Lecture: Advances and Thoughts Concerning Glaucoma Medical Therapy

Glaucoma medical therapy and the approaches to medical treatment of glaucoma are constantly evolving. Each of the major classes of medication available for medical treatment of glaucoma will be reviewed, along with recent new additions to our armamentarium, including fixed combination options.

Lecturer: Dr. Louis B. Cantor, Professor of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA

Transcript

DR CANTOR: I’d like to welcome everyone who’s joining us today. I look forward to a very interactive discussion. I want to thank you not only for participating, but there were a number of really great questions submitted in advance. I’m sure there’ll be some others that will be submitted during today’s webinar. That you can submit, as through the instructions. So please avail yourself of that opportunity, as we go through the talks, to submit any questions. As I hope to make this a very interactive discussion. And I again want to thank those of you who submitted questions in advance. There are some outstanding questions, and I hope we get through all of them. So with that, why don’t we get started? This morning we’re gonna talk about a lot of options with glaucoma medical therapy. And how some of the things are changing, but also a review of our medications, of the availability of medications, the different classes that we have, and some thoughts concerning each of these classes, which I believe are important. First, I think it’s important to really emphasize that glaucoma, again, is defined as this very characteristic optic neuropathy with associated visual field loss. For which elevated intraocular pressure is but a risk factor. It is the only really known improvement risk factor that we can modify. There are many other factors, which presumably — and for which there is a great deal of evidence — that contribute to this optic neuropathy, that may be beyond IOP, or even independent of the intraocular pressure. Blood flow, neuroprotective factors, neurodegenerative conditions, even some inflammatory collagen disorders and other things that may predispose the optic nerve to glaucoma damage. But today the only proven way we have of modifying the course of glaucoma is through modifying the intraocular pressure. And that’s what we’re gonna focus on with regard to medical therapy today. So we know that elevated intraocular pressure is the primary risk factor for progression. We also know that the intraocular pressure does not have to be elevated to cause glaucoma, or to lead to glaucoma progression. Individuals have a great degree of individual variability in their susceptibility to glaucoma damage. We know that for many patients, glaucoma develops without ever having an elevated pressure. We know that patients, as the disease gets more advanced, even if they had elevated pressure — but the more advanced the disease gets, perhaps the more susceptible the nerve is to further damage. So it becomes more sensitive, and even lower intraocular pressures are necessary in more advanced disease than may be required in someone with early disease. We know that there’s good evidence that lowering the intraocular pressure slows or stops progression. Though not in everybody. There are some patients who have a progressive optic neuropathy that is glaucomatous in nature, with that characteristic optic neuropathy, but they may continue to progress, despite the pressure. Again, just to reemphasize: Lowering the intraocular pressure is really our only proven target for effectively treating patients today. There are other factors, and we’ll talk about these a little bit, that I think can be taken into consideration, but the primary consideration is still intraocular pressure reduction. So this is one way of looking at it from the American Academy of Ophthalmology. Just one flow diagram about maybe how we begin to approach our average glaucoma patients. And when I’m talking about these patients, we’re primarily talking about patients with open-angle garden variety glaucoma. If you will, your average glaucoma patient, in most populations. Though obviously populations do vary a bit, and the incidence of normal tension glaucoma, angle closure glaucoma, and so forth will vary, based on different populations. But in our average open-angle glaucoma patient, we’re gonna initiate — when we determine that we need to initiate glaucoma therapy, which is a separate discussion, in some respects — not all patients who have some findings that suggest glaucoma may need therapy to start with. They fall in that “glaucoma suspect” category. And in general, with glaucoma suspects, I’m rather conservative in starting therapy myself. I think our bias in the past has largely been to overtreat glaucoma suspects, and treat too many people who maybe just have some elevated pressure, or a suspicious appearing optic nerve that mimics glaucoma, but who may not have glaucoma. We tend to overtreat those patients. But then, on the other end of the spectrum, we tend to undertreat real glaucoma, where I feel we need to treat aggressively. So I think that our shift — that there needs to be a shift in our thinking to be, if anything, more conservative with suspects and more thoughtful in really determining who we might consider to be at high enough risk to consider treatment, but once we’ve established that a patient needs treatment, and that they definitely have glaucoma, I think we then need to approach them more aggressively than maybe we have in the past. And so, getting back to our flow diagram here, when we do diagnose a patient, and we decide that it is reasonable to initiate glaucoma therapy, the most common first line therapy today is a prostaglandin analog. They are in general our most effective agents, on average providing pressure lowering in the 30% range and up, which meets the targets and definitions that have largely been set, although we’ll talk a bit about target pressure, and maybe we can talk more about it in the Q and A. But usually with our initial therapy we’re usually looking for at least a 20% to 30% reduction in pressure, or more. Depending upon how high the pressure is, what the patient’s other risk factors are, their family history, and so forth, and how advanced the disease is. The more advanced the glaucoma, the more aggressive we’re gonna want to consider our target pressure, and lower it even more. If the pressure is controlled, then fine. We monitor that patient for progression and stability. We don’t have any good way of predicting, other than based on pressure and some diurnal variability, who might progress. So we monitor those patients. If the intraocular pressure is still too high on our monotherapy, we want to assure we’re on the most effective monotherapy, first of all. We’ll talk about that a little bit more. And then we will move on. And when I talk with patients, we talk about all these options. We talk about more medicines, laser, surgery even. And the majority of patients are gonna add another agent. Sometimes we may want to switch to another agent. Maybe we’re not on the most effective monotherapy to start with. Maybe a patient was started on a beta blocker initially, which can be very effective, but if they didn’t get much response to that, do we want to add another drug to an underperforming drug, or maybe try a switch, to try to keep that patient on fewer medications and enhance compliance? So those are all discussions that we have. And then we may consider laser surgery. But usually for me that’s the next step beyond adding a second agent or switching. And some of the following steps after that. I don’t do surgery, certainly, very often, initially. And laser I’ll often use, but not as a primary therapy. But more in that second or third line therapy realm. Of course, that all depends on what’s available in certain regions of the world, where I know that perhaps surgery and other interventions may need to be considered sooner, because of the availability of some of the medications. So let’s look at our classes of medications. And I broke them out broadly here. Beta blockers. We’re gonna talk about each of these classes. Adrenergic agonists. Carbonic anhydrase inhibitors, cholinergic or parasympathomimetic agents, prostaglandins, and our newest entry, the Rho kinase inhibitor drugs. I’ve listed here the majority of the drugs in these classes. There are certainly maybe globally other drugs that fit into these classes, that I haven’t covered here. But these are the general drugs we’re going to talk about, and agents. And the ones that I’ve highlighted are because they’re sort of the representative drug that I’ll talk about. For example, in beta blockers, timolol is sort of the prototype initial beta blocker, non-selective beta blocker, that we have available. So we’ll sort of use it as our example of the beta blocker class. It’s important to also, I think, just have some knowledge of and awareness of how these drugs work. And what their mechanism of action is. There are multiple effects that these drugs can have. With our prostaglandin analogs, these drugs primarily increase uveoscleral outflow. Though they have been shown to have some trabecular effects within the class as well. Probably not consistently the same from drug to drug, but they can have some trabecular outflow. So these are — prostaglandins are outflow drugs, primarily on the uveoscleral side of the equation. Beta blockers are aqueous suppressants. They work on the ciliary body through cyclic AMP and the metabolic pathway to reduce aqueous production in the ciliary body. Carbonic anhydrase inhibitors work through the carbonic anhydrase cycle. And that process within the ciliary body, to also reduce aqueous production. So those are aqueous suppressants. Going over to the left of the slide, the selective alpha 2 agonists are now the primary drugs that we use. And they increase uveoscleral outflow, and also have some effect on reducing aqueous formation. So they seem to have a dual mechanism of action, both on the inflow and the outflow side. Which can be advantageous, and which may in part make these agents pretty effective. Our cholinergic agents like pilocarpine, being the prototypical one, they act on the trabecular meshwork as their primary effect, in improving trabecular or pressure sensitive, as it’s called, outflow. The newest class of drugs that we have is the rho kinase inhibitor drugs, and these are interesting drugs. They do increase trabecular outflow. It seems to be perhaps the primary effect. Which is nice, and good that we have that. Because cholinergic agents, pilocarpine and so forth, have been used less and less over the years. And so we’ve kind of mostly abandoned or moved away from drugs that have an effect primarily on trabecular outflow. And of course, trabecular outflow is the primary site of resistance for elevated intraocular pressure. So it’s good to have a new class of drugs or a new tool that gets back to the trabecular meshwork but doesn’t have the four time a day dosing requirements and some of the side effects of the cholinergic agents. The rho kinase inhibitors also appear to reduce aqueous production, and there’s also some evidence — still to be elucidated and better understood — that these drugs can have an effect on episcleral venous pressure. So maybe another outflow mechanism that we have not been able to take advantage of in the past may be available to us through rho kinase. Through the rho kinase class. And here’s just breaking it down simply to outflow drugs, inflow drugs, some that do both, and then the rho kinase inhibitor, possibly adding a new outflow, if you will — so it should be on the outflow side, but it’s episcleral venous pressure, something novel, that we haven’t had before. So here’s our first poll question. Which class of agents does not increase aqueous humor outflow? Here’s your choices. Rho kinase inhibitor, beta blocker, prostaglandin analog, cholinergic agent, alpha 2 agonist. If you’ll go ahead and submit your response, we’ll see what everybody came up with here. There’ll be just a few seconds while everyone’s results are being polled and collected for 20, 30 seconds here. And then we’ll get to see everyone’s results and discuss. Okay. So we have pretty good agreement with beta blocker leading the way in our poll here. And indeed it is beta blocker. As we recall, beta blockers are aqueous suppressant drugs, and that’s their pure and primary effect. So let’s talk about the beta blockers. There’s lots of beta blockers. Here’s just some of what we’ve had or have available in the US. There are certainly a number of beta blockers globally. A lot of these are marketed under different names. Generic names. And so forth. There are some differences within the beta blocker class, starting from left to right here. Timolol is, again — that’s our prototype. That was the first beta blocker in the late 1970s that was introduced for glaucoma care and treatment, and it’s a non-selective beta blocker. Meaning that it hits any beta adrenergic receptor. Levobunolol, next to that, is also a non-selective beta blocker. It’s both beta 1 and beta 2 sites. And its effect works very similar to timolol. Maybe a little bit longer acting. Carteolol is also a non-selective beta blocker that has a little interesting tidbit to it. It’s said to have intrinsic sympathomimetic activity, so it may also help stimulate the adrenergic pathway a bit. And that may sound like we’re blocking part of the adrenergic pathway but stimulating another part of it, but that’s how complex glaucoma pharmacology is, and the effect of some of these drugs — but can still be effective. Metipranolol, another non-selective beta blocker available pretty broadly. And then betaxolol there at the end is our beta 1 selective. So being selective, the main purpose in this drug was to reduce some of the side effects that we’ll talk about. Particularly the cardiopulmonary potential side effects of a beta blocker. So let’s look at some of the side effects. These drugs — we typically think of beta blockers as lowering pressure 20 to 25% from baseline. As a monotherapy agent, in multiple trials. So they’re considered by today’s standards still very effective, but moderately effective. The issues with beta blockers are twofold. Number one, in terms of their effectiveness, they are effective, as I mentioned, but there’s a fairly high rate of what’s called tachyphylaxis, where a tolerance to the drug builds up over time. And after two to three years, various studies have shown that 20% to 25% of patients on a beta blocker will stop getting a beneficial effect. Now, that’s always difficult to ascertain sometimes, because we don’t know if, when the pressure creeps up in our patients under treatment, if it’s the glaucoma getting worse or on the other hand it’s the drug getting worse. Is it no longer working? The only way to really assess that is to do what’s called a reverse therapeutic trial, where you stop the drug, see if the pressure stays the same or goes up. If it stays pretty stable, that’s an indication that the drug was no longer effective. And so instead of just adding to it, we may want to switch or just add another different drug, but stop that one. If you stop the drug and the pressure goes up, then it may have been doing something, obviously, and so we probably want to continue that drug, depending on how far it goes up. But at least it lends support that that drug was working. In terms of side effects of our beta blockers, generally these drugs are pretty well tolerated. That’s the issue with beta blockers. They’re pretty comfortable. We don’t see a lot of ocular side effects. But they do — and one of the side effects I’d like to highlight is that beta blockers by their nature stabilize cell membranes, and so they cause a mild anesthetic effect. So mild corneal anesthesia. So that may be one of the reasons why beta blockers are so comfortable, and why patients may not be as aware of their dry eye or other issues, and so those issues can then get worse, because a patient doesn’t have the associated symptoms. The major concerns with beta blockers are. Cardiovascular and pulmonary side effects, however. These drugs can slow the heart rate, lower the blood pressure, cause bronchospasm. In the early years, when beta blockers were first introduced, there were several patients who died from status asthmaticus. These cases were collected. Because patients died because of acute exacerbation of bronchospasm and asthma. Unfortunately, I have the daughter of one of those patients as a patient. And so I’ve heard about this firsthand. And that was because, early on, we didn’t really appreciate these effects so much, because in the clinical trials that were done, patients with cardiac and pulmonary disease were excluded from the study, as is typical for a lot of drug studies. So it took us not long, but it did take a while for us to come to appreciate that these effects happen, and that they can at times be severe. So we have to be aware of a patient’s medical history. Unfortunately, in our average glaucoma patient, we don’t check their heart rate. We don’t check blood pressure in the office. We don’t check their breathing. We don’t listen to their lungs, for example. So we don’t tend to do the type of medical surveillance, if you will, that would tell us if a patient is having any of these problems. And patients often don’t associate systemic problems that they may be having or symptoms with their eye drop. So we do have to be vigilant about these side effects, and be aware of them, and actually ask about these issues, and if necessary involve a patient’s other physicians, or if a patient seems to have some risk factors for beta blockers, maybe go to a different class that won’t expose the patient to the same side effects. There are also central nervous system side effects and so forth that are not uncommon, and that we are not good at screening for, and patients don’t often volunteer these side effects, unless specifically asked. Now, moving on to our adrenergic agonists, we have several adrenergic agonists, but we’ve moved primarily to our alpha 2 agonists. We do have things — drugs such as dipivefrin, which is dipivaloyl epinephrine, a prodrug of epinephrine, and epinephrine drugs that are available for patients that are non-selective adrenergic agonists. But for chronic glaucoma therapy, the majority of patients who are being treated with an adrenergic agonist today are gonna be on an alpha 2 agonist, primarily brimonidine. Apraclonidine is also effective, often used in the perilaser period, but unfortunately with chronic therapy there’s a high rate of allergic or follicular conjunctivitis. So brimonidine is sort of the prototype drug for adrenergic agonists, and is an alpha 2 agonist. These drugs also lower pressure on average 20% to 25%, in most patients. So again, effective, but considered moderately effective in general. Obviously patients vary quite a bit in these drugs. Tachyphylaxis and loss of effect to these drugs does occur. But not at the same rate as what we see with beta blockers. It’s less frequent that patients develop loss of effect. Probably 10% of the time or less. The primary reason why we may end up having to discontinue the alpha 2 agonist brimonidine is because of ocular side effects, particularly the follicular conjunctivitis. But also some drowsiness, lethargy, fatigue. Some patients will complain of dry mouth and dry nose. But we’ll talk about some methods or one simple method for decreasing at least those systemic side effects. But the follicular conjunctivitis really is the primary issue with these drugs. Some hyperemia and so forth does occur in red eye. The follicular conjunctivitis and hyperemia — if the patient is asymptomatic, that’s okay. A lot of these ocular side effects are patient-defined. It isn’t bothering the patient. If not, then perhaps we’re fine continuing on it. It’s when the patient becomes symptomatic that it becomes an issue. If they become symptomatic with a follicular conjunctivitis, your only alternative and the only treatment is to stop the drug. And at that point, you’ve also lost the class of drugs. You cannot go back to an adrenergic drug once a patient’s become sensitized. They will develop the same reaction over again. This reaction is dose-dependent. The original concentration of the drug that was marketed was a 0.2%. There’s a 0.15%, and there’s a 0.1%. And the rate of the follicular conjunctivitis is less with the 0.1%. Unfortunately that’s often not available except as a branded medication, which may pose some cost barriers and so forth. But when we use the 0.2%, we’re also increasing the risk that the patient may develop this side effect, and then we’re no longer able to use these drugs anymore, and this class goes off the options list. We can’t go to alternatives within the family. Moving on to our carbonic anhydrase inhibitors, for many years we had really only oral agents. Acetazolamide, methazolamide, and other agents, but beginning in the mid-1990s, we began to have the availability of topical carbonic anhydrase inhibitors, and that’s primarily what we use today. Brinzolamide and dorzolamide are the primary drugs now today in that class. Probably most represented by dorzolamide as the originator in this class. And that was a major shift in therapy. Many patients could not tolerate oral carbonic anhydrase inhibitors long-term, because of systemic side effects. Fatigue. Lethargy. Bad taste. And all sorts of things that could occur. They’re very effective drugs. They also cause a metabolic acidosis, which could cause issues in certain patients. So these drugs — the oral agents remain still very good and very effective. Primarily for when we need short-term pressure control for an acute glaucoma that we can manage or prior to surgery. And still some patients will tolerate these drugs long-term. But the vast majority we’ve now moved over to the topical carbonic anhydrase inhibitors. These drugs also typically lower pressure 20% to 25%. So again, moderately effective. The issues with the topical CAIs tend to be mostly ocular. The stinging — the allergic conjunctivitis that they can get. Dryness of the eye. Some induced myopia. Superficial punctate keratopathy can occur with the topical carbonic anhydrase inhibitors as well. But it’s mostly the stinging and the irritation and some red eye that causes most patients who fail these drugs to have to stop them. Again, the rate of tachyphylaxis and loss of response with time with these drugs is fairly low. Under 10%, again. Some of these patients do get some systemic side effects, even with the topical drop. Particularly the metallic taste and so forth. And you do have to be careful of patients who have a sulfa allergy, as these are sulfonamide-related drugs, and any skin rash is of concern. The other side effects are more with the oral agents, though occasionally a patient I’ve seen will get some paresthesia in their fingers. The aplastic anemia and Stevens-Johnson syndrome — those are idiosyncratic-type responses to this class of drugs. So they’re not dose-related. So at least theoretically, the rate shouldn’t be any different with an oral or a topical, because it’s not dose-related. Fortunately these types of reactions are rare, even with the oral agents. But they have been reported with the oral agents, and with the topical agents. So any patient who starts to show skin changes, who starts to get easy bruising and things, we need to be very cognizant of and keep in mind that that could be a drug-related reaction, and get them off the drug as soon as possible. Now moving to our prostaglandin family, the primary drugs represented here, Travoprost, Latanoprost, Bimatoprost — the Latanoprost led the way in this, in 1998, I believe it was, when it was first introduced. So we’ve had over 20 years now of prostaglandin analog use in glaucoma. And this really changed medical therapy dramatically. We had a once a day, a consistently once a day therapy that was more effective than anything else we had. 30% to 35% reductions in pressure. We’re seeing consistently within the clinical trials some more patients could be controlled more effectively with monotherapy. Which was a significant advance in our therapy. In our regimen. So quite an improvement. Rates of tachyphylaxis and non-responders do occur, but again, they’re fairly small. Down around the 10% range. What’s been somewhat interesting in this class is that different from other classes, if someone wasn’t responding well to timolol, we wouldn’t necessarily think of switching them to Levobunolol and seeing the effect of the drug regained. But there may be some slight differences in these drugs that have been demonstrated in a few trials, where maybe a patient, for example, who is a non-responder to Latanoprost — you can switch them instead of adding another drug, or just stopping the class. Sometimes you can stop the Latanoprost and put them on Bimatoprost, and get a response. So there’s a small percentage of the non-responders who can respond to a different drug in the class. The reason why that’s important is because it allows us to maintain monotherapy and more simple therapy for patients sometimes. And it’s just something to keep in the back of our minds and consider when initiating therapy, since we most often start… We don’t know when we’re starting therapy on a patient how they’re gonna respond to any drug. And there’s so much individual differences in how patients respond to drugs. We don’t have a crystal ball that says: Ah-ha. We just know, based on studies, on average, these drugs are gonna do X in a population of patients who have glaucoma that were studied with pressures within a certain range. The generalizability of a large group, several hundred or sometimes thousands of patients, to that single patient sitting in the chair in front of us, is where we have the challenge. So we often have to try different things, and sometimes within this prostaglandin family, a within-class switch may actually allow you to stay on a prostaglandin drug. Just because they failed one prostaglandin doesn’t mean they’re necessarily gonna fail all of them. The side effects of these drugs — again, the prototype is probably Latanoprost. Ocular side effects are certainly the most common. Iris pigmentation, conjunctival hyperemia, and what’s called the periorbitopathy. The periorbitopathy is the most common side effect. It’s where they get that darkening of the skin around the eyelids. Sometimes a little bit of a deepset orbit from some fat atrophy. Can get some ptosis. There’s lash growth. And all of that that’s occurring around the eye. I use the periorbitopathy if a patient is on a prostaglandin as my assessment as to how compliant they are with the drug. If they don’t have periorbitopathy, they’re not using the drug. This occurs in 100% of patients, to some degree. So the periorbitopathy is very common. Whether or not it’s asymptomatic or bothersome to the patient is, again, a patient-defined issue. And some patients are. Most patients aren’t. The iris pigmentation is a novel effect of prostaglandins. It’s increased melanin within the melanocytes. It’s not really proliferation of melanocytes. But it may be permanent, and probably is, and doesn’t reverse with stopping the drug. The irides that are most predisposed to this are not the light blue or the dark brown, but the ones in the middle. The sort of hazel green irides, that have some moderate or mild iris pigmentation. Those eyes can over time show darkening of the iris. Most patients aren’t concerned about this. If you’re treating bilaterally, in both eyes, you get a little bit darker. It’s generally not noticeable. Where it has been an issue is with monocular treatment, where only one eye needs treatment. And I’ve seen two patients where a prostaglandin was being used in a child, to early teens, in one eye, and it caused iris pigmentation, and that raised a big issue, and the parents wanted to sue the treating doctor in both cases, because they didn’t discuss this with them. So it just highlights that if you’re treating one eye, make sure the patient’s aware of this and discuss the options at length. If you’re treating both eyes, they should still be aware of it, but most patients will probably not be aware of it, even if it occurs. And hyperemia is very common, as long as some of the other side effects… Uveitis and CME are potential side effects of any prostaglandin. They are inflammatory mediators and related. So you have to use these drugs carefully in patients with uveitis. They can be used, particularly if the uveitis has been quiet and well controlled for a period of time. But if the uveitis becomes exacerbated while they’re on a prostaglandin, you should probably get them off the prostaglandin pretty quickly, so that you’re not trying to treat a drug-related side effect. The same goes for cystoid macular edema. Prostaglandin is probably one more risk factor for it. So if a patient is pseudophakic with an open capsule, or has some inflammatory disease, has diabetes, those are all risk factors for CME. And then you add a prostaglandin. It may just tip them over and actually cause CME. So it’s not common, but it’s something to keep in mind. Systemic effects are pretty rare, but there are a few patients who, for some reason, even with the extremely low dose of these drugs, they get almost like this flu-like feeling, where they get headache, they get some muscle and joint pain that can be drug-related, and when you stop the drug, it goes away. Our cholinergic agents I’m not gonna spend a whole lot of time on. There’s a lot of them out there. I know they’re used a lot globally still. They’re used very infrequently in the US anymore, because of all the alternatives. We have so many drugs to use these days. We can’t use everything. And some of these drugs are even hard to get nowadays. But pilocarpine, Demecarium, echothiophate, carbachol — and pilocarpine can come in different forms. I know there’s a lot of different formulations of this around the world, at different concentrations. It still can be a very effective drug. I mean, I have a few patients who are still on these drugs. But they are few. I may not see a patient on one of these drugs in a given week, or sometimes for a month. And then I’ll have a patient come in. Still very effective, though. 20%, 25%. Trabecular meshwork function is affected, and outflow through the trabecular meshwork. So useful drug, still, in certain circumstances. There are some patients, for example, with longstanding aphakic glaucoma, where echothiophate is still about the only drug that seems to work in them. And they tolerate it. So there are those circumstances. They’re just infrequent. The main reasons why we use them less is, number one, the dosing regimen was often complicated. Particularly with pilocarpine. Where to really be effective, it had to be used four times a day, because of its short duration of action. But all of the ocular side effects were the primary anchor that weighs this class down. The pupillary characteristics, the ciliary muscle spasm and eye pain, switching, in patients who are phakic, cataract formation. Allergy. And so forth. If you overuse these drugs, you could get some general systemic side effects as well. And I saw this a couple times, where patients were using their drug too much, surprisingly. Not something we see with most patients. But they would almost have to be overusing the drug. So let’s go to our next polling question. Potential side effects of beta blockers include each of the following except… So we’ll put up our — go ahead and read the responses here, and go ahead and mark your response. Bradycardia, lethargy, bronchospasm, D, periorbitopathy, E, psychosis. And while the results are getting polled, we’ll just pause for a second here. There we go. The periorbitopathy. Yes. Periorbitopathy is not a side effect associated with beta blockers. The bradycardia, lethargy, bronchospasm, and CNS effects such as psychosis can absolutely be associated with beta blockers. We talk a lot about some of the systemic side effects, and I always like this slide, because it shows two things. But just decreasing the amount of the drug that drains off the eye through the nasolacrimal system into the back of the throat, where it hits mucous membranes and gets immediately absorbed, after an eye drop like timolol, there’s been blood testing done, where within seconds there’s detectable levels of timolol in the bloodstream. And that’s because of this nasolacrimal drainage from the eye and the fact that it hits mucous membranes right away. Which is equivalent to giving a sublingual drop of it underneath your tongue, essentially. A lot of techniques have evolved for this. One is to do punctal occlusion with your fingers, and to push on the side of the nose. Unfortunately, I find patients have a hard time doing that. This patient is supposed to be demonstrating how to do it, but you’ve got to really push posteriorly and way back, in order to do that. The other mechanism, as was shown many years ago by Tom Zimmerman, actually looking at blood levels, was just simple eyelid closure. So this patient is doing both. She’s doing punctal occlusion with eyelid closure. I tell patients: Just sit with their eyes closed and count to 100, slowly, in their head, after they put in their drops. And that will in general decrease by at least 50% the amount of the drug that gets absorbed systemically. So it is a very effective means. It’s very simple. All patients can do eyelid closure. I find that most patients cannot do punctal occlusion appropriately, because you really have to push firmly and posteriorly and be in the right place. So it’s not as easy to do punctal occlusion as just simple eyelid closure, because it’s the blinking that really acts as the windshield wiper, if you will, that forces fluid down through your tear ducts. If your eyes are closed and you’re not blinking, the fluid just is absorbed locally. So let’s talk about target IOP, just briefly here. Now that we’ve talked about the drugs. So the target represents an acceptable range, number one. I would encourage people not to get too fixed on a number, but have a goal in mind. Whether it’s midteens, low teens, 10 to 12. And where you think — and at which the patient has demonstrated — that progression of their glaucoma is likely to be delayed or halted. It has to be very individualized. What pressure did the glaucoma occur? How severe is the damage? What other risk factors do they have? Age being a big one. A patient who’s 50 — we’re probably gonna set a different target than a patient who’s 85 and in poor health. You know, race. Family history. If they have five family members who have gone blind from glaucoma, we’ll probably treat them differently than the family that has multiple members with ocular hypertension and maybe they’ve had some peripheral visual field loss demonstrated, and so forth. And then always costs and risks of treatment. You know, their systemic status. Do they have diabetes? Do they have hypertension? What other things? And there are local cost issues. And the target is also dynamic. You can’t just set a target and be stuck on it. You have to be willing to reevaluate that target. Maybe you didn’t set an aggressive enough target to start with. And they progressed. Maybe the target’s too aggressive, and we’re exposing a patient to too much treatment and risk of side effects, and maybe we should back off. I do that a lot. Particularly in patients who come in who may even be glaucoma suspects, who are on three medicines. And because of some predetermination, there was some target set that said the pressure needed to be in the mid-teens, but they were only 24 to start with, with no cupping or maybe just suspicious cupping. Maybe they don’t need those three medicines. And so forth. Again, intraocular pressure is simply a risk factor. Patients within their target range may still get worse. That may be because of other factors outside of pressure. Or it may be that we haven’t set the target low enough. There are a lot of new insights in the glaucoma pathophysiology that are leading to some pressure-independent approaches to glaucoma therapy. At least to consider. For example, our alpha 2 agonists. There’s pretty good evidence that they may have neuroprotective effects with brimonidine, and that it may slow the progression or make the nerve more resistant to progressive damage. That’s not a primary reason why we use it. But it can be a secondary reason. We still have to lower pressure as our first goal. So because of that potential neuroprotective effect, for example, some people may lean more towards an alpha 2 agonist like brimonidine in low tension glaucoma, thinking that there’s other things going on. But we still want to maintain our initial pressure goal, which is to lower the pressure at least 30%. We don’t want to sacrifice that, because that’s what’s proven. That’s what’s been shown in studies. And then safety is really critical, evaluating safety and side effects in any patient. Again, achieve the lowest pressure on monotherapy, if you can. We have a tendency just to keep adding on medicines, if the pressure is not low enough, rather than reevaluating the medicines that we’re already on. Sometimes we need to stop a drug and add a drug or switch to a different drug. You want to look for drugs that have high response rates, that have low non-responder rates, that are consistent. You want to check diurnal variability in patients. You want to make sure patients are compliant and adherent to their medications. There’s a lot of things that go into medical therapy. Patients have to be able to first obtain their drug. They have to be able to then remember to get it in on a regimen, and then they have to actually get it in the eye. Some patients may be able to get the drug, and they may be fine putting it in once or twice a day, and they know when it’s supposed to go in. But they are horrible at getting it in the eye, and they miss the eye the majority of the time. So that drug has no effect or minimal effect. And we also want to minimize side effects. And then we want to make sure we’re on the most effective monotherapy, again, before resorting to and adding adjunctive therapy. A lot of times, targets can’t be reached with monotherapy. There’s a number of reasons for that. And our second line agents should provide at least an additional 15%, more like 20%. We look for 20% to even 25% for most patients. 15% is sort of the minimum hurdle. We maybe start to consider secondary variables, such as complementary mechanisms of action. Maybe the best thing to add to an aqueous suppressant isn’t another aqueous suppressant all the time. And we want to focus on safety and tolerability. This is just from one study, about the number of patients in a glaucoma — large population database — that were on one medicine versus those on two, three, or even four. So, again, depending upon the population you serve, the averages are 40% to 60% or 70%. Maybe controllable with monotherapy, but a lot of patients need adjunctive therapy. One of the reasons patients are on multiple medications is also that we’re setting target pressures lower than in the past. Which I think is good for patients who really have glaucoma. We’re being more aggressive. As patients have more advanced disease, we recognize they need even lower pressure. And sometimes even our most effective medicines don’t get all patients to the low targets. And we have to keep adding. So what do you add? If you start with a prostaglandin, obviously you’ve got every option available to you. And they’re all potentially very effective. And how you choose an agent is subject to your own personal experience, what’s available, but any of these are acceptable additive agents to a prostaglandin. The one thing I will say is that I think there’s been a general trend towards going to fixed combinations, which we’ll mention in a minute here. Earlier or more quickly. I think it depends on your target. So I would encourage you to think: How close am I to my goal in this individual patient? If I’m close to goal, let’s say I want them in 15, and I’m at 17 or 18, and I think they really need to be in the mid-teens, then adding a single agent will probably get through. But if your goal is 15, and you’re still at 23, you’re not likely gonna get there with a single agent. And so in order to shortcut, if a fixed combination is available, and to get patients to their target more quickly, we may go to a fixed combination more often in that patient, rather than just one drop at a time. The downside of that is you don’t know what drug is doing what. Because you haven’t given them each a trial. So you don’t know how effective each drug is, within the fixed combination. But that’s one of the trade-offs within fixed combinations. And it does make compliance generally easier for patients, when they’re available. Again, safety issues you have to keep in mind, and tolerability issues, when you’re doing additional therapy and complicating things. And you’ve got to really maximize the safety by looking at these risk factors. I’m not gonna go through all of these in detail, because we’ve talked already about a lot of this. But we’re adding systemic risk factors. We’re adding ocular risk factors when we add drugs. We’ve got to really weigh the risks and benefits. We’ve got to monitor them. We’re adding more preservative to the ocular surface, and so forth. And it’s also important to educate patients. And again, some side effects such as hyperemia — we can make that a big deal when it’s not. So a patient comes in with a red eye, and you ask: How are you doing? And they say: Oh, I’m doing fine. You say: Isn’t that red eye really bothering you? Now we just made a patient really self-conscious about a side effect that really wasn’t bothering them, and we may end up then sensitizing them to that issue, and they may then want to consider going off the drug, when it really wasn’t bothering them. Hyperemia and dilation of the surface vessels is not harmful to the eye. It’s only an issue if it’s an issue to the patient, really. So let’s go to our next question here. Some important principles for instituting medical therapy include: We’ll go ahead and put up our choices here. Striving for monotherapy. Choosing agents with a high response rate. Choose agents with consistent IOP lowering. Consider the individual side effects of each medication. Or all of the above. So go ahead and vote your choice. And while we’re pausing here, I want to thank Lawrence in the background for helping us all get organized and stay on track. Great. So all of the above is correct. So again, going back to our adjunctive agents, there’s been a lot of variability in response rates reported when adding a beta blocker to a prostaglandin. Anywhere from 1 to 3 millimeters. So these drugs — beta blockers can be additive to a prostaglandin. But they had been a little bit disappointing at not achieving greater pressure lowering, and we might have expected more. And it would have been ideal. Give a prostaglandin at night, a beta blocker in the morning, and we would be home free. But unfortunately the combined effect of the two drugs given adjunctively has been a little bit disappointing. And still good, and it still varies a lot from patient to patient. But this data is one of the reasons, quite honestly, why a fixed combination of a prostaglandin with a beta blocker was never approved in the US. I know they’re available many other places globally, and can be very useful, but they’re not available to us in the US. Brimonidine, as I talked about, has this dual mechanism of action. So it seems to have a good effect, when combined to a prostaglandin. Usually you can expect about an additional 20%. Brimonidine is a pretty versatile drug. In part probably related to that mechanism of action. And seems to be particularly so when added to prostaglandins, because of that dual mechanism of action. This is our carbonic anhydrase inhibitor. So if we’re working — if we have a uveoscleral outflow drug, and we add an aqueous suppressant, those are complementary mechanisms of action that may add well together. So we often can see pretty good response from a topical CAI added to a prostaglandin. So medical therapy is obviously continuing to evolve, and these individual targets are important. Safety and tolerability. Cost and availability. I want to conclude with just a couple topics real quick. Some of the advantages of the fixed combinations — obviously using one bottle instead of two helps for convenience and patient compliance. You don’t have to worry about a patient putting in one drop and then five seconds later putting in the other drop and washing each other out. Where insurance is an issue, maybe they only have one co-pay. So there are some advantages. But the primary one is the convenience and compliance. These are the fixed combinations that we have available in the US. There are many more fixed combinations globally. So this is by no means a global list. And so there are many alternatives, some you may have access to. Timolol/dorzolamide was one of the first to be combined, and then brimonidine/timolol. More recently, brinzolamide/brimonidine, and the most recent one is Netarsudil/Latanoprost fixed combination. All of these have good effects. They have a significantly greater effect than either agent given alone. But there are some caveats. This is from one of the early studies, looking at dorzolamide/timolol as a fixed combination, compared to concomitant administration of dorzolamide and timolol separately. And this is what the data looked like. And the effects, number one, of the fixed combination, which is the dark circles, compared to the concomitant administration, were both good. But the fixed combination, if anything, was slightly less effective. And this was consistent, and in some other studies was even a little bit greater. So there may be some compromise with some fixed combination agents. You just have to look at these as a new drug, and there may be… You just can’t always assume it’s gonna do the same. The majority of the time, it does. And again, the convenience factor sort of makes up for most of the other issues. This is the brinzolamide/brimonidine fixed combination in the sort of light pink or tan or whatever it is — reddish bar — is the fixed combination. And the other bars, the gray and the blue, are the individual components. Not given together, but independently. And you see it was more effective. But across the board, not always a lot more effective. Particularly at 3:00 pm. If you look at that. It’s more effective than brinzolamide or brimonidine given alone, but only by a modest amount. So there are some compromising — you have to dig into these drugs a little bit to understand them. So prostaglandins first. Generally. Consider switching before adding. Consider your goals. Fixed combinations, I think, are likely to play an increasing role. And the last topic I just want to mention is generics. Because generics are big and have gotten a lot bigger in the US, and I know that they’ve been big everywhere globally. Here in the US, under our federal plans, the majority of drugs that are dispensed are now generic. 60% to 70%. In some classes, up to 80%, 90%. There is a cost savings in general, in our system. Generics are cheaper, depending on the generic. We have some generics that are very expensive. There are some disadvantages to generics. Even in the systemic world, there’s been things noted. There may be some variations in how the drugs are manufactured, and there’s certain variances that are allowed under some of the guidance for how these drugs are to be made. From our FDA and globally, where maybe the particle size or some of the excipient, which are the inactive ingredients, may vary by plus or minus 5%. Which doesn’t sound like much, but when you start adding up four or five things that can vary by 4% or 5%, in a formulation as complicated as an eye drop — which are complicated. Eye drops are much more complicated than pills. The approval process is less rigorous for generic manufacturers. While they are supposed to have the same active and inactive ingredients, there again is some variance that’s allowed from the innovator drug. And they’re said to be identical in strength, dosage form, and route of administration, and are bioequivalent. Which means they look the same on paper. But there’s no proof that they’re therapeutically equivalent. In other words, there’s no testing in patients required. They can rely on all the previous clinical data from the innovator drug. They don’t have to do a study that says that the generic — a particular generic. Say to Latanoprost — has ever been compared to regular Xalatan, the branded innovator product. So we don’t have the same type of data, and by and large, generics have worked out well. But there are exceptions. There have been issues with oral generics. There’s a couple of areas with antiseizure medicine and antidepressants, where patients were switched from a branded to a generic, where patient effectiveness was not the same. And even led to the American Academy of Neurology issuing a statement at one point on this. We have unique challenges in our generics as well. As I said, it’s difficult to assess bioequivalence. Now, systemically, even, say with a seizure medicine, you take it orally — they can measure it in your bloodstream, and see if the drug is getting absorbed. So while they don’t have to do testing that it controls seizures as well, they can at least see that maybe it’s getting into the bloodstream. For an eye drop, we can’t do that. We’re not gonna assess how much drug is getting absorbed in the eye in studies by sticking needles in the eye and taking out the aqueous, to see if the drug is getting absorbed. So the bioequivalence testing is even limited. It really relies on just — it has to look the same on paper. And again, no therapeutic equivalence. And there have been some issues where there have been various generic formulations of different drugs over time, which have had problems. Or have been withdrawn, or weren’t — were shown not to be as effective. And I’m not gonna go into these in detail. There’s also packaging differences. How the bottle looks. The drop size can vary. Normally we want approximately a 30, 35 microliter drop to come out of a bottle. Some of the generics are made so that the drop size is 50, 60, or 70 microliters. So they get a much bigger drop than they need, and what that needs to is that the bottle doesn’t last as long, so they run out. And then you have gaps in therapy and so forth. So we really don’t know that a generic is gonna do as well, until we test it in a given patient, and how might these inactive — the excipient ingredients — affect the safety and tolerability? We really don’t know until we get a sense for these drugs, because we don’t have the data from a clinical trial to help direct us, because those trials don’t exist. And there’s also other clinical considerations related to cost. And do we have to bring patients back more often when they’re on generics, to maybe check some of these things? How much money is really saved, if that’s the case? And what is the impact on novel therapies and research? And lastly, the bottle cap colors. At least in the US, bottle cap colors — most patients have no idea the name of their drug, and they can’t remember it. But they know the color. But sometimes the generic manufacturers don’t have to. These cap colors are only suggested. And some of the generic manufacturers don’t adhere to this. So patients may get drugs of a different cap color. Usually just plain white. Which is now what our rho kinase inhibitor class is. Even the fixed combination rho kinase/Latanoprost is white. At least in the US. So we have those issues. Just to bring your attention to them. So my little slide of generic therapy. This is our facility that we have here at Indiana University. I thank you all for your attention, and I would now like to open it up, and we’ll field some of your questions. And I see there’s a number that had been posted. So I’ll start going down the list here. I see we’re probably a little over. My apologies. But we’ll try to get through as many of these questions as we can. So first question is about: What is my opinion about a new paradigm shift in glaucoma treatment? When SLT in patients with ocular hypertension and early glaucoma is performed before medical treatment? Well, there has been a lot of evidence of the safety of SLT. Even as primary therapy. The problem with SLT is, in my mind, twofold. The average pressure lowering from an SLT is about 20% to 25%. Oftentimes, our goal with initial therapy is more than that. So if we want to achieve a 30%, 35% reduction in pressure, there’s a low likelihood of achieving that with an SLT. And then they may need a medication otherwise. The other is that laser does wear off over time. On average, only about 50% of patients who have laser still have an effect after two years. Having said that, for certain patients who are adverse to medical therapy, are maybe likely to be poorly compliant with medical therapy, I think an early laser certainly can be considered, and even as initial treatment. I would not treat patients with just ocular hypertension or glaucoma suspects too aggressively, though, and consider SLT, probably, for the majority of those patients, unless you’re really sure they have glaucoma. In early glaucoma, certainly it’s an effective alternative. The next question: What are the most effective methods for neuroprotection? Again, a lot of this is unproven, and based on a lot of data, but not the gold standard-type data. Probably the greatest evidence exists for alpha 2 agonists, for brimonidine. There’s a number of studies that show neuroprotective properties in a number of models, both in vivo and in vitro models, and there’s also a study that I think is underdiscussed. It was the LOGIT study, but it looked at low tension glaucoma patients who were randomized to timolol or brimonidine. And briefly what that study showed — that was a large study. That was followed out long-term in a number of patients, looking at visual field outcomes, and it demonstrated in that population that visual field progression was, if anything, less in the brimonidine group than the timolol group, despite similar lowering of intraocular pressure. There is also evidence for most of our other drugs. Even carbonic anhydrase inhibitors and so forth. For neuroprotection. But we still don’t have what many would consider level one gold standard evidence for neuroprotection. It’s a very hard thing to demonstrate, because you have to look at issues surrounding visual function, optic nerve, and those take a long time. There’s a lot of variability in the endpoint. So neuroprotection has been a very difficult thing to demonstrate. The next question had to do with nitric oxide donating mechanisms. That’s our latanoprostene bunod. It has a nitric oxide donating group. That’s supposed to give a little bump to the pressure, and nitric oxide is also very vasoactive, so there may be some vasodilatory effects, or some impact on ocular bloodflow. Again, very interesting data. How that really affects outcomes is still unknown. We don’t have definitive evidence on how nitric oxide may impact the long-term outcomes of visual field survival. Next deals with: Which drug is most effective in pediatric glaucoma? A great question. Pediatric glaucoma is a challenge, and for the majority of those patients, we’re gonna want to move to surgical therapy a lot earlier than we do in our glaucoma patients. In congenital glaucoma, that’s really where we want to be. And most of the time, medical therapy is just a bridge until we get the surgery, temporarily. But for patients who have conditions that haven’t responded to surgery, or who need medical therapy, I think the whole panoply of drugs is available in pediatric glaucoma, as it is for adults. You have to look at the angle in pediatric glaucoma, as you do in all glaucoma. But if the angle is particularly underdeveloped, or has angle closure, then drugs that affect trabecular outflow probably are not gonna be very effective. So more often than not, we’re going to aqueous suppressant drugs in pediatric glaucoma, perhaps, in those patients. The next question: Is there a place for vitamins and supplements for the treatment of glaucoma? Yeah, I get asked this question a lot. You know, there is no evidence that vitamins and supplements have any impact on glaucoma. Including ginkgo and a number of things. I’ve studied these drugs with my colleagues here. Alain Harris has done some of those studies. We don’t have evidence for nutritional supplements in the treatment of glaucoma as we do for macular degeneration, for example. So patients ask about it. I generally say: There’s probably no harm if you want to take some vitamin supplements, but we don’t know of really any benefit that’s been demonstrated. The next question was asking to talk about the mechanism, autodysregulation, as it relates to normal tension glaucoma. So autodysregulation, or probably what’s being asked has to do with vasodysregulation… And loss of vascular autoregulatory capacity… Does seem to be present in some patients with normal tension glaucoma. For example, we see more patients who have migraine headache. Who have Raynaud’s phenomenon. And so forth. And normal tension glaucoma. The majority of patients who have Raynaud’s or migraine headache never get normal tension glaucoma. But we do see those conditions and other sort of vascular dysregulatory-type conditions more often in normal tension glaucoma than you would expect just randomly from the population. So there does seem to be something. I think we have to identify those patients. In particular, in normal tension glaucoma, we have a discussion about blood pressure. Because a lot of… It seems like a lot of normal tension glaucoma patients have hypertension. They’re on therapy. And they may be using their blood pressure medicine at night, for example. When blood pressure normally drops anyway. And so if their glaucoma is progressing, we have a discussion so that they can have a discussion with their primary care doctor about maybe changing chair medication around a little bit. Maybe just using their blood pressure medicines in the morning. But I also have some patients who have just really chronic low blood pressure. And they have low ocular perfusion pressure. They will — I have one patient who comes in with his grafts all the time. But his systolic blood pressure is rarely over 80. And he’s often in the 70s, and his diastolic blood pressure is often in the 40s. And we look at diastolic perfusion pressure. It’s just the diastolic blood pressure, and we abstract the eye pressure. And if that’s under 50, it starts to get in what we consider a gray zone. If it’s under 30, you kind of cross a sign that’s seen from previous studies, in terms of progression. Because of low ocular perfusion pressure. So if someone’s diastolic blood pressure is already in the 40s or even 50, and they’ve got an intraocular pressure of even 15, that puts their perfusion pressure way down in the 30s. And maybe even under that. So I think we do have to look at these things and take them into account in individual patients. But we have no definitive therapy for low blood pressure. We can have them take salt tablets and stuff. But I think we have to move on. Next question is: What is the dosing and concentration of the topical CAI? Well, the concentration is how it’s provided. 2%, I think, is what dorzolamide is, typically. The dosing is interesting. A lot of the labeling says three dimes a day. I rarely use these drug more than twice a day. But the three time a day dosing recommendations come from monotherapy trials for approval. Because when these drugs are approved, they’re approved as a single standalone agent, not as a combination agent. So when a drug is used as an adjunctive therapy, so you’re adding a topical CAI to a prostaglandin, that’s very different than just — because you’ve already got a treated baseline. So I typically only use these drugs twice a day. Except for in some rare fair shares, where they seem to benefit from a TID or three time a day dosing. The next question, setting target IOP for normal tension glaucoma patients, has always been challenging. Any tips? Well, the best tip for normal tension glaucoma patients comes from the Normal Tension Glaucoma Study. There was a large study conducted over many years, that looked at normal tension glaucoma patients, and they were actually randomized to treatment versus no treatment. And to briefly get to the results, what that study demonstrated was that a 30% reduction in pressure or more is beneficial. So similar to our POAG patients, but wherever their pressure started, whatever their untreated baseline is, our initial goal is to achieve at least a 30% reduction from that level. The next question has to do with maximum medical therapy. How long can we give it before giving to filtration surgery? Ah, depends on the patient and depends on how they’re doing. I have some patients who are extremely meticulous. They can use five medicines indefinitely, and it controls them. And they would rather avoid surgery. That’s kind of the exception. So I think this is a very individualized discussion with each patient. I think that we know that compliance in general goes down with each bottle that we add. And as others have shown such as Alan Robin, for example, in studies that he’s done, adding a second medication even impacts the compliance with the first medicine. Where they start using both, and then you add a third bottle it is, and it starts getting more and more complicated. So the more medicines we add, the more likely we are gonna recommend moving forward to laser or surgery, but it really depends on the patient. There was a question posted about the G6 laser therapy. Cyclodestructive procedure. I do cyclophotocoagulation, but sparingly. I’m not a big cyclodestructive fan. The problem in glaucoma is outflow. I’d like to treat that as much as we can. And normalize things. But I primarily reserve for myself cyclodestructive procedures for advanced glaucomas that have failed other procedures, have poor visual potential, already have a tube shunt, or maybe two tube shunts, in the eye, and we need something additional, and we want to spare the patient another significant surgery. Next question: How long do we wait to determine if the full effect of a drug has been reached before adding or switching? Great question. Depends on the class. So with beta blockers, it’s a month. For prostaglandins, in general, it’s 6 weeks. Although you’re mostly there in a month. But you can still see some effect up to 6 weeks, before they reach a stable baseline. For the adrenergic drugs, it’s 2 weeks. For most of our parasympathomimetics, our cholinergic drugs like pilocarpine, 48 hours is probably enough. So it really depends on the class of drugs. The next is: Which of the fixed combinations reduces IOP the most? You know, they’re all pretty similar. And you have to look at the data from the studies. We don’t have a lot of data going forward yet on our newest addition, which is the Latanoprost combination with our newest drug, Netarsudil. So that’s really kind of not known yet. But in general, they all work somewhat similar in terms of efficacy. And the different combinations sort of depend on what other drugs the patients are on. The next question — both open and closed-angle glaucoma. Use beta blockers. Beta blockers are certainly a useful tool for any type of glaucoma. The rest of the question I’m not quite following. Swollen cataract? So for advanced cataract, you can certainly use beta blocker or other drugs, but obviously the treatment there is to get the mature cataract out. My email. Somebody asked for my email or my mail. I’m happy to forward. It’s just [email protected], is my email. If anybody has any questions. I’m also reachable if there’s any cases to discuss through Cybersight. Through Orbis, and happy to work with anybody on any cases they want to submit. The role of neuroprotective drugs — not only drops, but oral tablets — there’s nothing orally that’s been proven for neuroprotection, unfortunately. The largest study that was done was memantine, which is an NMDA antagonist, which is approved for Parkinson’s and Alzheimer’s in Europe and other areas. But we have no approved oral agent that has demonstrated efficacy and neuroprotection in glaucoma. The next question, about topical medication for uveitis… Generally in uveitis, the only drugs that we typically avoid have been prostaglandins and our parasympathomimetics or cholinergic agents. Where our newest drugs will fit into that I don’t think we know yet. But generally aqueous suppressants are effective. Beta blockers. Carbonic anhydrase inhibitors. And brimonidine is also a pretty effective drug in uveitis. Now, the next question: Should we ask physicians should change systemic beta blockers in all patients to measure actual IOP? Yeah. That’s a great question. Systemic beta blockers are very common. And they can have a small effect on the intraocular pressure. Usually a millimeter or 2. And then we add our topical beta blocker. I don’t recommend that anybody change their systemic beta blocker, just so we can measure the pressure. In fact, if it’s lowering the pressure another millimeter or two, that’s fine. What the advantage is also of a patient being on a systemic beta blocker is that they’re being monitored by a physician. They’re tolerating a systemic beta blocker well. The amount of additional beta blocker load that we’re gonna give them from an eye drop is actually small. So the fact that they’re on a systemic beta blocker makes me feel better about putting them on a topical beta blocker, because I know they’re already being monitored systemically, and they’re not having side effects from a systemic beta blocker. So that makes me feel good. I just notify their physician, that we’ve added a beta blocker to their regimen. So that they’re aware of it. The next — what is the dosing for the combination drug timolol and dorzolamide/Latanoprost? I don’t know if this is referring to the triple combination, which we don’t have in the US, but I know is available elsewhere. What is the rationale for it, considering timolol is given every 12 hours? Yeah. Any fixed combination, especially ones with beta blockers, are often compromised, as I mentioned earlier. And particularly with beta blockers. I didn’t emphasize this, but for the majority of patients on a beta blocker, they’re gonna do fine with once a day morning dosing. We know aqueous suppressants don’t work as well at night, because aqueous production drops by 50% anyway. So… For example, when we’re using a fixed combination that’s to be given twice a day, that includes timolol, we’re giving the timolol twice as much as they really probably need it. And subjecting the patient to the increased risk of side effects and so forth. But that’s always a trade-off, then, against how much is it helping compliance, and what’s needed for the other drugs to be effective. We also know that, if there’s a fixed combination that includes Latanoprost, that in general prostaglandins were shown to be less effective when used twice a day than once a day. If anything, the effect was reduced. So if there’s a fixed combination out there somewhere in the world, where it’s being recommended twice a day, and it includes a prostaglandin, you’re not gonna get as full effect from your prostaglandin, because you’re overdosing with it, and too much of a good thing is not always good. Now, the next is a question about pregnancy. What is the best drug to use in pregnancy? And the answer is nothing. Without consultation with their obstetrician. There’s been multiple articles written about this. None of our drugs are proven safe in pregnancy. That being said, a lot of… There are women who are of child bearing age who are on glaucoma medications, and need it. So what we do is we really individualize this. And we’ve had discussions with patients and their obstetricians. We’ve taken patients off medication for the duration of their pregnancy. And just tried to control their pressure as best we could. We’ve even done lasers in these young women, sometimes, which we know isn’t gonna work very well. But if we can buy them a few months of effectiveness, that may get them through the pregnancy. Often we’re not having this discussion in the first trimester. It’s usually about the… It’s usually right after that. So if we can get even 6 months, we’re fine. Sometimes we only need to get 3 or 4 months. Our carbonic anhydrase inhibitors can have teratogenic effects. Prostaglandins can increase uterine contractility. That’s where they were first noted, prostaglandins. So they’re actually — some of the prostaglandins are used as abortifacients in animals, horses. So we really try to avoid medicines. Probably if you have to use something, a once a day beta blocker, 0.25%, epinephrine drugs. But those drugs have problems in fetuses and young children as well. Timolol is concentrated in breast milk, so a nursing mother shouldn’t be using timolol. And infants can develop cardiopulmonary depression from an alpha 2 agonist. So I think you have to be very careful about any of these drugs. And we try to minimize drug use, control the glaucoma some other way if we can, even including lasers and occasionally surgery, until the pregnancy has completed. And there’s another question. What is the role of phasing in diagnosis of normal tension open-angle glaucoma? I’m not exactly clear what’s meant by phasing. But if we’re referring to staging of disease, the rule really is — the general rule is, whether it’s normal tension or open-angle glaucoma, but particularly in open-angle glaucoma — is the more advanced the disease, the lower the pressure needs to be. Normal tension glaucoma is harder to predict. Normal tension glaucoma patients — you really have to look at what’s their history been. Some patients with normal tension glaucoma look really scary on their visual field, but you look back in time, and they haven’t changed for years. Oftentimes normal tension glaucoma is very episodic. And patients aren’t gonna progress as quickly. So we got through all those questions. I know there were some other questions submitted prior too, that we’re not gonna get to, because of the time here. But again, I just want to thank everyone for their attention and participation, for great questions, and to thank Orbis for sponsoring this, and Lawrence for his help in allowing all of us to come together. Thank you.

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October 4, 2019

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