole, sometimes they make the hole too big. And so, the drop size is highly variable. It leads to a very non-standardized drop delivery. Whereas a standard drop should be, you know, 30, 35 microns. I’ve had some patients bring in these bottles where you put out a drop and it’s — it’s — I mean, milliliters. It’s just such a large drop because they made a humongous hole in the top of the tip. And so, we have these non-standard bottles. Also, the bottles feel different. Some of them have very thin, some of them are very hard to squeeze. You get generic differences in bottles which affect how patients perceive their drug and what they’re getting. There’s actually been some data, there’s been some studies. Here’s one looking at a timolol solution versus a generic. It showed that the generic in the blue line there on the right didn’t lower pressure quite as well as the branded product. This is the generic latanoprost that came out of India. Just one version a few years ago. May have changed. But showed that the latanoprost in the blue didn’t work quite as well as the branded product. And here’s one where a cross-over study was done where, again, it showed a generic not being quite as effective as the brand product. So, I mentioned these packaging differences. The packaging differences and fill rates of the bottles are also important. And how quickly are patients gonna run out of bottles? Not only a question of getting a big drop out, but if a big drop is being delivered, the bottle’s gonna run out sooner so then patients may run out of drugs before they can get more. And therefore, have a gap in treatment.
So, will your patient do as well on a generic? You know, in most cases, I would say they do. But we can’t assume that 100% of the time because there’s really lack of data on the generics. It’s assessed to — it’s difficult to know what impact those differences may mean. The numerous generic manufacturers mean that even if a patient gets a refill on a medicine, they may get a different manufacturer for a generic. And the bottles and the bottle fill rates may vary. Some of the components could vary within that — within certain degrees of freedom, within the guidance. And we have a big issue in the US because we — we’re used to very — often having samples around. But that’s only for brand name products. You never get a sample for a generic. So, I often drink these patients back more often because I feel like I need to in order to understand how well therapy is working. And how much money is really saved because of these extra visits I think can be argued sometimes. And it’s also impacting our ability to develop new drugs, I think, going forward. But this was the world today. So, here is a picture of our Eugene and Marilyn Eye Institute which I have the privilege of working. I’ve really appreciated everyone’s attention. I would like to now move to the Q&A, if I may. And see what questions have come from the concern come from the group. And I hope that this has been useful for everyone.
So, we have a first question here about the role of prostaglandin analogs in pseudophakic eyes. Good question. I think it stems from the pseudophakic eyes and sis today macular edema. There’s a risk of cystoid macular edema, but it’s very low. What I do in patients who have risk factors for cystoid macular edema, if they have a capsulotomy, and previous macular edema from a vein occlusion. I will treat the patients, especially if they’re going to undergo some sort of surgery with a non-steroidal. But I think you can use them comfortably. And the majority of patients who are on prostaglandins are okay, but take a look at the macula if you see a change in vision. They’re safe to use. Analyze your patient and see if they have other risk factors to macular edema where you may be adding just one more thing. There’s a question about can we use Rho kinase as initial treatment? Yes, you absolutely can. Where I have probably done that most often is in patients who would have a contraindication to a prostaglandin, for example, a patient with uveitis. Could be considered a reasonable candidate for initial Rho kinase treatment. I will often — I will often in those patients start with other drugs, you know, aqueous suppressants and things, but I think a Rho inhibitor is not inappropriate in that circumstance. There is a question here about tear film disturbances with — in patients with chronic glaucoma therapy. You know, I prescribe — I think what we have to do is for patients that we’re putting on medical therapy is we want to make sure that their baseline ocular surface is as healthy as possible. So, if they have any blepharitis, treat it. If they have pre-existing dry eye, treat it. With artificial tears or whatever so that we’re not adding then the burden of the glaucoma medication and preservatives to the situation. So, we should be concerned about tear film abnormalities and ocular surface disease. And we should address those up front in our glaucoma patients to make them more likely to be more successful with their medical therapy. There’s a question — not related to this — but it said the TNT rule in glaucoma. I wonder if that isn’t referring to the TSNIT which is the relative thickness of the nerve fiber around the nerve. I apologize if I’m looking at that wrong. But that just refers to the relative thickness of the retinal nerve fiber layer as you go around the nerve. So, there’s an interesting question — in my opinion, what’s the efficacy of prostaglandin analogs compared to SLT as first line treatment for ocular hypertension and glaucoma? I think that most of the evidence today suggests that out of the gate in a previously-untreated treatment-naive patient, you can get a pretty equivalent initial production with SLT or a prostaglandin analog in a patient. Of course, patients vary and so forth. The problem is that laser, by and large, is not a long-term treatment. On average, you get a couple years, let’s say. Whereas if someone is effective to a prostaglandin analog, the likelihood is that drug will continue to be effective because the rate of tachyphylaxis is very low, 5% or 10% at worst estimate. Whereas with SLT, 50% of those lasers will not be working within two years. So, I think it’s fine to consider initial SLT treatment, but that doesn’t mean you’re probably not going to end up repeating the laser and going on to add medication at some point. Because glaucoma is usually for most patients a 20 or 30 year disease. So, we have to think of a long-term. There’s a question about the role of ALT, argon laser trabeculoplasty, and that and SLT work equally as primary treatments. There’s no evidence that shows any difference. The only evidence that shows a difference is with retreatment. There’s a much higher rate of success with retreatment with SLT. Regardless of whether a patient initially had an SLT or an ALT. Doesn’t seem to matter. But the success rate for repeat laser is much higher for the second laser if it’s an SLT. There’s a question about the PAP, that’s the periorbitopathy side effects, will it be reversible if you stop? The answer is yes. The periorbitopathy, the eyelid skin darkening, lash growth, all of that, absolutely will reverse after stopping a prostaglandin. There’s, you know — there’s the rare patient who is may get some iris darkening. And that will probably reverse as well. But it’s much slower in my — in my experience. And it’s very infrequent as well. And it’s usually just in those mid-colored irides who are light-tan who get a little bit of darkening. Yeah, after initiating glaucoma medication, when will you follow-up with the IOP, visual field, and OCT? Yeah, sort of a couple different questions in that. So, I think any time you start a medical therapy, you need to give it sufficient time to see if it’s effective and how well it’s being tolerated and to make sure that the patient understands what they’re doing and is administering it correctly. So, you know, that depends a little bit on the medicine. But in general, you know, if you — if you can check their pressure a month or so after starting therapy, that’s gonna give you some idea of how effective it is and if the patient is having any problems or side effects from it. And if they understand it and are using it correctly. As far as the visual field and OCT, it depend on the stage of disease. If you’re at very early disease and there’s not much going on, you can repeat it several months later. Or get a new baseline whenever you want. If it’s someone who has more advanced disease who has progressed recently and you’re adding therapy to try to stop progression, then you should probably repeat the visual field and OCT and look at the nerve more often. So, rather than waiting six months to do your next field, maybe in two or three months you want to repeat a visual field to number one, to confirm what you thought was progression. It was really progression before, and number two, to study if it’s getting any worse. There was a question about the cost of Rho kinase compared to fixed combinations. You know, cost issues are so local and so variable around the globe, I think it’s hard for me to say, other than that, you know, the Rho kinase is our newest class of medicine so they’re usually brand name drugs. And are the most expensive drugs in the US right now because of that. So, I think you really have to look at your local environment and what the various costs of drugs are in your region or your area. Does using a nano dropper decrease drug efficacy? Great question. In general, the amount of an eye drop that goes — that actually gets absorbed is a very small amount. Probably 80% of the drug. If you put a regular 30 microliter drop on your eye, about 80% of it is not gonna be absorbed. And the nano droppers can be very effective in prolonging the medication. And even reducing the side effects by reducing some of the preservatives. So, I’ve never seen any evidence that suggests that these nano droppers decrease the drug efficacy as long as they get applied properly and the entire nano dropper drop gets in the eye. With the standard-size drops, I usually tell patients, you know, they’ll feel I got some of the drop in my eye, but a lot of it ran out. And I say, if any of it got in your eye, it was more than enough. So, I think that if a nano dropper is used it gets in the eye completely, it should be fine. There’s a question about which drug do I prefer to use after trabeculectomy, if any? First of all after trabeculectomy, I’m hoping for no drug. After glaucoma surgery, I’m hoping to get them off drugs. I do more with trabeculectomy sometimes. If it’s such that I need a lower target or the trabeculectomy, you can go back to the standard order of drugs. I don’t think it really matters. Just like if you were treating, you know, a patient who hadn’t had surgery. So, you know, and this is assuming the trabeculectomy and you’re healing well. If you’re having trouble early on with the trabeculectomy for the first month or two and it doesn’t look great, that may mean it’s a trabeculectomy that’s on its way to failure and may need intervention to needle it or raise it back up or modify that surgery. Cut sutures, to try to get better flow by mechanically manipulating the BLEB.
Where do MIGS stand in the severely of glaucoma and long-term control as an alternative to TRAB? Great question, whole different talk. Other than to say we’re in a highly-fluid environment when it comes to glaucoma surgery and the role of MIGS and the different MIGS procedures. Whether they’re device-based MIGS procedures or non-device-based that leave something in the eye. How does the wound healing happen? I think that’s undergoing evolution as we speak. People are at different points in the scale on that. I primarily use MIGS procedures with cataract surgery. Myself in patients with more mild to moderate glaucoma. With advanced glaucoma in patients that I’m really concerned could go blind from glaucoma, I’m still going trabeculectomy.
And we got a couple more minutes here. What is the first choice in normal tension glaucoma in a highly myopic eye? I think still the first choice for medical therapy, if that’s the question, would be the prostaglandin. I don’t think that’s an unreasonable start. The key is where to you say your target pressure? And from all the studies and everything we know, you know, number one, you have to understand the diurnal characteristics of what the normal tension is doing in a high myopic patient. And then we’ve got a set of target pressure reduction of at least 30% below baseline. And go from there. When should we consider tube shot surgeries for glaucoma is another question. For me, I don’t do a lot of primary tube shunts unless they’re in eyes that are likely going to fail a trabeculectomy. If I feel they need surgery for primary open angle glaucoma and they have advanced glaucoma, I will usually go to a trabeculectomy myself. In patients with, you know, uveitic glaucoma and others, those I go to a tube shunt. Those others are the patients who have failed the trabeculectomy. I’m still fairly standard on this. I have been at it for a while. I feel fairly comfortable with trabeculectomy surgery. But again, this is an area where over time things are starting to evolve and shift. But it basically boils down to how low a pressure do you need? If you’re gonna be okay with a pressure in the mid to upper teens on one or two eye drops, a tube shunt’s likely gonna get you there. Yeah, however, if you need a pressure of 10 on a patient who has had multiple problems with glaucoma therapy, you’re not gonna get there with a tube shunt. So, you have to think about goal. What is your goal for the surgery? And to choose an option that’s likely get you there. There’s a question about advanced glaucoma, which eye drops do you prefer? Unfortunately, none of our drops have proven to be particularly safe and — because most studies aren’t done. All of our medicines have potential — beta blockers can be concentrated in breast milk. Alpha-2 agonists like brimonidine can cause hypotension or apnea in a newborn or young children. You know, prostaglandins are probably pretty safe, but, you know, prostaglandins were first discovered in research on uterine contractility. And can be used as an abortifacient in horses and other things. So, you know, there’s carbonic anhydrase inhibitors early on in early pregnancy can maybe have some limb abnormality risk. So, I think you have to use medications with caution in pregnancy and in consultation with the patient and their — their OB or physician who is helping that patient.
Does long-term anti-glaucoma medication make the lens soft and a more difficult cataract surgery later in life? I don’t think it makes it more soft, but glaucoma medication is probably over time do increase the risk of developing cataract. But not necessarily make the cataract surgery more difficult. I think that, you know, this disruption of the aqueous environment can certainly have a response. You know, unfortunately, we are at our — our witching hour here for the close of today’s webinar. I wish I could stay and answer all the questions. But there were some wonderful questions. I hope this was useful for everybody. And thank you very much for your time and attention today.