 Good morning everybody, thanks for coming and we'll go ahead and get started. So I'm actually going to try to cover a couple of things today. Some with some slides and some with just talking to you, but I wanted to, last time I was here I wasn't able to get this slide presentation called up, I apologize about that, but I do want to go over a couple of these clinical trials. They're just so essential for glaucoma management these days and I wanted to cover specifically the ones that are in the basic science book. This is the new glaucoma book, it's revised this year and it looks to be pretty good and again the glaucoma looks pretty small and easy to get through and what you need to know for not only for OCAPs and boards, but just kind of managing the clinic is really this pretty good book, I think would be a really good job of glaucoma sessions. And it is my experience both when I was taking boards and OCAPs and things like that at your or the guy's stage, but then also I just went to my 10 year board recertification over the past couple of years so I've been taking all of the recertification exams including now, you have a regular test, a proctor test just like you guys have to do. And the things on those exams really are out of these books very much and especially if you find things highlighted in a table, almost for sure you're going to be tested on that in some way. And in the section on open-angle glaucoma there are four of the clinical trials mentioned specifically in that section. Now I just thought I'd go over those four clinical trials. And the four that they talk about, they talk about ages as well and sigits and the early manifest glaucoma treat the trial and the ocular hypertension treat the trial, those four. So just going to say a couple of things about those. So the ages study is one of the older studies and I was just looking here. The recruitment for the ages study took place between 1988 and 1992. So the recruitment was quite some time ago. And these are people with advanced glaucoma and it's a big study. There were over 700 eyes, a very good study, very rigorous follow up, a very specific entry criteria but again these were people already with what was considered advanced disease. And the initial reason for the trial is something that now we wouldn't really do but they were interested at that time about a sequence of treatments. And when you had to treat these people with multiple procedures which we all do, what was the best sequence? Was it to do a trabeculoplasty first followed by a couple of traps or to do a trap and then ALT afterwards and then do a trap. Now again, that's not something we would do these days but back in the day when we didn't have all that many options, that was something to be considered. And in your book right here, right in this table that is on page 114, they list, the one thing about this study is there are multiple reports that have come out of this study. It's an incredibly well described and rigorously followed cohort that's been going on now for 10, 15 years and they're still publishing some papers from it. And they've listed here that highlighted 14 different publications, all right. But the one that gets all the attention really is this ages report number 7 and that is one that's highlighted right here. And what ages report 7 indicated was this following right here that if you looked at this group and they had divided them up into what they called the predictive analysis and the associative analysis. The predictive analysis was just trying to look at if you were to follow very carefully what happened in that group for the first 18 months would that be predicted for what would happen to this group long term. And then the second was just to look at the long term follow up with those state patients. So in the predictive analysis what they did is that they divided these patients by their intraocular pressure. So they would go through that treatment sequence and then they would monitor their pressure and they divided them up into those patients that always had a pressure of less than 14. Those that were between 14 to 17 and those that were above 17, all right. And then in the associative analysis the report, this ages report 7 came out after six years of follow up. And those groups were divided again based on their intraocular pressure and it was a percentage, the number of visits with an IOP less than 18. Was it always less than 18? Was it less than 18, you know, 75% of the time, 50% of the time were less than 50%. So those are the four groups that they followed and again they were all divided up strictly by intraocular pressure, all right. So in that predictive group, you know, does what happen in the first 18 months predict what happens after six years? They found the following that eyes with pressure greater than 17 had more visual field worsening than those with a pressure less than 14. And the amount of worsening kind of continued. So that early worsening based on intraocular pressure, it was somewhat predictive in that it just kept getting worse in that group that was above 17, sorry. Now in this day and age now, I mean, my gosh, it's getting almost 20 years now since this stuff was published. I can't believe that but it is. You know, to you guys, that might just be second nature, of course it is, the pressure is higher than it was. But understand that at the time that all of these tests that we're going to go over today were getting recruited and the studies initiated, we just really didn't have that kind of information about just lowering the pressure and really make a difference in terms of pressure lowering. And you might think that's crazy but it really was the case, okay. So the next one was this associative analysis and that is just looking at these patients after six years of follow up, divided up based on what their intraocular pressure was at every visit. And did that predict, you know, how did they do? And what they found that eyes with a pressure less than 18, you know that was one of the categories, less than 18 was the cutoff, 100% of the time, all visits. So this is this group that every time they came in their pressure was less than 18. Even in advanced disease they had almost zero visual field progression. And in that group the average pressure was about 12.8, okay. So the one thing about this study that gets quoted a lot and that's where a lot of people have in their mind, you got to get the pressure of 12, okay. And it's based on this study right here. Now it really didn't say that, it didn't say to get the pressure to 12. It said get the pressure less than 18 in all visits. And that really makes a difference, okay. It's just that the average of that group was 12. And that's pretty remarkable. And that was remarkable data for us to see that even in advanced disease that those patients with a pressure less than 18 all the time did amazingly well over the six year follow up period. And then conversely eyes with less than 50% of visits with IOP less than 18. So half the time their pressure was 18 or above. They had pretty significant visual field progression. That was greater at seven years than two years. And that was what the predictive analysis said. It just kept on progressing during that time, okay. So that's the ages study. The advanced glaucoma intervention study mentioned specifically in your book. So that's one we ought to know. This is another one. The collaborative initial glaucoma treatment study or the SIDGET study. Again, it's been going on for a long time. And this one was recruited. Let me just get the dates exactly here for you. This one was recruited between 1993 and 1997. This was came in response to a study that was published out of more fields in England at the time that I was a resident. So it was published about 1992, 1993, this more field study that just took patients that were just diagnosed with glaucoma. First diagnosis, and they randomized them either to surgery or medicine. And they found that the surgery group did regularly do that. Now, we'll talk about that study. I have it in my slides, but it's not mentioned specifically in your book. But, you know, that was a good study, but it wasn't done with kind of the size and rigor and the follow-up criteria that kind of one of these large NIH sponsors, like the age study, we just went over. It wasn't in that same kind of rigor. So in 1993, very shortly after that, more field study was published, this American consortium got together to really do one of these big NIH kind of type studies. And it started recruitment in 1993 and ended about four years later and then followed. And what this was, again, a lot of patients, 607 patients, very rigorous entry criteria and progression criteria and all of that. They were randomized either to medicine first or traumatic elective. And the one thing about this study that is important relative to other studies is that this was one study where they allowed the treating physician to titrate up the use of medicines, okay? And also it's one of the very few studies of these big trials that allowed prostaglandins, which, you know, they come out now, right? They were available. And, you know, of course that prostaglandins revolutionized medical management in Oklahoma. So one of the most important things in this study right here, and it's actually mentioned specifically in the book in your table here, is that in both arms of this study there was really very significant pressure lowering. In the surgery group it was 48% and in the medical group it was 35% also. So both of these groups had a lot of pressure lowering. And what was found is that in both groups even, and this is an initial publication that over five years, the five year data was the first published data that almost, that both groups had virtually no visual field progression, right? There was greater acuity loss in the surgical group at first, but then it kind of evened out over time. There absolutely was more cataract surgery required afterwards in the surgical group, okay? And the kind of the conclusion of that five year study was that the present data did not support altering the current treatment regimen, which for most of us is to start with medicines, okay? Now subsequent to that initial, this is mostly the five year data. Subsequent to that, there's been a couple of other reports that have come out from the surgical study that are mentioned again specifically in your table here. And one of the things it said is that if the visual field loss was great at the time of diagnosis, so they had pretty severe glaucoma right at the time of diagnosis. In that group, those that got surgery first maybe did a little bit better, okay? It's not like whopping better, but there is an argument for going to surgery early if the initial diagnosis is very advanced, okay? All right, so that's the SIDGET study, another very important one to know. Another one again mentioned specifically in your book here is the early manifest glaucoma treatment trial, okay? Now this was a study that was randomized again between 93 and 97. And I'm always interested in this one because this is NIH sponsored study that was done in Sweden. And basically the reason was that it would never get through an IRB really here in the United States because already by this time there was mounting data that treatment of glaucoma was beneficial to lower the pressure really made a difference, okay? But what this study did is that 255 patients, they had early glaucoma. They met all the diagnostic criteria of having glaucoma and part of them were randomized to no treatment. That's the part that you really couldn't, you know, there's no way this study would, you know, be done today, right? You're going to randomize glaucoma to no treatment, but that's what they were. And then the treatment arm got trapezoleplasty plus betaxelol, you know, by definition. That's what they got, okay? They had very rigorous end point. They had six years of follow-up and they had, you know, good retention in the study. And this study found that those that were treated, now one of the differences between this group and the CIDGET study is that in the treatment arm here, it was just ALT of betaxelol. And so the pressure lowering was only about 20, maybe 25%, but it was more like about 20%, okay? So it didn't have that great big 35% pressure lowering that the CIDGET study had. But in this group, that progression was less frequent in the treated group. But notice that there was a fair amount of progression in both groups, okay? You know, 45% and 62%. So both groups kind of progressed. And so, you know, this is one where we looked at, yes, treatment made a difference, but there was still a fair amount of progression, and especially compared to the CIDGET study, everyone believed it was mostly due to just the lack of more aggressive pressure lowering, okay? Again, one of the definitive studies that shows that lowering pressure was beneficial, okay? So another very important thing. Now, the last study I wanted to go over, and I'm just going to talk about this one real quickly, is the ocular hypertensive treatment study. That's the fourth study that's mentioned in your book, okay? So the OAT study is one that randomized patients between 1994 and 1996. 6,750 patients. So, I mean, a lot of patients, all right? And again, these patients, the difference from this trial is that these patients did not have glaucoma. By definition, they had ocular hypertension. They had high pressure, but they had normal fields, normal nerves, okay? And they were randomized to either treatment or no treatment, okay? And again, in this study, the treatment arm only reduced pressure by about 20%, right? And in this study, the two groups, as they were followed over a five-year period of the five-year data, the rate of progression was decreased in those that were treated, and it was decreased by about half. Those that were untreated, about 10% progressed, so not that many. It's interesting, not that many. 10% progressed to manifest glaucoma over five years, and in the treated arm, about 5%. The actual numbers are 4.4 versus 9.5, okay? A five-year follow-up. So that's where this idea comes. You hear this out there a lot. The treatment of ocular hypertension reduced the risk of glaucoma by about 5%. Okay? The other very important things that came out of the OAT study that are listed right here is that the importance of doing the chemistry. All of that came out of the OAT study. That that actually came out as the number one kind of, you know, risk factor. Even more than any drop of pressure. So all of the importance that we have of the chemistry, and it is incredibly important, the chemistry, I use that almost every patient where I'm going to make a decision about treatment. I look at their chemistry, you know, and that all came out of the OAT study. So that's a very, very important thing. And then finally, another thing that came out of the OAT study is that after so, once you watch these patients, okay, and then restart them. So this observation arm, and especially those that progressed, they were taken out of the study and they were treated. Okay? So the question is, well, did delaying treatment over that period of time in the end make things worse? Okay? And the answer is it did not. Okay? So let me just read what it says right here. The primary purpose of the follow-up study was to determine whether delaying treatment resulted in a persistently increased risk of conversion to glaucoma even after the initiation therapy. Although the two groups diverged with respect to the development of glaucoma during the original study period, there was no further divergence in the follow-up. So the idea being that those curves kind of stayed the same. And so delaying treatment until glaucoma was actually manifest didn't make the end point worse. You didn't understand what I'm saying there. So just for just watching those people with ocular hypertension didn't worsen their prognosis long-term. So the idea being is that, you know, if someone has truly ocular hypertension, we still watch them. And then the final thing about the OAT study that's very important is that's where this whole idea about risk stratification came to ophthalmology. You know, like people have been stratifying patients relative to heart disease forever, you know, their age, the weight, blood pressure, et cetera. And we can now take, you know, what the four factors are, their age, their initial cup to disk ratio, their initial visual field parameter, and their pochemistry and pressure. They can factor all those in and you can basically spit out an equation that kind of allows you to assess risk, you know, their risk of developing glaucoma, all right? And, you know, there was those risk factors and they were kind of popular for a while and I don't think people necessarily, I don't generate numbers now you can. You can type in those variables for every patient. I don't do that. But I do have in my mind, very definitely, kind of what I call, you remember this original graph, is kind of the upper left and down and right. And the upper left are the higher risk people. So what are the higher risk people that have ocular hypertension? They're older. They have a higher cup to disk ratio at the start and they have thinner pochemistry and then, of course, if their pressure is higher. So, you know, if you take somebody that has a pressure of 26 and their initial cup to disk ratio is 0.6 and their pochemistry is 480, I mean, that person, their five year risk of developing glaucoma is 40%. Because they have a higher cup to disk ratio, thinner pochemistry, a little higher pressure. But on the other hand, if you take somebody with a pressure of 24, they're a little younger and their cup to disk is like 0.2 and their pochemistry is 580. I mean, their risk is 5%. So I kind of, just separating that. The upper left group is higher cup to disk ratio at the start, thinner pochemistry, higher pressure. And this group down here that has very low risk is lower pressure at the start, smaller cup to disk ratio at the start and thicker pochemistry. So any questions about those? Again, those are right out of the book and so they're important. I promise you they're important. Okay, very good. So thanks for letting me catch up there. I'm going to actually turn the lights on right now and just talk to you about some things here about medical management of glaucoma. So, medical management of glaucoma, again, the idea of treating with medicines is get the pressure down. Just a couple of kind of basic factors, basic things about that. So when you're looking to start treatment, I think that you basically are thinking about a 20% pressure lowering, okay? And especially with prostaglandins, you almost count on getting a 20% pressure lowering to start with. And if you don't get a 20% pressure lowering, just kind of in your own mind, maybe I would try a different drug, okay? So some of the basic tenets of starting therapy are you're going to look at risk profile. You're going to kind of, you know, weigh off the side effects in your mind, but quite honestly, most of the time, these days, you're going to pull a prostaglandin on the shelf as the first line of treatment. And you're looking, again, at least a 20% pressure lowering to that drug. Thankfully, most of the time, you do. And then of course, you're going to look at tolerability and how well the patient's doing, okay? And then you might have to step it up from there. But that's kind of what we're looking for. And so the key to this chapter in your book, and not just for taking no capture, just the practice of the medical management of glaucoma, the key is this table right here, okay? And this table is what dominates this section. The entire section of the book is basically just a narrative of this table. And I always want to concentrate on this table because I know when I took my own boards, there were like three, count them, three questions on this drug called Derenite. And I thought, what the heck is Derenite, you know? I had really never even heard of it. And then I went back and because I remember, I said, well, I got to look at Derenite. And Derenite was just one drug that was just mentioned in this table. And that's kind of the only place it was mentioned. And yeah, there were like three questions on my actual boards about Derenite. And I will guarantee you, and then like I said, I've just taken a recertification and all of the medical management glaucoma questions basically came right out of this table. So in the new book, the table is on page 171. So what I want to do for the remainder of our time together today is just kind of go through some of the key points of this table. And basically what the table is is it just outlines the various drug classes. All of the available drugs within that class, basic things about side effects, profile, expected efficacy, that kind of thing. And it divides them up by drug classes. So when we think of the pharmacologic agents of glaucoma, we divide them up in our mind by drug class. We just have them kind of associated in our mind of what's the risk profile of that drug class and then what might be the best ones to choose. And quite frankly and honestly, a lot of what you do within that drug class will depend on the patient's insurance and what's covered and what's not covered. You hate to make decisions based on that, but we do it all the time. And so there's some practical realities of it. But most of it is just kind of thinking about what's the expected efficacy of that class. What adds together well, right? Because that's about knowing the mechanism of action and why x-drug might work with another, you know, things like that. So let's go over a few things and we'll go over together. So the way they have divided up, I think really in order is not alphabetical, but in the order that they are most used, quite frankly. So the first class is the cross-glanded nanologs. Cross-glanded nanologs. So Xalitan was the initial cross-glanded nanolog that came out when I was a resident. Saw that 1993, 1994 Xalitan. And it was revolutionary in its uniqueness. And I'd love to talk to you about the history of the development of Xalitan. It's a fantastic story. It's maybe one of the best stories of drug development anywhere in medicine. The collaboration between academia and, you know, pharma and, you know, the big drug company. It's really remarkable. And the biochemistry of it is absolutely remarkable. You know, this cross-glanded N2 alpha, which is a naturally occurring cross-groid, you know, from the 1970s, we knew that you could give that drug to somebody and it would dramatically build up pressure. But the side effect profile was just too dramatic. And so, you know, these scientists, especially ones back in Columbia, veto back in Columbia, working with pharma just basically spent years kind of separating the side effects from the efficacy of the drug and it went through all of the different molecules and came up with Xalitan. And it was just fantastic, you know. Its side effect profile is so mild and its efficacy is so great and truly a great story. And so it was released in 1993, and like I said, we didn't know what to think of it. It was just so different and new, but gradually as we started to use it and use it in patients, he said, oh my gosh, it seems fantastic, you know, relative to the other drugs that had been, that we had available to us. And so it's really remarkable. And then you look at the others, you know, the others that came after, and there's always the M2 drugs, right? Xalitan was the main one and it was so unique. And it was so revolutionary that it was given, I think, it just went off paths a while ago. It was given like a 17-year pattern. Now if you get a 17-year pattern, I mean, it's got to be something remarkable in terms of how unique it is. It was so unique, and it was so unique, and it was so revolutionary that it was given, I think, it just went off paths a while ago. It was remarkable in terms of how unique it is, right? And it was unheard of. It was a 17-year pattern. And so these other drugs that came out, Xalitan and Luminan, you look at the difference in those, just look at them biochemically and what the Xalitan developers found, the main side effect was this redness and hybremia, okay? And they modified the drug, but what they found is that there was one double bond in it, they saturated that out. That took away like 90 plus percent of the redness, okay? Well, Xalitan and Luminan, right? We all know they cause a lot more redness than especially branding Xalitan. And the reason is that they still got that double bond in their molecule because to take it away, we didn't finish unpacking it, right? So they had to leave that in there. So it's very simply explained why Xalitan and Luminan cause a lot more redness than the redness that went double bond, okay? So it's really, really interesting just from a biochemist standpoint. So what are the main drugs that you use that are in the cross landed category? Well, what are the generic names? There's Latinopros, what are the others? Latinopros. Vomitopros, right? And then we have one other which is Topopros. The Xalitan drug, you have to preserve it free, okay? So when you think of those drugs, what are the main advantages of the cross landed drug that you use? Dosing is huge, once a day. It was the first truly once a day drug that we had in Nezra Marble, okay? So dosing is huge. What are the other advantages of those drugs? Ethics, yeah. I mean, there's nothing else like that. As a single agent, it is not uncommon with those drugs to get 30%, 35% pressure lowering from a single agent. And the clinical trials that I was showing you there, they substantiate that dramatically. Of all those clinical trials, and we could talk about the normal attention of the treatment trial in addition, again it's not mentioned here, it's a huge trial. The only trial that allowed the use of prostaglandins was that SIDGET study. And it was the only one that had 35% pressure lowering in the medicine group. Nothing else even came close to that. They're all around 20%. So efficacy is tremendous. So dosing, fantastic. Efficacy, fantastic. What are the other advantages? Yeah, tolerability. Really, really pretty exceptional. Especially with the old brand names out there. They tended to be comfortable. And well tolerated. So when you think of side effects issues and issues that come in your mind, what are the issues and side effects that you tell your patients about? Iris change. Lashes. Lashes is almost universal. And eye color change. It happens. I think it's overstated initially and it hasn't seen to be a problem. We've been using these drugs forever. The eyes that really are the ones that are most susceptible to a color change I think are kind of this kind of brownish-green color going darker. A straight blue eye I don't think I've ever seen that affected. I've seen kind of a brownish eye being made more brown. And especially kind of this brown-green color. I think that's the one that's more affected. But a dark, dark brown eye seldom gets darker. And a blue eye, I don't think I've ever seen a blue eye change nor heard more. A blue eye is usually not the one. But it is real. What are some of the other things? More recently, what's been described with the prosecuting drugs? Skin darkening. Skin darkening? Definitely. Yeah, the orbital fat thing. That's one that we missed as a profession for quite a long time. And when someone finally kind of brought up everyone's attention and we started looking for it, that is real. Kind of that orbital fat and that loss of volume in the orbit, that's very real. So those are the things that we think about as side effects. They are great drugs. They truly have revolutionized the medical treatment with glaucoma. The number of trabeculectomies performing in the United States, you can just look at it. Since 1993 and before all these other surgeries came in, there's a significant decline. And it was the introduction of the prostaglandia drugs. They do have some side effects and most of them are chlorated. What are some of the other things that are mentioned about exacerbation of arthritis? You know, CME. I think those things are probably real, but they are overstated. What I mean by that is if I'm dealing with a mediated patient and it might be that that might be one group of patients where a prostaglandin might not be the first drug that I pull out the shelf for them. But if I'm looking at a prostaglandin surgery or starting a prostaglandin, absolutely I'm going to start a prostaglandin and even the worst uveated before I slap a tube in or something like that, you know. And I've found that it almost never exacerbates their arthritis or their CME. But it is something to be having in mind. If you have a patient that has chronic CME or retinopation or something like that and they're on a prostaglandin I'll try to take them off of you. All right. But excellent drugs. The lumigant or rheumatoprost, you know, that is a drug that all of those side effects that I mentioned, lash growth, darkening, skin darkening, redness, those are all worse with lumigant and that's probably just a straight concentration issue. You look at the concentration issue, the concentration of lumigant versus the others, it's an entire order of magnitude greater than the others, okay. So I think it's just a straight concentration issue. The preservative-free, the xyoptin, you know, I think that has real benefit. There are lots, you know, we know that. There are lots of people that don't tolerate benzalconium chloride and so I end up using xyoptin quite a bit and their problems is expensive, okay. And it's not usually covered by insurance. So, Latinoprost is now generic and you know, I do think that there is some difference of efficacy sometimes in the generic Latinoprost. I think that, I wish that weren't the case and I think part of the problem you know, I think right now there are like nine manufacturers of generic Latinoprost that you never know exactly who you're going to get but I do think there is potentially some loss of efficacy with the generic Latinoprost but it's the one that now is, you know, so many insurers insist that you use. There is now a generic travertine, there's a travert prost that is out there now that you can usually write for as well, okay. Very good. Any questions about prostaglandins? I mean they are our drug of choice for most cases. So, let me ask you this then. So, when you have travertine and you're, excuse me, one of the prostaglandins you're using them and you feel like you need to get a little more pressure lowering. Any thoughts on what you might choose to add to the prostaglandins? What might be your first choice? Or is there a first choice? There's no always the correct answer but you know, I would say still most of the time a beta blocker, if there's not other contradictions, might be the one that's added next, okay. So, let's talk about those, the beta blockers. And that is indeed the next category. The beta atrogygous you know, the beta blockers. And they were always referred to as the beta atrogygous atrogygous antagonist. So, beta blockers have been around forever. Timbalol Timoptic was introduced in the 1970s I think right at the end of the 1970s. So, it's a drug that's been around for a long time. And we know a lot about it just out of use, okay. So, what are the non-selective beta blockers? And what is, that's the main category of the beta blockers is selective versus non-selective. And what's the difference there? What are the non-selective beta blockers? They block. It's beta 1 and 2, right. And the selective block selectively which ones? That's correct, okay. So, the idea is is that the beta 2s are mostly are predominating in the lungs, right. So, that's where the potential for asthma issues come. And so, beta-taxolol which is the selective beta blocker is a little less blocking the beta tubes and a little more selective for the beta ones. And so, the idea is that, you know, you might not have as much asthma exacerbation. You know, with the other drugs that we have available now that are non-beta blocker, beta-taxolol I really kind of lost its niche. And so, I don't know I mean, I have very, very few patients on beta-taxolol, right. Because if I'm going to try to stay away from asthma, I'm just going to kind of use a non-beta blocker altogether and we have other options now. So, that's kind of lost its niche. But of the non-selective, the classic one is timbolol malade, right. That's timoptic. There's timbolol hemichydrate that, the branding that is beta-lol for a lot of years. So, those two timolol drugs and then there's another couple of non-selective beta blockers that still are listed, level of unolol is one, okay. Metacolol or excuse me, metacranolol is another and cartiolol is another. And I mentioned those because they're still in this table and therefore testable even though you probably will never use them. And I just recently on my board recertification, there was a question about cartiolol. So, let's talk about those just a little bit. When you think of timolol malade, the classic non-selective beta blocker, timoptic is its brand name. So, in terms of efficacy and dosing, what are some of the things you think about? Let's talk about dosing first. It's FDA approved as a BID drug, right. But we very often use it as a single-day drug and there's lots of good data to support that. But after you've used the beta blocker, topical beta blockers for a while, you know the receptors become so saturated that you can probably use it once a day, okay. And so I use a lot of timolol once a day. But it is true that if you're going to dose it once a day when do you need to dose it? In the morning. And that's also been very well-established data that timolol or beta blockers work best during the day. And they don't provide a lot of nighttime coverage. So once a day dosing in the morning is probably pretty effective. And I've, you know, over the years I've tried it and you almost get zero bump from adding that you know, PM dose. So using the timolol in the morning once a day is usually pretty effective. But the FDA approval is twice a day. In terms of surface or just topical tolerability of the beta blockers, do you think of them as being good or not so good? Yeah, it's topical. I think it's good. I mean, it's, you know, just most people tolerate timolol from just a topical standpoint. So it's pretty well tolerated, especially just once a day. You might have some allergy itching you know, your heat without any drug. Benzoclonium chloride issue is usually the biggest concern. But it's a pretty well tolerated drug from a topical local standpoint. Of course, the big issue with with the beta blockers is the systemic part, right? The systemic side of it. Asthma is the number one, okay? And it truly is, I think, still contraindicated in anyone with asthma, reactivary COPD. I mean, I just don't do it. All of us, if you follow along and have all of us have been surprised by really making somebody worse or something you didn't know about or something just didn't know somebody had asthma or whatever and you give them that and you make them really worse when they're breathing. I think we've all done that. So we know it's very real. So, you know, in my mind using the beta blockers in that you know, group I just don't do, okay? But let me just ask you, what have you found in using them have been other categories of patients that have really struggled with topical beta blockers? Yeah, heart block is real, okay? Very definitely going to be careful with that. I don't mean if I read my mind, but the other groups that are very real, number one, is those with depression. You absolutely absolutely can exacerbate depression with just topical beta blockers and that's very real. Another thing that I we try to pay attention always to other drugs that people are on but when I'm looking about beta blockers, if they're on antidepressants I usually go to a different category of drug. Or the other thing I watch for especially is if you've got a patient that you've been treating maybe for a long time on a beta blocker and they come back and they're suddenly now taking an antidepressant, as a new drug for them, I usually take them off their beta blocker in that case. They come back on and they've been started by their physician or symptom known on antidepressant patients to stop their beta blocker to see. And then the other the other category that's very real with the beta blocker is centering dysfunction, okay? And that's another you know drugs that I watch for. So they do have they do have their systemic issues. Now the things you need to know about there's one thing you need to know about MediPramolol and another about Cartiolol because they're just testing questions, okay? And they don't use these drugs anymore. I think I have one patient that's on Cartiolol that I still write because he's been on it for 25 years in parallel. But what is the difference about Cartiolol? What's the one thing about it that is unique about it? You know, what I refer to it is this intrinsic sympathomimetic activity. Have you heard about that? That there's a little bit of alpha agonist activity in that drug. And so it is felt that it has a little less effect on nocturnal hypotension alright? And a little less effect on modifying the lipid profile. Now that's another thing that's very real about the beta blockers. It can adversely affect the cardiac lipid profile of patients. And that's there's good data to support that. Cartiolol is felt to have a little less than that and a little less effect on nocturnal hypotension. We just read that they say exactly for Cartiolol. It may have less effect on nocturnal pulse blood pressure, you know. So there's the trivia testing trivia about Cartiolol, alright? And then there's one testing trivia about metapranolol. Yeah, cause it's been associated initially with uveitis. And it probably was the carrier actually that was the problem, which has since been rectified. But we don't write for the drug anyway, but there it is on the table and there is the little question there reported by Ritis. So there's the little trivia back, alright? Now then to just say a word about the selective betaxelol you know lower risk pulmonary complications that's the only reason why it was even brought to market to begin with. It has, I think the only thing you need to know about it is truly less efficacious than the non-selective. It lowers pressure less than timbolol does. Okay? Okay, very good. So that's the beta waters. The next category of drugs that are listed here are the alpha 2 adrenergic agonists. Okay, the alpha 2 and that mostly consists of two main drugs in that alpha 2 agonist group. Which are those? Bermondings one, absolutely. And Afro-colonins the other. So these drugs came out just prior to the release of xalatant. Just prior, okay? So they were one of the very first drugs that got released by the FDA that were not a beta blocker. So, you know, when I started my residency, so 1991, when I started my residency, even then, believe it or not, we had timbolol, epinephrine derivatives, pyrocarpene, and all of that. So it's just in my professional lifetime that these other drugs have been introduced. And the alpha two agonists were in that drug category. Some of those drugs were released. They also came out when I was in my residency. Acroclonidine. Now, Acroclonidine had been released a little bit earlier in its preservative free form in these little vials for the prophylaxis of IOP spikes and antiretroviral surgeries. So when I first started my residency, we did have these little foiled couches of Acroclonidine in a little vial because it was preservative free that we would open up and we would use around laser treatments. And it was revolutionary. It was unbelievable. So I have never lived through the age of pressure spikes after laser treatment. We still see it sometimes. But they used to see it just because they would see it all the time. And these drugs were fantastic for that. But those little vials were not available for long-term use. Okay. So the first drug that was introduced was Acroclonidine in a 0.5% concentration in a bottle to be used chronically. And it was a three-time-a-day dosing. And then shortly thereafter, and again, the drug companies and their battles, Acroclonidine is an alkan drug and then Bromodidine or Alpha-Gan is an alkan drug. Alpha-Gan keeps on shortly thereafter. So when you think of those drugs, what do you think of them in terms of efficacy? Yeah, it does. They work. But it's still on the order. I mean, your book here says 20 to 30%. I think the 30% is definitely pushing it. They are more of a, in my mind, more of a 15 to 20% kind of pressure alone. Okay. But they do lower pressure. And I use these drugs all the time. And they, I think they work. I think they add well to prostaglandins. And on these days, these other drugs, one of their main qualities is how well do they add to a prostaglandin? You know, a beta-blocker, it might not be that great. You know, it's not... One of the reasons we use beta-blockers is that you get by with once a day. But they might not be the best addition to a prostaglandin drug, okay? And in fact, the combo drugs, like the Zalcom and those that are available in Europe, a combination drug of Latana Prost and Timlilalt can't get approved here. And I think they've given up. I don't think we'll ever have them here in the United States. And the big part of the deal is just the additional pressure-lowering benefit is not as great as we might hope for. And so, like I said, I think the company has given up on combining those two drugs, okay? Here in the United States, they're available in Europe. But the alpha-2 agonist, I think, added pretty well to prostaglandins. And what are the issues related to these drugs that you think of just in the clinic in terms of tolerability issues and concerns? So you're going to get about, you know, 15% to 20% lowering you hope for. What are the downsides? Higher risk or lower risk? Yeah, it's allergy. I mean, it's all about allergy. Any of these alpha agonist drugs, you know, epinephrine, you know, falls in that same category, propene. And so, like I said, when I say epinephrine, propene is the drug that we had and allergy is the issue. With all these alpha agonist, allergy is the issue. And it's still the issue. With bramonidine, it's allergy. I mean, if you didn't have these allergy problems, you would end up using it so much more and for longer. I mean, that alpha-gant allergy, that bramonidine allergy, you can recognize it from across the room so you can walk in and let your patient know, okay, we're stopping bramonidine today. And unfortunately, it happens in a lot of patients. And I think, I truly think that here in this very dry environment that we have, that it's even more prevalent than it is. And I think that was well proven when the brand name drug was out. You know, you would have so much more trouble with the cure than say it didn't see out or something where they had a much more human client. So, allergy is the whole issue, really. I mean, it's the major issue. Okay. But there are a couple of others that are, I think, are very important that you talked about with particularly bramonidine. Okay. And what's the main thing about bramonidine that you don't want to, who do you not use bramonidine in? Absolutely. Yeah, children, especially infants. And actually, we were the ones here that published that initial kind of warning. And yeah, I mean, it is absolutely real. And there have been some reports of putting infants into the hospital. But to certainly sedate them for 12 hours is, you'll do it. So, we don't give that drug to any child. And who knows what the cutoff is. But I kind of think something like you know, less than 8 or something like that, you can make them at least very tired than an infant. It's absolutely contraindicated. Much so with the apropaninine. In fact, as much less. It just doesn't cross the bloodline barrier as much. But alpha-gand bramonidine definitely does. Now, the other thing about that though is you can see it in the elderly as well. And it's something you need to watch for and ask about. That you can put an elderly person to sleep with these drugs as well. Or make them much more soft. And you know, I remember when an elderly person had started the drug about a week later I got a call from the family that just said, you know, since we started that drug grandma has just not gotten out of bed. And all we do is just open her eyes now and put the drop in. She's like, has been asleep since we started that drug. So it's real. Okay. So allergy is the biggie, but this kind of bloodline barrier issue especially infants in the very elderly is a possibility too. I mean, I use a lot of the drug. I will say this and I'm a, you know, a fan of generics and et cetera, but the alpha-gand, the alpha-gand P okay, brand name alpha-gand P is a way, way, way better drug than generic 0.2% Bermuda name. There's less allergy and the P stands for a different preservative, you know, a pyrite preservative. And so alpha-gand P, of course, is not covered very well by insurance, so you end up writing for 0.2% Bermuda all the time but way more allergy way less tolerated than alpha-gand P. That, you know, it just irked us all that when Comba-Gand came out which is an allergen drug, you know, who makes alpha-gand P Comba-Gand has the 0.2% Bermuda name. It doesn't have that 0.1% with the pyrite playing in. And, you know, that's all about money and drug development. So, you know, Comba-Gand will give you way more in my opinion, will give you way more allergy than brand name alpha-gand P because of the concentration and the lack of a different preservative, okay? All right, very good. So, those covers those drugs. Now, this the next major category of topical drug is the topical carbide antihemian. Okay? So, that's another drug. That was the first drug that came out, topical drug that came out right at the beginning of my residency. TruSoft was the drug. And that was the first kind of non-timalol drug that came out. It was also not that natural. Okay? So, boom boom boom during the time of my residency the order were released TruSoft, alpha-gand and this alpha-gand. And all three of those came out, you know, 20 how many years ago that is now? 20 plus years ago when I was a resident. So, we had all these drugs. So, TruSoft was a drug. It's a good drug. And it was really fast-tracked through the FDA. The FDA was just, you know, clamoring, give us a drug other than timalol that we can get approved because we know we need it. Right? And so, TruSoft was fast-tracked. It's topical carbionic antihydrogen. It was we use it, and we still use it like crazy, but initially it was kind of disappointing because it's three-time-a-day dosing. That's the other thing about, I wanted to say about alpha-gand and Brahminidine. Those are truly three-time-a-day drugs. Now, we use them a lot twice a day. But they are only approved by the FDA as TID dosing. And there's a very, very definite drop with that if they don't take that mid-day dose. So, unlike, you know, I said about the Bay of Blockers adding that PN dose, sometimes they don't do much. That third dose of alpha-gand and Brahminidine, that makes a difference. And, you know, the problem is that's the hardest one to get in. You know, that mid-day dose is the one that's so hard to get in just from a... that does make a difference. And the same can be said of dorsolomide. It is truly a TID drug. Okay? So, this is another drug that, let me see what your book says here. Yeah, it says 15 to 20 percent. And that's, that is, that is real. I mean, it's a 15 to 20 percent additive drug or it used by itself. The great thing about dorsolomide, you know, the topical carbide and hydrogen inhibitors. The great thing about it, in my opinion, is the systemic safety profile. I mean, I think it is as safe as we get. I was going to look at what they say here. You know, they kind of list the, you know, on common systemic... Yeah, less likely to induce systemic side effects of carbide and hydrogen inhibitors. Yeah, I mean, like way less. Compared to oral dialogs, they're like incomparable in terms of side effect profile. The biggest thing with the dorsolomide is you get kind of a bitter taste. That's probably the biggest thing you'll hear your patients describe. It is. It's pretty much universal. But it's, I think, a very safe drug. It is probably my number one drug that I pull out the shelf to treat infants, pregnant women, that need to get treatment. I think this is tops. All right? So it's about a 15 to 20 percent pressure lowering drug. It has a great systemic side effect profile. It stings. No doubt it stings. And also it does cause some allergy, absolutely. Not as much as bramonidine, but definitely more than either Timorol or the prostaglandins. So your number one allergy drugs, the number one is the epinephrine drug which you want to use, probably. But number one that you'll use is bramonidine. That category. It's the topical carbonic unhygiene. So it's your number one allergy drugs. Why do I say that? Well, when you have a patient that's taking three drugs and they've got an allergy and you want to try to find out stop the bramonidine first. If that doesn't do it, stop the carbonic unhygiene inhibitor and then finally stop something else. That's the order you would go in to try to find the drug. But it's almost always the bramonidine. Okay, very good. So I like the drug. I like these drugs a lot. Use them a lot. And then finally, brinzolomide which is azopt. Azopt is still available, brand-name azopt. Unfortunately, very, very expensive now. So we practically don't use it. But azopt in terms of comfort is way better, way better than generic dorazolomide. And it truly is. It's way, it's much more pH now. That's a pH issue. The pH of the azopt is much more physiologic, so it just stings less and is much more comfortable. But it is prohibitively expensive now for most people just because of insurance. All right, very good. Any questions about that? So those are the big four, right? You got the prostaglandins, got the beta blockers, got the bramonidine type, the alpha-2 agonist, and then we have the top of our carbonic anhygiene inhibitors. Okay? Now in the CAI category, there's a lot of talk about acidosolomide and metasolomide. You know, you can't, we've been spending the rest of the day talking about the side effects of those drugs. They are many. And, you know, there are, most of the time we think of those, I think of those drugs now as kind of temporizing agents. You know, you've got somebody with a acute glaucoma for some reason, or your pressure is 40 and you're going to take me all over and put them on that. You know what I mean? You're trying to temporize. I do, though, I have more than a few patients who are on this drug chronically for various reasons. The main one being that they, you know, we feel that their surgical risk is high enough that it's worth trying this. And the patient understands that. We all have the side effects, but they prefer that versus taking the risk of surgery. And I can totally understand that in some cases. You know, some of these patients are the ones that have had an adverse outcome of surgery in the other eye. You know, when I was a resident, everybody was on dialogues. And so, you know, the glaucoma clinic was the most miserable patient clinic. You know, people felt horrible all the time. And we knew that, but we just didn't have any other options. But we still pulled off the shelf. So, you know, we had a lot of dialogues for this kind of temporizing kind of category. I will say this, and it's absolutely true. If you are contemplating using one of these drugs for chronic treatment, use methods all the way, it is definitely more tolerable. Again, the problems are it's a little harder to find and it can be more expensive. So, if I'm thinking about using this as a chronic drug, I try methods all the way. Great. We're out of time, but again, just refer to your table here about the few remaining drugs which are the cholinergy agonists, the palocarpine group. Again, we use them very seldom. We use them all the time, very seldom now, but you'll still have a few patients on them. And so, you know, just review those and then the congo drugs. A Comagant and Crosop, I'm using the brand name, of course, and then Simbranza. So, you know, all of those drugs are good. I think of those drugs, the one I use the most is probably Dorsolomite Timolol because I think the tolerability profile is the best of that one. And I mean, Combo drugs, let's be honest, I like them a lot. You know, you can be a purist and I try to be kind of a purist, but there are many times. So, here's the thing. So, you've added a prostaglandin drug and, yes, you're number one and you've got, you know, 20% percent lowering, but the pressure's still too high and you still need to lower it. You know, your target's less than 15 and they're starting at 28 and you started prostaglandin and you've got the pressure to, you know, 20 and you think, well, okay, that's a reasonable response. I'll take that, but it's not what I want to be. I've got to have another 25% lowering of this pressure. You know, I sometimes will, in that instance, I will add a Combo drug right off and, you know, I could say the purist would say you don't do that, but, you know, the reality is you've got another 25 to 30% lowering. The chance of getting that with another, any single agent that you have available to you is incredibly low. So, you know, I used a lot of Combo drugs and in that setting I'll add them right off without step-wising, okay, but most of the time I still do step-wising. If I need about a 20% lowering, I still add just one drug. I'll add a beta blocker or add Dorsolamide or something by itself and then go to a combination, but if I still need 25 to 30%, I'll just go with the Combo drug. Dorsolamide, Timelol, I like a lot. I think it's well tolerated for the most part. It's cheap. You know, Comban is good also, but it's expensive. You know, there's no generic of it yet. But I think that drug will come off patent pretty soon because it's just two generic drugs put together to make a brand name drug. You know, it's drug games. So, because of the fact that it's just already two generics that are available, I don't know when the patent runs out. They usually don't tell you that, but it won't be very long. So, you know, we'll have a generic combination Comban before much longer. And then, Sambrenza, again, the one thing about Sambrenza is that Sambrenza is matched with Brinzolamide, which is still a brand name drug, so that patent might be a little bit longer. You know, Sambrenza, I don't use a lot of Sambrenza. It's, you know, it's just two drugs that are readily available and you still get all the allergy issues because it's got the 0.2% hormone in it. So, and it's very expensive. So, I don't see a lot of use for Sambrenza. I just use it some, but not that much. I usually use the separate agents. Okay, I don't want to keep you any longer. Thanks a lot. Have a good day.