DIP Episode 42 - Pharmacology of The Eye

Okay, welcome. My name is Divine. I am a PGY1 resident. Welcome to the 42nd episode of the Divine Intervention Podcasts. It's been a while. It's probably been about two weeks. Last I made a podcast, which is kind of unfortunate. The residency gets a little on the busy side, but I'm glad to be back again. And over the next few days, hopefully I should put out a couple of podcasts. So let's begin. In today's podcast, really, I'm just going to talk about the pharmacology of the eye. It's going to be a short podcast, but I'm just going to also try to integrate a few things from Reno and from some other body systems, both I want to basically use this podcast to round up our discussion of neuropharmacology that we know we're done with that permanently. So the eye, really, the drug that work on the eye, there's not many of them. There's just a few higher things you want to know here and there. But I feel like this is something that occasionally, like a noise people. So I'll try to make it as logical as possible so that it's very easy to remember. Really, eye pharmacology is not terrible. You just learn it in a logical fashion and it just sticks to your brain really well. So what if you got an exam question about a 70-year-old male that is losing central vision? What are you thinking about? Well, I hope you're thinking about macular degeneration. Remember, in macular degeneration, you lose the central vision first and then you lose the peripheral vision later.

Okay, versus glaucoma, where you lose peripheral vision first and then lose central vision later. Okay, and there are two types of macular degeneration. So there's the dry kind and the wet kind. The dry kind, basically the pathophysiology involves the deposition of something known as drosen. It's like a yellowish kind of extracellular material. And for the most part, you really cannot treat dry ARMD. I mean, there are some things you can give in the literature, like you can give vitamin E, you can give anti-oxidants, you can give beta-carotene, you can give zinc, but for the most part, it's not very treatable. Now, the wet kind of ARMD, this one is more dangerous, but it's actually treatable. So the thing that happens is that the thing that sort of destroys the eye is that you follow these new blood vessels. So the boss phrase you're looking for in tests is a neo-vascularization. And those blood vessels are kind of fragile. So they bleed and as they keep bleeding into the macular, you begin to run into trouble. So the thing is there is this enzyme that makes new blood vessels. It's known as vegeth, vasculendothelial growth factor. It helps you make new blood vessels. So if you know that vegeth helps you make new blood vessels. And it's these new blood vessels that are causing all these problems in wet ARMD. If you then make sense that you should try to inhibit vegeth. So you can give a patient monoclonal antibodies against vegeth like beversizumab and runbizumab.

Usually those drugs are given as intraocular formulations, so you literally inject it directly into the patient's eye. Now, the next topic I'll talk about is glaucoma. So in glaucoma, again, like I said earlier, you lose peripheral vision first and then you lose central vision. And remember, it's associated with an increased uptake cop to disc resure. So, classically, it's more than 50% on the exams. And if you do some kind of tonality, you'll not increase the intraocular pressures. And don't forget some other high-yield associations with glaucoma. Especially this one. So steroids, actually, if you take steroids chronically, it actually does increase your risk of glaucoma. But steroids do many bad things to you. They can cause like osteoenoccurusies of the hip, they can cause osteoporosis. So steroids can actually cause compression fractures of the vertebra. And remember, steroids can cause peptic ulcer disease. That's why if a patient needs to be placed on a steroid for more than three months, usually you place them on a PPR. So just and the osteoporosis, that's why you have to place patients taking steroids chronically on this phosphonids. So, again, osteoporosis are prophylaxis. So steroids can also cause glaucoma. That's why I'm mentioning them in this context. Now, before we talk about the pharmacology of glaucoma, I need to talk about some quick ionadomy. So the thing is, the eye has two big sections. There's a posterior segment and there's an anterior segment.

The posterior, the thing that the divisor between the posterior segment of the eye and the anterior segment of the eye is the lens. The posterior segment of the eye lies behind the lens, the anterior segment lies in front of the lens. And in the posterior segment, that's where you make the posterior humor. Now, in the anterior segment, there are two sub compartments. So again, I said there's a posterior segment. There's an anterior segment. The anterior segment has two compartments. It has a posterior chamber and an anterior chamber. I know it's annoying, but it's something that's high you to know. So posterior segment, anterior segment, anterior segment has a posterior chamber and an anterior chamber. Now, the thing that divides the anterior and posterior sub components of the anterior segment is the iris. So the iris, the posterior chamber of the anterior segment is behind the iris. The anterior chamber of the anterior segment is in front of the iris. Now, there's a special population of cells known as the ciliary body, the rest in the posterior chamber of the anterior segment. The ciliary body makes a curious humor. And it makes it through an enzyme known as carbonic and hydrates. Now, carbonic and hydrates, hopefully you remember that it's one of those high yield enzymes that are pre-tab the proximal convoluted tubule of the nephra. Remember, that's what's inhibited by carbonic and hydrates inhibitors like acerezulamide and bersulamide.

Remember, those are all sulfur drugs. And don't forget osteopatrosis. It's associated with an osteoclast defect with a mutation in carbonic and hydrates too. That's the disease you treat with interferon gamma. So, carbonic and hydrates is one of the big enzymes you need to make acerezulamide from the ciliary body, which is part of the posterior chamber of the anterior segment. And this production is actually stimulated by the activation of beta-2 receptors. Remember, those are adrenergic receptors. Now, when you make the acerezulamide in the posterior chamber of the eye, it flows around past the iris and then drains through the canal of shlem. The thing is the canal of shlem is a blood vessel. So, because it's a blood vessel, it can be acted upon by visual activity. You see what I mean as we proceed further. Now, one of the things you want to know is that the ciliary body, for the pupil, whenever you have construction of the pupil, you actually draw the iris away from the cornea and that actually promotes drainage through the canal of shlem. So, that is the angle that they refer to when they are talking about glaucoma is the angle between the cornea and the lens.

And, you see, that angle, you can decrease that angle and decrease drainage through the canal of shlem by causing my dry asses, very dilation, but if you had a pupillary construction, aka miosus, and you made the pupillus smaller, that would increase the angle and that would increase drainage through the canal of shlem. So, in open angle glaucoma, so this is classically an older person, African Americans, they actually have a pretty high risk. And the pathogenesis really of open angle glaucoma is either making too much acusumer or you are having too little drainage of acusumer. So, think of it as either a production problem, you are making too much or a drainage problem. So, the works have been clogged up, so you are not draining things as well. So, now let's talk about glaucoma drugs. Really, if you understand all these things I have mentioned, the drugs make a lot of sense. So, I already said that beta 2 receptors, when you activate them, the beta 2 receptors on the silire epithelium, you begin to make a ton of vacuous humor. So, if you wanted to treat glaucoma, you would want to go ahead and block those beta 2 receptors, and you can use drugs like timolol and needleol. Those are non-selective beta blockers, but they can also act on beta 2 receptors. So, by blocking those beta 2 receptors, they decrease the production of vacuous humor. Now, some other drugs that also use that are beta blockers, are a sebutolol and pindolol.

But hopefully you have not forgotten from the adrenergic pharmacology podcasts, that are autonomic pharmacology podcasts, that these drugs actually partial beta agonists. So, the thing is, in the presence of Norepinephrine, it's like we are still in Norepinephrine's thunder, if you make, because if you had Norepinephrine around, you'll exert the full or I guess epinephrine, since we're talking about beta 2 receptors. Because Norepinephrine really has no effects on beta 2 receptors. So, if you have full epinephrine around, it activates those beta 2 receptors, you get full epinephrine effect. But, if these guys like a sebutolol and pindolol are hanging out on the beta 2 receptor, you're getting a partial effect, you're not getting the full effect. So, it's like you're having a reversal, if you make like a functional reversal of the effects of epinephrine. So, that is blockade, relatively. So, these partial beta 2 agonists are actually pretty good beta blockers, and again, they are used for glaucoma. So, drugs like a sebutolol and pindolol. Now, alpha 2 agonists can actually be used to treat glaucoma as well. So, you see, come on, divine. This doesn't make any sense. Alpha 2 agonists is that known as adrenergic receptor, is that known as activated in business? Well, if you step back to the autonomic pharmacology podcast, you may remember that I said that alpha 2 receptors are GI coupled. So, it's an inhibitory G protein that's coupled to the receptor.

So, if you activate that alpha 2 receptor, you actually cause an inhibition of adenylate cyclists. And by inhibiting adenylate cyclists, you actually have less release of neuroepinephrine adrenergic synapse. So, think about it. If you are releasing less adenergic synapse, you can already begin to imagine that you have less of an agonist available for the activation of beta 2 receptors. And really, I think for this, I would say that beta 2 receptors, in fact, let me call back something I've said. So, if you notice, I've been saying that for the silery epithelium, you have beta 2 receptors. If I'm not mistaken, so I'll have to look this up. So, I may correct this in a little podcast. I believe there is actually beta 1 receptors as well on the surfaces, on the cell membranes of the silery epithelium. So, don't think just beta 2 receptors. Also think of beta 1 receptors. I'll check on that and get back to whoever is listening to this in a little podcast. But I'm almost certain that's the case. So, if you activate alpha 2 receptors, you decrease less than an epinephrine. Remember, those alpha 2 receptors are a negative feedback system for the sympathetic nervous system. So, you activate those. You release less than an epinephrine. So, you have less activation of the beta receptors on the silery epithelium. If you have less activation, you produce less agonist. So, that's how drugs like upper clonidine and brimonidine work.

And if you really sound out the names of these drugs, if you notice the all-endendine, just like clonidine, clonidine is a blood pressure met that works by activating alpha 2 receptors because it causes a decreased release of neuroepinephrine. Now, the next set of drugs I want to talk about are the cabonic and hydrism inhibitors. The big one I want to mention here is acetyzolomide. Acetyzolomide is a ubiquitous drug. It can work for many, many, many things. One thing you can use acetyzolomide for is for the treatment of glaucoma. I mean, it's not talking about glaucoma now. So, that should make sense. And again, by inhibiting a cabonic and hydrism, you inhibiting one of the enzymes necessary for the production of itchia suma. So, you have a decreased production of itchia suma. Now, some other high-youthins here. Acetyzolomide is actually used also to treat idiopathic intra-crenial hypertension. Also known as pseudo-tumor cerebrum. So, remember, if a patient has IiH, they have too much CSF, basically, in the ventricular system. And then it can cause trouble. Classically, on the exams, they'll tell you about young female, like 20s, 30s or early 40s. That has a high BMI, so like 35. And they could tell you that, oh, she takes vitamin A, or she's being treated for acne, with a vitamin A derivative, and she has like eye pain, she has headaches, like chronic headaches. And they tell you, oh, you do a physical uponoscopic exam, and you observe papillodema.

So, that's pretty classic for idiopathic intra-crenial hypertension. So, if you know that too much CSF and elevated CSF pressures, I implicated in the path of physiology of this disorder, you can try to kill an enzyme that is necessary for the production of CSF, like carbonic and hydrates. Another thing you could also do for these patients is to do like a large, like to do like a lumbar, like serolumbar punctures, to just drain off some of that fluid. Now, another thing you can use as a lumbar for is altitude sickness, right? So, let's think about some physiology here. If you go to higher elevations, what happens to your O2 tension? Your oxygen tension? It should decrease, right? Because yes, your FIO2 is not going down, it's still like 21%, but remember the higher you go, the less the atmospheric pressure, right? So, as you go higher in the atmosphere, atmospheric pressure goes down. So, if you're taking 21% of like 700 as against 21% of 760, you can already begin to see that you have a decreased oxygen tension as you go higher, right? So, because the oxygen tension in the atmosphere decreases as you go higher, right, to higher elevations, you begin to get hypoxic, right? And the way your body tries to respond to that is by encouraging hyperventilation. Now, if you hyperventilate your blowing of a ton of CO2, right? So, that causes a respiratory alkalosis, okay? Causes a respiratory alkalosis.

Now, the thing is your body will take a few days to try to compensate for that respiratory alkalosis. Remember, your body will compensate for that respiratory alkalosis with a metabolic acidosis. You can speed that compensatory process along by giving us a desolamide. Remember, by inhibiting carbonic and hydrates at the level of the proximal convoluted tubule, you do not reclaim by carp at the PCT. So, that by carp is dumped in the urine. When you dump it in the urine, you actually create metabolic acidosis as a side effect. In fact, remember that acidosolamide is one of the few diuretic. In fact, it's probably like the only high-yield diuretic that causes a metabolic acidosis as a side effect with a concomitant hypochylinear. That is very rare, right? Because most of the other diuretics cause metabolic alkalosis and hypochylinear. You use the metabolic acidosis side effect of acidosolamide to make that compensation by the kidneys faster. So that you can create that metabolic acidosis to compensate for the respiratory alkalosis that you get from hyperventilating to bring in as much oxygen as possible. Now, remember again, they could make this like a nifty question on the test. Because acidosolamide, basically by virtue of its mechanism of action, causes a type 2 renal tuberculosis, right? Because again, it's acting at the level of the proximal convoluted tubule. So it's causing a proximal RTA, which is a type 2 RTA.

Now, one of the high-yield things you probably want to know about acidosolamide is actually a few more high-yield things you want to know about acidosolamide. One is that it can actually be used to treat central sleep apnea. So the thing is, I always wondered, like, why is that the case? The thing is, I really have not found any convincing explanations online, but or like in papers or whatever. But there is something that makes teleologic sense to me. So I'm going to try to explain it in that context. So I already said that acidosolamide inhibits carbonic and hydrates, right? And inhibits carbonic and hydrates. I already told you that you get a metabolic acidosis, because you are dumping a lot of bicarb in the urine. Now, think about it. When you get a metabolic acidosis, how does your body try to compensate? Well, I hope you're thinking that it compensates with respiratory alkalosis. And to achieve that respiratory alkalosis, what do you need to do? You need to hyperventilate, right? So if a patient has a central sleep apnea, where they have like a decreased respiratory drive, you could try with acidosolamide to essentially create an acybase deficit that will force the body to hyperventilate as a compensatory response. So that's my teleologic means of understanding why acidosolamide could potentially be used for the treatment of central sleep apnea. Now, other high-yield things with acidosolamide, right? So you probably know about cysteineria, okay?

It's like a defect in cola transporters at the level of the nephron. The level of the proximal convoluted tuberitis. So remember, cola is the C stands for cysteine, the O stands for ornithine, okay? The L stands for lysine, and the A stands for arginine. Remember, arginine is used to make nitric oxide. Now, those things, because that transporter doesn't work, they all show up in the urine, okay? Now, the thing is, cysteine can form kidney stones, okay? Remember, it's the kidney stone that looks like a benzene ring. It's a six-membered ring. In fact, there's this fancy pneumonia you've probably heard of as you study it. That cysteine sounds like 16, okay? To help you remember that cysteine stones are shaped like a benzene ring. Now, so they're hexagonal crystals. So the thing is, these cysteine stones, you can actually increase, like you could actually dissolve them in the urine, and sort of like prevent a kidney stone, if you may, by alkalizing the urine. Now, by virtue of us, it is a long-mine mechanism of action, right? You can alkalize the urine. When you alkalize that urine, you basically increase the pH of urine, and by doing that, you can dissolve those cysteine stones. Now, also don't forget that as a zoolomite is a sulfur drug, right? So if a patient has a sulfur allergy, no as a zoolomite. The hyaluronic, you probably want to know about, that is not a sulfur drug, is the loop diuretic ethycrenic acid, okay?

It's just, it's not used very commonly because it's auto toxic. Now, also don't forget that if a patient has like a proteus mirabilis UTI, for example, remember proteus is a urese positive bunk, a zoolomite could technically worsen that, right? Because again, it raises the urine pH by dumping more bicarb in the urine, because it's inhibited, carbonic, and hydrates. Now, the last set of drugs I'm going to talk about are the prostaglandin analogs, okay? So these drugs are ending prost, right? So like latano prost, travel prost, bimado prost, they are all used for the treatment of glaucoma. The thing is again, I mentioned earlier that the canal of schlem is a blood vessel, okay? So if you give a prostaglandin analog, remember prostaglandin caused visodilation, you can dilute that canal of schlem and promote the drainage of ethycrenic sulfur, okay? The big side effects you want to know with these drugs, you can cause like a discoloration of the eyelids, okay? They can cause like a discoloration, or they can cause like thickening of the eyelashes, okay? So you just sort of keep that thing in mind. Now, whoops, I made a mistake. So just some real quick things. I guess I'll go ahead and talk about like close-down Google of coma, right? So close-down Google of coma, basically, if you have anything that suddenly dilates your pupil, okay? Say for example, you go to the movies and in the movies, right? Because of the, let's say you step out into the light, right?

I mean, sorry, that, for example, right? So if you're in, if light is showing your eye, right? You have like a popillary constriction, right? And then let's say you then go into darkness and then you open that darkness, you're getting into causes-popillary dilation. That can acutely narrow the angle between the iris and the cornea, okay? And that can trigger a closed-angle-glo coma, classically on exempts it's in young agents, okay? So, so for closed-angle-glo coma, what could you do, right? So you could give a serosolamide, although that's probably not first line. But the other things you could do, right? Classically on exempts, you do like a laser aeridotomy. So you basically use like lasers to burst holes in the iris so that you can promote drainage of that ekeosumer. But another thing you can do is you can actually give muscarinic agonists, right? Because muscarinic agonists, they cause pupillary meiosis, right? So pupillary constriction. So that increases that angle between the iris and the cornea so that you have better drainage through the canal of slim. And don't forget that closed-angle-glo coma classically shows up as a rock-hard eye in a patient with nausea and vomiting on tests. So, that is where I'm going to end today. Thank you for listening. I will hopefully make a 43rd podcast soon. And we show the best. Have a wonderful month and God bless. Thank you.

Central vision loss first, followed by peripheral vision loss later.

Glaucoma.

Carbonic Anhydrase (CA).

Anti-VEGF monoclonal antibodies (e.g., bevacizumab, ranibizumab).

They activate $\alpha_2$ receptors, which are negative feedback mechanisms for the sympathetic nervous system, leading to decreased release of norepinephrine and thus less agonist available for ciliary body $\beta$-receptors.

Increased risk of glaucoma (and osteoporosis/PUD).

Cysteine stones; they are hexagonal crystals formed due to defects in cysteine transport.

Dry ARMD involves drusen deposition (non-treatable); Wet ARMD involves neovascularization caused by VEGF, which is treatable with anti-VEGF antibodies.

Nebivolol or Pindolol.

Carbonic Anhydrase (CA).

Acetazolamide.

Type 2 Renal Tubular Acidosis (RTA).

The lens.

Prostaglandin analogs (e.g., latanoprost) or possibly beta-blockers/alpha-2 agonists, but prostaglandins are most directly linked to this mechanism.

Dry ARMD involves drusen deposition (non-treatable); Wet ARMD involves neovascularization caused by VEGF, which is treatable with anti-VEGF antibodies.

Nebivolol or Pindolol.

Carbonic Anhydrase (CA).

Acetazolamide.

Type 2 Renal Tubular Acidosis (RTA).

The lens.

Prostaglandin analogs (e.g., latanoprost) or possibly beta-blockers/alpha-2 agonists, but prostaglandins are most directly linked to this mechanism.