Episode 96: PD Medications and Side Effects

Dan Keller 0:07

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

Most people with Parkinson's disease take medications to alleviate symptoms, but along with every drug comes the possibility of adverse effects, also commonly called side effects. These unwanted side effects to medications can be minor or more troublesome, such as dyskinesias and hallucinations, so most therapies are a balance, minimizing the downsides of a drug to increase their tolerability, making people more likely to take them, and thus increasing their benefits. The good news is that side effects do not affect everyone taking a certain drug, and moreover, they can often be minimized or alleviated by working with your healthcare team.

I spoke with neurologist Dr. Irene Richard of the University of Rochester, who described various approaches to alleviate side effects of drugs. A key aspect is to be aware of what may occur when starting a new drug, reporting problems when they do occur, and having reasonable expectations for the benefits of a drug, as well as its downsides. When people go on anti-Parkinson drugs, what are some reasonable expectations in terms of what symptoms they may alleviate and what they don't attack?

Dr. Irene Richard 2:03

I think that it's important, like you said, to have realistic expectations of what symptoms may improve, and of course, between you and your physician, you have to have an understanding of what medication might be helpful for what symptoms. So the way that we look at this, we might call them dopa-responsive symptoms versus non-dopa-responsive symptoms. So if you think about early on in Parkinson's disease, when you think about what core symptoms are, we usually think of bradykinesia, right? So a slowness of movement. In reality, people will have both slowness as well as a reduction in kind of the amplitude, so the movements will be smaller, as well as a worsening in the rhythm. What happens is that normally dopamine would control our movements such that, you know, they were quick and they were big and they were rhythmic.

The control of movements and dexterity is one of the core features of Parkinson's disease that does respond very well to medications that improve the function of dopamine, as does what we would refer to as rigidity. Even though someone may or may not be aware of the fact that they have rigidity, both rigidity and bradykinesia do respond relatively reliably to medications that improve dopamine. On the other hand, the third core feature of Parkinson's disease that people will often have early on would be a tremor. It's usually a resting tremor present when they're not doing anything, and it tends to go away or improve as you move the limb, but tremor is something that is variably responsive to our dopaminergic medications. So some people will get a good response to a medicine that improves dopamine function, some people will get a modest response, some people will get a little response, and then there are people whose tremor does not respond at all to any of our dopaminergic medications. And if you look at the cardinal features, the two things that get better reliably are bradykinesia and rigidity, and tremor is a little bit hit-or-miss, and you don't know until you try, and you may have to go to higher dosages.

On the other hand, there are symptoms that people will often get with Parkinson's disease that not only don't respond to dopaminergic medications, but, you know, they may not respond to any medications, and those might include problems with balance and problems with thinking or cognition, for example.

Dan Keller 4:41

Let's talk about adverse effects, or as people more commonly call them, side effects of some drugs used for Parkinson's disease. What side effects are often encountered with which kinds of drugs?

Dr. Irene Richard 4:54

In general, the majority of medications that we use to treat the motor symptoms of Parkinson's disease, they increase the function of dopamine, because that's what's missing. Anything that increases the function of dopamine will tell you to improve movement, but it also runs the risk of causing what we call mental status changes, so that could be confusion or visual hallucinations, for example, and really those can happen with any of the medications we use to treat the motor features, although some people are more vulnerable to those side effects than others. In the same vein, certain medications are usually a little bit worse than others, you know, in their ability to cause that.

So if we were going to break down classes of medications, what I would say is that the medication that's the most effective, and that we know has been around for a long time, and is the most likely to help with Parkinson's motor symptoms, that's the medication we often refer to as Sinemet, carbidopa-levodopa. The side effects of Sinemet are actually relatively mild. People can get nauseated, but usually by starting at a very low dose and going up very gradually, we can prevent or minimize nausea. Another side effect might be lightheadedness when you first stand up, and that's caused by a combination of the fact that blood pressure control is disordered in Parkinson's itself, and then the medications like Sinemet kind of contribute to that, so those are kind of the short-term side effects if you were to look at Sinemet, or carbidopa-levodopa.

Another class of medications, which are called the dopamine agonists—basically, the brain receptors think that they're dopamine, even though they're not, and these are medications like pramipexole, the brand name of which was Mirapex, or ropinirole, Requip, rotigotine, or the Neupro patch. So those medications, they can help motor symptoms, not to the extent that the carbidopa-levodopa would, but they can. So the most common side effects that they have that we usually are concerned about: they can be sedating, so they can make people sleepy, and sometimes that sleepiness can come on suddenly. Some people have referred to that as sleep attacks, which is obviously a big concern—for example, somebody's driving and they may not have much warning before they fall asleep. Another is edema, and that's actually swelling of the extremities. It's usually swelling in the legs. In and of itself, that's not particularly dangerous, but it's something of which to be aware, so that you don't go, let's say, pursuing an entire workup with your primary care doctor. They are probably a little more likely than levodopa to cause visual hallucinations in people who are vulnerable to them, and that tends to be people who are older or who have cognitive impairment.

And then the other really important potential side effect of any dopaminergic medication, but probably of most concern, or most commonly with the dopamine agonists, we refer to them as impulse control disorders. And this is basically compulsive behavior, so people can't control their impulse and will do things that they ordinarily wouldn't, or they don't necessarily want to. And the best example I would say is what we refer to as pathological gambling. And there are people who have never gambled in their life, and they start a medication like a dopamine agonist, and they've gambled away their life savings. And when the drugs first came out, we didn't realize that association, and once that association was recognized, it's become really important to let people know about that, because it doesn't seem intuitive that one would think this medication taken for my Parkinson's disease is making me gamble, but the reality is that it can. So we always like to kind of warn people ahead of time just to be aware of it. It doesn't happen to everybody. Younger people tend to be a little bit more prone to it, and certainly people who have either a personal or family history of impulse control disorders or substance abuse, but plenty of people who develop it really don't have a personal or family history of such things. So, you know, that would be with the agonists.

Another medication that we use is called amantadine. It's kind of in a class of its own because it does a lot of different things. It can help the underlying symptoms of Parkinson's. It can also help reduce the dyskinesias that people get over time when they take dopaminergic medications. So those are those wiggly, wriggly movements that people have, and amantadine can not only help the underlying things like the slowness and the tremor, it can also help reduce those dyskinesias. The side effects of amantadine are similar to the others in that it can cause confusion or hallucinations, but in addition, it can cause the swelling in the legs, as well as a rash—a very distinct rash, which is a kind of lacy-patterned reddish rash on the legs. It's not dangerous, but it is something that can be associated with amantadine.

And then probably of most concern with amantadine are what we refer to as anticholinergic effects, and those are basically things that, for the most part, people with Parkinson's already had problems with, so they can get even worse. That would be things such as confusion, problems with, let's say, being forgetful, dry mouth, constipation, difficulty starting to urinate—all of those things, again, we refer to as anticholinergic side effects, and those can be seen with amantadine. In addition, amantadine can sometimes cause insomnia. And the one other thing to keep in mind with amantadine is that, unlike the rest of our medications, it's cleared by the kidneys. If somebody's kidneys, let's say, aren't really working perfectly well—if somebody has some difficulty with their kidney function—the amantadine will build up in their system, so they'll be more prone to getting side effects of it.

Sometimes we add medications, we mix medications. People are aware of that one class of medications called the MAO inhibitors. They decrease the amount of dopamine that's broken down in the brain and therefore increase the available dopamine, and sometimes they're added on to existing medications just to kind of prolong the effect or kind of give a little extra benefit. Those really have similar side effects to the others that I talked about in their potential to cause hallucinations, also their potential to cause a drop in blood pressure when first standing up. And the one other thing I guess I'd mention about them is people will get warnings along with their—when they get their prescription filled, or even the doctor, a warning might pop up as they're making the prescription—that you don't want to combine those with some other medications, including commonly prescribed antidepressant medications. We prescribe antidepressants along with those MAO inhibitors all the time. We just let the pharmacist know, "Yes, we're aware of it," but that's a very commonly prescribed combination.

Dan Keller 12:14

What can be done? Can you just list some things that help to mitigate side effects in general? What sort of approaches do neurologists take to help people overcome them, or even hopefully eliminate them entirely for a certain kind of drug?

Dr. Irene Richard 12:31

The first thing is just, first of all, to establish for sure that it is a side effect of the medicine. It's usually pretty obvious, though not always, so you hopefully only make one change at a time, so you know what's causing what. But if it does appear as though you're having a side effect related to a drug that you started, one thing you might do, it depends, first of all, how serious the side effect is. Right now, for example, if you were to start Sinemet, or carbidopa-levodopa, and you got nauseated, one approach would be, "Okay, let's back down, let's start at an even lower dose, and go up even more slowly to let your body get used to it," because even though you might not have been able to tolerate a rapid increase, maybe if your body gets used to it over time, you will be able to tolerate it, and actually that's usually the case. Another possibility would be that you just have to lower the dosage, you know. Everybody is different.

I would say that one important thing to think about, I'd mentioned to you that all of these medications can potentially contribute to this drop in blood pressure when you first stand up. That's called orthostatic hypotension, and that's actually a pretty big problem, because people stand up and they get dizzy, their blood pressure drops, and all of our medications that I just mentioned, except for amantadine, tend to do that. We will often tell people, "Okay, well, get up slowly, make sure you're well hydrated, you know, add salt to your diet." There are a lot of things that you can do that are, you know, quote conservative measures, but the other really important thing is to look at your other medications that you're on, perhaps for different indications and prescribed by a different doctor.

And the most common ones are medications that you have been taking, for example, for high blood pressure. So you might have had a history of high blood pressure, be on a medication for high blood pressure, and all of a sudden you get Parkinson's disease, and then, particularly when you take a medication to treat it, you no longer need that high blood pressure medicine, and in fact it can worsen that phenomenon of the blood pressure dropping. And another example of a medication that can do the same thing, there are certain medications that are used, particularly in men who have prostate problems and initiating urination—Flomax is an example—that can also cause that orthostatic hypotension. So you kind of have to look and make sure that you're not having an additive effect of two different medications, and in some cases you may just have to make a choice of, you know, well, if you really need the other medication and your conservative measures don't work, you're going to have to either stop the Parkinson's medication or you can treat a side effect with another medication. It's not what we like to do. We don't like to keep adding more medications, but there are medications that we do use, not uncommonly in Parkinson's disease, to increase blood pressure. So depending on the side effect, depending on the medication, there are a lot of different ways that we can kind of deal with the side effects. And the other thing to keep in mind is that there are some side effects that are problematic and, you know, very difficult to just live with, and we really need to do something. There are others that it's important that you notice them, so that you and your doctor are aware that it is a side effect, but it doesn't necessarily mean that you need to do anything differently.

Dan Keller 15:49

I suppose one key to this thing is to be able to work with your neurologist to alert them to these kinds of side effects. Do neurologists typically go beyond just saying, "Are you having any problems?" but saying, "Oh, I see you're on XYZ medication. Have you noticed this, or this, or is it troublesome?"

Dr. Irene Richard 16:10

Yeah, no, that's a good point. What I would say is that generally, when we first prescribe a medication, we would tell people what the most common side effects are, what to look for. I mean, obviously, if you read a package insert, it contains everything, so we don't recommend doing that. But, for example, with Sinemet, when we prescribe that, I'll say, "You know, it can cause a little bit of nausea, that's why we go slow. It can cause some lightheadedness when you first stand up, that's why you want to take your time." On the other hand, with dopamine agonists, it's really important that we warn people about the potential for both the swelling in the extremities, as well as this impulse control disorder, because people might never put the two together or even think that it's a side effect.

So, from a patient standpoint, it's always helpful to ask what potential side effects might I experience with this medication, and it's important from the neurologist's aspect to be proactive and tell patients, you know, you don't want to scare somebody, but you can tell them, "Not everybody gets this, but potential side effects, ones that we see commonly, are X, Y, and Z." I'd say that most neurologists tend to be rather conservative, and that we'll start at a low dose and we'll go up gradually. It depends upon the neurologist, but we'll tell people, "Why don't you contact us when you get to, let's say, a certain dosage, and then we'll let you know what to do from there." In other words, let's say you get up to one tablet three times a day of Sinemet. If that's worked and you're tolerating it, you could just stay there. On the other hand, if you're tolerating it, but it didn't really help, let's say your dexterity or tremor, we may then say, "Okay, let's keep going up, then."

But it's certainly important if you are on a medication, particularly if it's a recently started medication, and you are experiencing a new symptom, it's important to bring it up to your neurologist, first of all, just so that they know, and they may be able to determine, "Oh, well, you know, that might be a side effect of this medication." Or even if it's not a side effect of this medication, maybe it means something else is going on that you should get checked out with your primary care doctor. So I do think that kind of being vigilant, but not necessarily overly vigilant, but on the other hand, if you're having symptoms, particularly something new, it never hurts to mention it.

Dan Keller 18:28

Is there any sort of nutshell message to patients and caregivers in this area?

Dr. Irene Richard 18:35

I think that when it comes to Parkinson's disease, it's good to understand that the medications we use are used to treat symptoms. I think one thing that I really do want to get out there, because I think it's such a prominent misconception, still seems as though people are very hesitant to start Sinemet or carbidopa-levodopa. We've really come full circle, and over the past 10 to 15 years, we've done extensive studies, and while it was a concern initially about should we wait to start Sinemet, the majority of Parkinson's disease specialists have come to the conclusion that when somebody is having symptoms that would respond to Sinemet and those symptoms are impacting their quality of life, they should not hesitate to start carbidopa-levodopa, because it will improve their function, it will improve their quality of life.

And even things like exercising that we know is really helpful for Parkinson's disease—in fact, it may even slow the disease progression, we know it slows emotional decline—Sinemet, for example, carbidopa-levodopa, there's even been studies that show that people get more out of their exercise when they're on Sinemet than when they're not. And eventually, because everybody ends up being on Sinemet for the most part, what you have to do is look a few years down the road and realize everybody looks the same at that point. In other words, it doesn't change the ultimate outcome, but what it does do is, if you start it sooner, in retrospect, you probably will have had better functioning, better quality of life for a longer period of time than had you tried to hold out on starting it. That's just one real important message, because I just see it so commonly.

Dan Keller 20:16

Very good, I appreciate it. I'm sure this will all be helpful to our listeners. Thanks.

And for more information on side effects of drugs used to treat PD, there's a wealth of information on our website at parkinson.org. Just search for side effects. While a lot of the information relates specifically to PD drugs, much of the advice and therapeutic approaches are also useful regarding medications for many other conditions, since side effects of drugs are a very common phenomenon. An expert briefing by Hubert Fernandez gives a good overview of many of the drugs used to treat PD, their efficacy, and side effects. Several fact sheets, along with our medications publication, cover many of the classes of drugs, including levodopa-carbidopa, dopamine agonists, amantadine, monoamine oxidase inhibitors, and more. You can find these materials in our PD library at parkinson.org/library.

You may also find useful information by revisiting past podcasts in this series. Emily Perrin covered pharmacy challenges in PD in a podcast with that title. In back-to-back episodes, Joe Quinn and Martha Nance discussed hallucinations. One podcast is titled Do You See What I See: Hallucinations and Parkinson's Disease, and the other is Hallucinations and Delusions in Parkinson's. Mark Groves addressed impulse control disorders in an episode called Clinical Issues Behind Impulse Control Disorders, and coming up in 2021 we will feature Greg Pontone giving some tips on how to talk to your doctor about impulse control disorders.

If you have questions about today's topic, or anything else having to do with Parkinson's, our information specialists can provide answers in English or Spanish. You can reach them at 1-800-4PD-INFO. News and updates about future events and resources are available by joining our email list at the bottom of our website's homepage. If you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts or wherever you get your podcasts.

At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO, that's 1-800-473-4636. Thank you for listening.

Dr. Irene H. Richard is Professor of Neurology with a secondary appointment in Psychiatry at the University of Rochester in Rochester, NY. After graduating from Cornell University in 1987 and receiving her MD from the Yale University School of Medicine in1991, Dr. Richard completed neurology residency at the University of Rochester in 1995, followed by NIH-funded fellowship training in Movement Disorders and Experimental Therapeutics in 1997. She joined the faculty of the University of Rochester in 1997. Dr. Richard provides neurological care for patients with Parkinson’s disease and related conditions and her clinical research program focuses on the psychiatric aspects of these illnesses. More recently, with support from a PF community grant, she has also been working with her team on efforts to optimize hospitalization for patients with PD. She is the author of numerous scientific articles, editorials and book chapters and has been the recipient of career development awards and research grants, including one from NIH to lead a multi-center clinical trial evaluating the treatment of depression in PD. Dr. Richard is Director of the University of Rochester’s Movement Disorders Fellowship Program, LBDA Research Center of Excellence, and Parkinson Foundation Center of Excellence.