Ocular effects of oral drugs

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I'm Dhineli Perera, your host for this episode and it's a pleasure to be speaking to Dr Hemal Mehta. Hemal is an ophthalmologist in Sydney, specialising in macular disease and cataract surgery. He also has an academic role at the Save Sight Registries at the University of Sydney. Hemal writes about the adverse effects that some drugs can have on the eye and ways to mitigate these effects. Hemal, welcome to the program.

Good afternoon.

Hemal, let's just start with something basic. What is it about the eye that makes it particularly susceptible to the adverse effects of medications?

So there are a couple of issues. The eye has a very good blood supply and therefore, when drugs are absorbed systemically, there can be a higher dose reaching the eye. In addition, there are a lot of very delicate visual apparatus in the eye, which can very easily be disrupted and hence, that's what we see with some of these common ocular side effects.

I guess that same susceptibility is what can also mean that medications that are administered into the eye can be absorbed into the systemic system as well?

It can work that way as well, although we tend to see more of issue being from systemic drugs being absorbed into the eye rather than the other way around.

Right, okay. Hemal, in your article, there's a super useful table, Table 1, that has a list of all the different classes of medications, the adverse effects, and some suggested management strategies for these effects. I was going to suggest to the listeners that it's a really nice one to keep handy as a reference, and one for you to check into the detail on your own time and those references. But one that I wanted to chat to you more about today was the angle-closure glaucoma caused by anticholinergics. How does this occur and who is it more likely to occur in? And finally, what are some of the signs and symptoms that a patient or prescriber needs to look out for?

Absolutely. Look, in terms of angle closure, it's one of those emergencies in ophthalmology because angle closure can cause the pressure to go up very high in the eye and damage the optic nerve at the back of the eye very quickly. Patients, if they do present with angle closure, often describe initially halos around objects and this is because the cornea, or the window of the eye, is developing a fluid or oedema and so as the light goes through the cornea, light rays become diffused and blurred and hence the halo phenomenon. Later on patients can report a lot of pain, often ocular pain, but actually there’re anecdotal stories of the pain being in other areas, for example, abdominal pain. Patients can report nausea and vomiting when the pressure gets very high, so it can be a number of symptoms. Signs wise, you'll often see a red eye, the pupil may not be moving as freely because the pupils become blocked in a certain position and stopping fluid leaving the eye.

Now, in terms of how do anticholinergic medications potentially cause angle closure, it's actually because they're working on the parasympathetic system and essentially that's the system that helps control pupil dilation. Now, with angle closure, it tends to occur in patients who are slightly older, maybe above 60 years of age in general, because they usually have their natural lens in place and the natural lens sort of pushes things forward, and the fluid is therefore unable to easily drain out of the eye through the trabecular meshwork at the front of the eye. You'll tend to find that this condition occurs more commonly in patients who are long sighted and have very shallow anterior chambers. Again, because they usually need to have their natural lens in place, it's very uncommon for patients who have had cataract surgery in the past to develop angle closure. It's quite a good screening question to ask as to whether patients have had cataract surgery before because it does tend to take that out of your differential list. Actually cataract surgery is one of the management options for a narrow drainage angle.

Fantastic. That's a great screening question, especially for all health professionals that might be seeing patients like this early on in their symptoms. Okay, so can you tell us a little bit more about the long-term use of corticosteroids, another really widely prescribed group of medications, and their ability to increase that intraocular pressure? Is it more specific to one agent and is it dose-related?

Yeah, absolutely. All steroids-based medications, regardless of the routes of administration, can cause the intraocular pressure to rise. Essentially, the steroids affect the trabecular meshwork and make it more difficult for fluids to leave the eye. Now, it does tend to be dose-related and also duration-related. You'll tend to find that if you're giving steroids for a very short period of time, it's probably not something you need to really worry about in terms of intraocular pressure rises, but if you're using the steroids for extended periods of time, then it can be useful to monitor the intraocular pressure. Especially because patients can remain largely asymptomatic, but still have pressures which are high enough to be causing damage to the optic nerve and gradually causing visual field defects from a secondary glaucoma, so it is something just to be aware of and to have a strategy in place for patients who are going to remain on steroids for a long period of time to have their intraocular pressure monitored. That might be with an ophthalmologist, it might be with an optometrist to be able to monitor that.

Now, as well as causing raised intraocular pressure, the other side effect that steroids can cause is cataract formation. They'll typically cause a posterior subcapsular cataract, which is very rapid in onset compared to the normal age-related cataracts that we see, and they often occur in a much younger age group than the typical age-related cataracts. Again, it's just something to be aware of, especially if you're putting the patient on steroids long-term, just to have that conversation with them at the beginning that they may develop symptomatic cataracts from long-term steroid use, but that it can be dealt with. Fortunately, we can do cataract surgery and restore the vision very effectively, usually.

Okay. That's excellent. So it's more about anticipating it because obviously people aren't on long-term corticosteroids often by choice. It's when other things have failed that we've ended up in that situation, or transplants etc. It's good to know that it's manageable. What about hydroxychloroquine, Hemal, and retinopathy? What are some of the risk factors for this adverse effect and how do health professionals who are not ophthalmologists like yourself, how do we screen for it?

Yeah. Look, I think it's a really important issue. Hydroxychloroquine is a very popular medication and has a role in a number of diseases, including rheumatological diseases and there are a lot of patients who are on this medication long term. The issue is that there's more and more evidence to show that, if you're on hydroxychloroquine or chloroquine-based medications long term, that there's a risk of maculopathy or damage to the macula gradually occurring over time and the problem is that, once that macular damage is established, it can't be reversed. Therefore, there is a role for screening patients who are on hydroxychloroquine. Now, the guidelines tend to suggest that you can start the patient on treatment and then try to arrange a screening visit in the initial six to 12 months and then after that, if the patient is low risk, you can potentially go all the way out to five years. Then, from five years of treatment, make sure that eye assessments are occurring annually.

But there are certain groups of patients where we would recommend the annual screenings start from baseline rather than year five and those tend to be patients who either have pre-existing macular disease, who have renal or liver impairment, because that can impair the excretion of the medication which means that there's essentially effectively a higher dose circulating, and also, those patients who are on a dose of the hydroxychloroquine that's higher than 5 mg/kg/day. Then the last risk factor would also be concomitant use of tamoxifen medication, which is another medication that can cause macular disease. If you have a patient in any of the above categories, then we usually recommend annual screening and if you don't have any of those risk factors, then you can start the annual screening after a baseline visit at year five.

Now, I just might mention a little bit about what the screening involves. We usually screen with a combination of a structural test and a functional test. These days the structural test is an OCT or optical coherence tomography, which is a very detailed image of the macula to look for subtle changes of damage. Then the functional test is usually a visual field test, although you can use electroretinography, multifocal ERGs as well. But the visual field test, I think the important thing to note there is that historically we were taught to do a visual field that just checks your central vision, but there's more and more studies that showed that hydroxychloroquine toxicity, particularly in patients from an Asian background, can get a more paracentral distribution of disease rather than being much more localised at the centre of the vision and therefore it's advisable to do a slightly wider field test, a 24- field rather than a 10-2 visual field.

Right, so both of these screening tests sound like they need to be done by an ophthalmologist rather than an optometrist, unlike the intraocular pressure screening?

That's absolutely correct.

Okay, that's really good to know and it sounds like it's probably something that should be just done routinely rather than looking out for symptoms or waiting for something to actually occur.

Exactly right, because it's too late in a way if the patient becomes symptomatic from hydroxychloroquine toxicity, it's by definition too late. There have recently been some updated guidance published by the Royal Australian and New Zealand College of Ophthalmologists on hydroxychloroquine screening and the reference is included in the paper.

Excellent. You also touch, later on in your paper, you've touched on the irreversible nature of macular atrophy. Is that the same thing that you're talking about here with hydroxychloroquine, or is that different?

Absolutely right, absolutely correct. There are different drugs that can cause this wear and tear or macular atrophy at the most important part of a patient's vision, at the central part of their vision. Other than hydroxychloroquine, there's chloroquine, which actually can cause even more toxicity and requires even closer screening. There's also tamoxifen that I briefly mentioned as well, which I think is an interesting one, tamoxifen, because we don't usually recommend screening all patients on tamoxifen. We only recommend it in patients who are on a higher dose of tamoxifen or who are on it for more than five years in duration. But again, it's something more and more patients are ending up on, 10-year courses of tamoxifen, and so that's something to consider if you have a patient who's been on it for a long duration of time, just to make sure that the eye checkups are happening as well.

Are there other ones, other agents that you would particularly like us to start keeping an eye out for with this?

There are. In terms of macular disease, the other ones that are probably worth knowing about is the glitazones, or in particular, pioglitazone which is a medication used for patients with diabetes. But what it can do is actually make diabetic macular oedema worse and so build up a fluid at the central vision. It's worthwhile knowing if you have a patient on that medication, especially if they develop diabetic retinopathy, because often it would be a good idea to try and change that medication, to see whether that's enough to help reduce the extent of the macular disease in those patients.

Great. That's good to know, especially given that most of the glitazones are no longer used anymore, so that's probably a good thing given that this is another list of reasons to avoid...

Very helpful, yes.

…yeah, to avoid it in general. So moving to fingolimod, which is used for patients with MS and this agent can also cause adverse effects on the retina. Can you tell us a bit more about these effects and how it's managed?

Absolutely. Fingolimod has been associated with the development of macular oedema and essentially, it often, if it does develop, it often develops in the first three to four months of use of the drug. Because it's been quite a well-recognised side effect of the drug with the development of this macular oedema, we do recommend that patients who are starting on fingolimod have an ophthalmology assessment, including OCT imaging, which can very closely look for any signs of macular oedema. That should be carried out at baseline and then also three to four months after initiation of treatment. The idea behind that is that you can pick up patients who are developing macular oedema quite early on, and then there's a decision to be made in consultation between the prescribing physician and the ophthalmologist. Sometimes if the fingolimod is the only real treatment option and it's having a very beneficial effect on the patient's overall quality of life, then we will sometimes continue the fingolimod and treat the macular oedema in the eye with local treatments. Whereas if there is an alternative drug available for the multiple sclerosis, then we may consider that instead.

So unlike the steroids, with this one we'd actually prefer to switch off it if we could? That's good to know. Now, moving to amiodarone. Now, this is a well-known drug that can cause effects all over the body. In terms of the eye, can you walk us through the effects on the eye that amiodarone can have? And given it is such a widely used antiarrhythmic drug, what should health professionals look out for to help minimise these effects?

Absolutely. First of all, there's common and then there's rare. Fortunately, the common side effect of amiodarone on the eye usually doesn't cause too many problems. What it can cause is corneal deposits, so essentially these micro deposits usually don't cause visual symptoms and they're usually quite a good exam question for physicians because usually these patients have stable signs with the amiodarone corneal verticillata present, and they can be seen on a slit lamp. So other than torturing medical students, essentially, usually it doesn't cause too much in the way of visual problem. However, rarely you can get such a build of the corneal deposits that patients become symptomatic and, if that was to be the case, then in that setting we might recommend finding an alternative to the amiodarone, but that's pretty rare.

Now, the other issue with amiodarone, which is fortunately quite rare but actually more serious, is that it can cause optic nerve disease, or optic neuropathy. That's very rare, but it's worth being aware of as a potential adverse side effect of that medication. The signs that a patient might describe if they had optic neuropathy are blurred vision, a visual field defect often with an enlarged blind spot, maybe impaired colour vision or red desaturation. These are some of the signs and symptoms you might look out for and if you had a patient on amiodarone developing those signs and symptoms of optic neuropathy, then we might consider stopping the medication.

Lovely. Well, thank you for that summary. There's quite a few drugs in there to keep in mind and I think I will just touch back on that table again for listeners to go back and have a look at in more detail.

Hemal, your article touches on the importance of reporting adverse effects to the TGA. In your research, did you come across some ocular adverse effects that were not detected in the clinical trials, but discovered via postmarketing surveillance?

I think a really classic example would be tamoxifen. We described how often you don't get side effects for somewhere up to five years after use of that medication, and most clinical trials were run for two years or less, and therefore, because of the delayed effect of that drug, we wouldn't really know about it unless clinicians had actually started picking things up and reporting them and then we'd build up the evidence base to help guide our management. I think that's probably one drug there, which is very interesting to look at.

The other one that's recently been described is a drug called pentosan polysulfate and this is a drug where again, there have been reports of it causing retinal toxicity, including retinal pigment epithelium lesions. Again, this can be dose-related and that's been picked up by clinicians reporting adverse effects in real world use.

What is that drug? I actually haven't heard of it before. What did you say it was?

It's called pentosan polysulfate. It's used in various conditions, including interstitial cystitis is one of the diseases where it's used.

Finally, Hemal, I really liked your take home message from the article, which is for prescribers or health professionals overall to really consider medications as a possible cause of any unexplained ocular symptoms. Is there anything else that you'd really like to add to this message for our listeners?

What I'd say is that Rawan, who's the pharmacist who I wrote the article with, and I were very keen to have a really user-friendly resource that busy clinicians can use. When you do look at the article, Table 1 is a summary of the main drug adverse events, and also how to manage those potential risks. We've also included Table 2, which is essentially the signs and symptoms of common eye disease that'll help you localise where in the eye the problem is likely to be. Please do use those summary tables and there's also a summary figure showing where each of the drugs affects different parts of the eyes. It's designed hopefully to be a user-friendly resource, because I know as busy clinicians, they've got to think about adverse effects of drugs for all parts of the body, but I think what I really wanted to do is just to highlight that the eye is particularly susceptible.

Wonderful. Well that's unfortunately all the time we've got for this episode. Thank you so much for joining us today, Hemal.

Thank you very much.

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The views of the hosts and guests on the podcasts are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.