Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk, Episode 52 I'm your co host, Dr. Kane.

Unknown Speaker  00:34
I'm Dr. Schuman,

Speaker 1  00:36
and I'm Dr. Patel. So today we're going to talk about topic that is near and dear to our heart, it's about drug interaction, drug mixology and dangerous consequences. And because there are so many of these to review and understand and maybe make recommendation and impact, we have divided into two parts. So let's talk about part one,

Dr. Sean Kane  00:55
and this is really a common area that pharmacists are experts in, in the sense that drug interactions are very common and also very complex. There's a lot of them, and then probably the most important role of the pharmacist is to decide how big of a deal is that drug interaction. You know, if you run a drug interaction check for aspirin, you're going to see a ton of drugs. But much of the time, those interactions aren't clinically relevant, or they just require a little bit more monitoring versus a never can use. Never can combine these two things.

Speaker 2  01:23
So there's a habit, especially if you're just simply doing it based on a very surface level report, and it's everything's gonna be black and white of always use or never use, and again, there's so many shades of gray in here that you really have to get into some of the complex pharmacology with the individual patient factors and many other things before is coming up a one size fits all answer.

Speaker 1  01:43
And I like what you both just said right now, because nowadays, with the computerized database, we have the flag warnings, and there seems to be like a physician warning fatigue going on, where all they do is suppress the warnings. Because some of these drug interaction like you mentioned, are not as important, and some are very much important, where we need to intervene and make recommendations.

Dr. Sean Kane  02:06
I would absolutely second the idea of alert fatigue caused by drug interaction, electronic checking. A great example would be checking Tylenol and an NSAID, and the interaction would be that you have duplication of therapy. Maybe that's okay to take Tylenol with an NSAID together, and maybe, really, there's nothing to be done with that interaction. So something as simple as that, when you get alerted on that, then it's easier to kind of ignore the really big interactions that are actually like big deal things absolutely.

Speaker 1  02:35
And I think that was a great example that you just provided, and just for our listeners purposes, these are the drug interactions that we thought were more important for pharmacy students and the clinicians to kind of think, however, this is not a comprehensive list. For one example. I mean, Walgreens got a whole bag full of drug interactions, and we could talk about a whole host of interactions just for an episode, but we haven't included them over here. But that being said, with your expertise, Dr. Schuman, we're going to get started talking about serotonin syndrome that comes from some of the drug drug interaction.

Speaker 2  03:07
This is one that, by far and away, is the most common question I get. I get the questions from for the pharmacist, potentially in the inpatient section, who call me and say, you know, they flag the order. Now, practically, is this something that we can modify a regimen? I get calls from the providers who are getting or the residents who are getting ready to put the orders in as well. Wanted to know, is this a medication we can use or another specialty provider, for example, the psychiatrist has patient on medication X, can I prescribe medication y for their pain or for their migraine, something like that?

Speaker 1  03:37
So basically, what serotonin syndrome stands for is just the surplus of serotonin in the nervous system. When you're combining certain serotonin acting or serotonergic drugs, we're looking at drug groups such as SSRIs, SNRIs, even monoamine oxidase inhibitors, which we don't really use in nowadays, things like Tramadol, tricyclic antidepressant, etc, and the resulting effect is what we call serotonin syndrome. So what kind of things or symptoms do you get to see as part of the syndrome? Dr. Schuman

Speaker 2  04:10
Serotonin syndrome, again, being a syndrome, it's a constellation of different symptoms, and I can mimic there's another one for those in psychiatric medicine thinking about it. There's also been called neuroleptic malignant syndrome, and they can be very similar, with a few exceptions that NMS is more related to excess dopamine blockade versus and just briefly, this is in regard to excess use of medications that increase serotonin. So we think about some of the symptoms there. Serotonin can be involved in with things like nausea and gi transit, regulation of your temperature level. So you may see hyperthermia occurring, tremors or clonus, again, from an increase in that serotonin. You can see sweating again. I mentioned hyperthermia, hypertension, tachycardia, but hyperreflexia is another big one that can distinguish it from other types of syndromes as well. So if you have a combination of it. Overdrive of your autonomic nervous system, combined with that increase in reflex then a lot of times, especially, combined with a medication history indicating some changes in regimen that that can tell you that this may be serotonin syndrome.

Speaker 1  05:12
There's only one case that I've encountered in my practice where, you know, I saw a serotonin syndrome with a combination of amitriptyline and fluoxetine, and we had to send the patient to the ER to get, you know, monitoring and make sure the medications out of their system. But I like how you distinguish between because some some of these symptoms overlap with Neuroleptic Malignant syndrome, so the mechanism is different, but some of the symptoms and presentation is kind of similar.

Dr. Sean Kane  05:39
So there's actually good news and bad news with serotonin syndrome. The good news is that it's self resolving. So if you remove the serotonergic drug or drugs, then it gets better, actually, fairly quickly. Within 24 hours, patients typically will go back to their baseline. Also, the good news is that it's rarely lethal, in the sense that usually we provide supportive care for that 24 hour period, remove the serotonergic agent, and the patient does fine. The bad news is that this is really difficult to predict, and there's a lot of inter patient variability, where one patient can take a TCA, SSRI and SNRI and be totally fine. Then another patient can get a little high on one single SSRI medication and then go into this serotonin syndrome. So it's frustrating, because when you're interpreting this drug interaction, it's really hard to say what camp that patient falls into in terms of what is their actual risk of developing the syndrome.

Speaker 2  06:34
And like with anything, it's nuanced in that looking at the patient, the risk versus the benefit, looking at the stability on the current regimen, the timeline of how long it's been, and also, again, looking at what you're trying to use it for, and all there are the reasonable alternatives that you need to consider.

Speaker 1  06:49
Yeah, like you said, I think that's that's very important to distinguish. And I think the best thing we can do, because some patients will get it and some won't, is to just educate them. You know, what are the kind of things that they need to watch out for and then report so we can give them proper supportive care. So for most combinations we mentioned, if you look up any drug interaction database, it's going to flag as a, you know, high risk or major drug interaction. But then there is one that also flags as a high risk interaction, which is triptans along with an SSRI or SNRI; however, triptans are not used chronically — they are intermittent/abortive therapy, typically taken as one or two doses per headache. Hopefully patients don't have more than one or two episodes of migraines per month. The American Headache Society has issued a position statement saying that occasional use of triptans should not be regarded as a very high risk for serotonin syndrome when used with SSRIs or SNRIs.

Speaker 2  07:50
What they said actually is that the risk of serotonin syndrome with triptans is very, very low on its own as monotherapy, and that risk really doesn't change much when you add it to existing medication regimen. So what you have is, you know, a very low risk that most people will ignore when they prescribe a triptan, yet suddenly, when we prescribe it in combination with an SSRI, SNRI, or TCA, suddenly we become fearful, and they're saying that's simply not the case. It's rare in both cases. And really, they specifically say the concurrent use of an SSRI or an SNRI should not prevent you from prescribing a triptan for abortive therapy for migraines. And that is a statement, again, that they have made. They actually petitioned recommended the FDA remove the warning off of the label. They didn't go so far as either, but they still have published this position statement, and they said this fifth thing, they said, getting back to what you mentioned, Dr. Patel, is education. They said, educate providers and educate patients about the signs and symptoms of serotonin syndrome, but in of its let them know what you're doing. They go ahead and still prescribe those medications. And we just did this for a patient the other the other day where we were managing PTSD symptoms and pain and insomnia and migraines, and using a combination that did include an antidepressant and a TCA with an abortive therapy regimen on board, and we were very clear, educated providers put a note in the system recommending education of the patient, so that every provider is aware, and that also in the future, you know when you have Patients seeing psychiatrists and primary care neurology, every that everyone's aware that as they feed into the patient, different meds from from each of their different practice settings, to be aware of what they're changing. And so to make sure we're not continuing to add more medications. Because, again, it doesn't mean that. Well, we can just keep on ad hoc, adding 34567, serotonergic meds, and it should be fine. You also have to use common sense.

Dr. Sean Kane  09:41
So then the next drug interaction that we identified was St John's wort. And this is an herbal medication that's available over the counter that is commonly used by patients who are kind of self treating, typically depressive type symptoms. But I'm sure that there are other indications that it's proposed for over the counter. And then

Speaker 2  09:59
this is. A popular one for individuals that prefer to avoid being on an answer, or they feel that there's a need, or providers discuss the need for an antidepressant, but a patient says, I prefer more natural medication. So a lot of times, you'll see this one, and it does work similarly, where it blocks the reuptake of serotonin, norepinephrine, and can have those antidepressant effects.

Speaker 1  10:18
And I think the substance you're calling the active ingredient out of this. What you're calling for is the hyperforin, right?

Speaker 2  10:25
There's kind of two components, Hypericum and hyperforin. Hyperforin is generally thought to be the active component. However, the thing we have to be careful of with these medications is that not only does it have some of the same properties as an antidepressant, but it is a very potent inducer of many of the metabolic pathways. And so you could just not play well with other medications as a whole. And so even though patients try to avoid, you know, they say, Oh, we have problems with antidepressants, therefore we want to avoid them, you end up with a medication that, in other again, call it a medication because of how it works, identically to an antidepressant works, but has a lot potentially more drug drug interactions than medications.

Speaker 1  10:58
And we're talking about those metabolic pathways being the CYP pathway, particularly CYP3A4/5 and other CYP enzymes. So we can call a lot of different medications where we just talked about SSRIs — they can lead to serotonin syndrome because of serotonergic activity rather than a CYP interaction. Antiretroviral drug concentrations can be reduced by enzyme induction. Not only are you making these antivirals less effective, but you're also putting patients at higher risk of developing resistance. For example, with antiretroviral therapy or cyclosporine for transplant patients, concentrations can be reduced and put patients at higher risk of treatment failure or organ rejection.

Dr. Sean Kane  11:48
So other ones are oral contraceptives. Those are fairly common. If you take medication like St John's Wort that induces your hepatic enzymes, it means that you're going to chew through this oral contraceptive quicker, so your blood levels are going to be lower, your risk of pregnancy is going to go up. And then also, there are certain anti cancer agents like Imatinib, where, again, the efficacy of the drug is going to be less because we're increasing the metabolism of the drug the half life drops. That means that drug levels of other drugs are going to go down.

Speaker 2  12:17
So this is one that I again, when I've discussed this with, students and also in chances with patients, which doesn't come up that often, is this one needs to be considered, as you would, another medication. Is this really needs to be if it's going to be used for depression? It needs to be used in full discussion, disclosure to the primary care provider, to the psychiatrist, any other, any other specialists that are involved in your care, because of the fact that it has so many of these interactions.

Dr. Sean Kane  12:41
One of for me, one of the interesting things with St John's wort is that, because it's an inducer, typically we see a lot more inhibitor-based and inducer-based interactions with the CYP enzyme system. A lot of times when you have an inducer where you're causing therapeutic failure of a medication, typically the patient isn't aware of that failure until something really bad happens. So, for example, your and the reason for that is that you're not having side effects from high drug levels. You're having less side effects from low drug levels. So your organ transplant fails, your HIV, viral load goes up, you become pregnant, all of these things like, it's kind of a late thing where it manifests, where, as with a lot of our inhibitor interactions, you get altered mental status or some toxicity of the drug. That happens fairly early on, which is one of the dangers of St John's Wort, is that you don't know until it's kind of too late that that interaction happened.

Speaker 2  13:32
And Dr. Kane to bring up a good point as well because of that, then the timeline becomes harder to predict. So you may not necessarily, because it may be delayed in terms of the ramifications, you may not instinctively think, wow, it's that medication I started a while ago, versus if it was causing side effects, you think, wow, I started it, you know, yesterday or two, three days ago. It's got to be that medication so it can be a little

Speaker 1  13:51
insidious there. Yeah, thank you for that differentiation. I think that's very important for the for the students and the listeners to keep it in mind

Dr. Sean Kane  13:58
and really going off of the CYP enzyme pathway. The next class is the statins, with the CYP3A4 inhibitors, which is statins being so common, we see a lot of these, oh

Speaker 1  14:09
yeah, very, very commonly. And sometimes it's part of those other fatigue that we talked about as well. And we know a lot of those statins go through the three a four metabolic pathway, and that's where the drug interactions are coming from. So if you're combining them with the three a four inhibitors, it can actually increase the area under the curve. Basically that translates into increased concentrations of statins in the blood. So when we're talking about CYP3A4 inhibitors, we're looking at certain fibrates, mainly gemfibrozil, some azole antifungals, amiodarone, certain macrolides (excluding azithromycin) such as clarithromycin and erythromycin, protease inhibitors for HIV treatment, and some calcium channel blockers such as verapamil and diltiazem that can also cause these drug interactions.

Speaker 2  15:08
this is an interesting one, because you think, okay, so, you know, so we're increasing the concentration of a statin for cholesterol. What? What could go wrong there? I might have better cholesterol control. Doesn't sound too much of a problem. But what it is we're looking at is the concerns about muscle pain terms like myopathy, myalgia, and even more severely, rhabdomyolysis, so the breakdown of muscle tissue that can occur from this combination. So it is something that's considered a major severity type of reaction. We do you know, if it happens again, it can be, it can be very problematic,

Dr. Sean Kane  15:38
and probably one of the best manifestations of this is the simvastatin dosing changes that the FDA instituted a couple years ago, where at one point, many patients were on 80 milligrams of simvastatin, and then the FDA released kind of a note to providers, saying, Hey, this is actually a fairly big deal, because when you start having some of these interactions, instead of getting simvastatin 80, it's as if the patient was getting double that or even higher. So they instituted kind of maximum dosing based on certain interactions, like some of the ones that you already mentioned, Dr. Patel. So especially with simvastatin, we've seen that in the labeling and in the FDA warnings. It doesn't mean that the other statins don't have that. It just happened that simvastatin kind of got the brunt of some of this because it was very common. It had this high dose and potentially had a higher risk of some of these myopathies and myalgias.

Speaker 2  16:25
Yeah, that combination of amlodipine and simvastatin became so common with metabolic syndrome and hypertension and hyperlipidemia, you would see so many of those combos, and again, leading to one of these increases in drug levels.

Speaker 1  16:38
Yeah, very important that you mentioned, and use simple statin as example. So there was following the search trial that came out in 2011 and then FDA kind of looked at the data and then asked the manufacturer to include those drug limits and drug interactions in their labels. So we no longer use the 80 milligram dose, and we really wonder that, you know, can such trials be done for other statins? And we're going to see more drug interactions, and we're going to see more drug limits and whatnot. It's very well possible. But I think the end point over here is to educate the patients again. So, you know, particularly explain them what type of myalgia are they going to you know, experience? Is it going to be more like I lift? You know, I lifted too much weight today, and I'm sore from exercising? No, it's not going to be that so big muscle groups, you know, sudden onset, severe onset, looking for the Coca Cola color urine. You know, that's very popular when we talking about rhabdomyolysis and stuff. So these are all very real, and we know that statins are such an important part of therapy for patients who have cardiovascular risks, and so we don't want to completely reverse them, but educating them will make them better informed and maybe adherent to even the statin therapy. So the best thing we can do is usually try to avoid the combination of the drugs that are interacting, but it's not always possible to do that. So we can use statins that are not metabolized by CYP3A4. For example, pravastatin goes through conjugation, and pitavastatin goes through a different non-CYP pathway. A common recommendation is that when patients are on a short course of interacting antibiotics like clarithromycin, they may temporarily stop their statin during the antibiotic course.

Dr. Sean Kane  18:37
So, Dr. Patel, I want to just focus on that last thing that you said, because I think it's actually really important when you tell a patient not to take their statin, sometimes that patient is going to say, oh my god, won't my cholesterol just go through the roof and then I'm going to have a heart attack and die. So how do you kind of manage that expectation of kind of the pharmacodynamics of the statin versus taking an antibiotic for five days? Absolutely.

Speaker 1  19:00
So again, antibiotics are going to be a definite therapy. It's going to be five days, 10 days max, for 14 days or 20 days, even. And while we say yes, go ahead and stop your statin, some of these statins are longer acting, you know. So the efficacy in the body is a little bit sustained as well. The effect of the statins on lipoproteins is not overnight, so that, like you mentioned, the pharmacodynamic effect are a little bit longer lasting. So it's okay for them to stop the therapy for a definite period of time, of course, not month or anything longer. And then when we when it's time to then recheck their levels, which is usually within four to 12 weeks. So we have them come back in three months and check the levels it's not going to be showing up in the lab, and say you didn't take your statin for two weeks. I know it might, yeah,

Dr. Sean Kane  19:49
and I think that you really have to think risk benefit. So the risks of myopathies is a lot higher when you have these drug interactions. And if you think the benefit of a statin is, let's say. 30% over a 10 year period. That 10 years is a really long time, right? If you're not on that statin for a week or two, that's really not a big deal within the grand scheme of things.

Speaker 1  20:10
Yeah, absolutely. And the impact on lipoprotein does not equivalent to the impact on cardiovascular risk. So I think you summarized it really well.

Dr. Sean Kane  20:18
So then I think the fourth drug interaction that we'll be talking about in this part of the drug interaction podcast episode is the idea of antihypertensives and NSAIDs.

Speaker 1  20:27
So I think there are about a couple of different mechanisms when we talk about combination of antihypertensives and NSAIDs. Over here, we know NSAIDs work by inhibiting Cox one and Cox two, and what this inhibition then leads to, it suppresses the prostaglandins in the kidneys, then in the kidneys, suppression of prostaglandin can lead to increased muscle tones in the arteries, and when that happens, there is more tendency of fluid retention in the body. More fluid in the body means more volume. If you put that in the whole equation together, more volume means more blood pressure. So while we are trying to decrease blood pressure using the antihypertensives, using NSAIDs chronically or at high doses can actually do the opposite by causing fluid retention, which can increase blood pressure.

Dr. Sean Kane  21:19
And if you think about it like who is a typical patient population that is going to be on an antihypertensive and an NSAID, this is typically your 40 to 50 plus year old who has osteoarthritis and also, you know, essential hypertension. So this is a very common patient population where they have chronic pain, typically arthritic type pain, and they also have hypertension. So this happens all of the time. And I

Speaker 2  21:42
would say even you start throwing the potentials for other kinds of metabolic complaints, things like diabetes as well, and you end up with potential issues with nephropathy and Further compounding the

Speaker 1  21:51
issue absolutely and when they're when they were looking at this evidence, they kind of picked apart a few NSAIDs that are available. So they found this effect to be more profound with NSAIDs such as indomethacin, piroxicam, or naproxen; the immediate effect can also be seen with ibuprofen or celecoxib, which are commonly used for osteoarthritis management. And then that second portion of drug interaction I was talking about comes from some of the antihypertensive that already hurt kidneys. So I'm talking about ACE inhibitors, ARBs, or even things like Spironolactone. We know we have to monitor creatinine because these agents can cause AKI. Now if we add another agent, such as NSAIDs, that can contribute to the risk as well. So the combination, the triple combo, they call it. It's definitely injurious to the renal health.

Dr. Sean Kane  22:51
And honestly, when I'm evaluating a patient for escalating their antihypertensive regimen, drug interactions is one of the first things that I look at, especially the NSAIDs. Or when we have a patient who presents to a clinic that has hypertension and we're trying to select something for them, I intentionally try to avoid the NSAID because of that same reason. So something like Tylenol, Acetaminophen is a very reasonable alternative for most patients that, for the most part, provides similar efficacy for pain, but doesn't have the hypertensive risk that these NSAIDs do.

Speaker 1  23:24
Yeah, and you know, for a shorter time period NSAID use, it's still okay, but in those patients where you're really struggling to get their blood pressure under control, you are looking at options to see okay, what is the mechanism behind this resistant type blood pressure you're getting. You have to evaluate and really look at the chronic use of NSAID being the culprit behind it.

Speaker 2  23:46
And one thing I've learned is, again, through just observing with patients, is also education on what an NSAID is. A lot of times, sometimes what we'll see is, for example, we have patients that are prescribed, let's say meloxicam, for example, or naproxen via prescription, and who maybe has more severe untreated pain, and who may augment that with some over-the-counter ibuprofen. So an education piece as well, that when we say, you know, being wary of use of ant of NSAIDs, we're also referring to these over the counter ones as well. And so when we stop on a prescription one and say, due to this concern of acute kidney injury, to not run right out and then go buy another NSA over the counter, because, again, we're still running that same problem. So that education piece, I think, can be very important.

Speaker 1  24:26
Yeah, and I wanted to make one clarification when we were talking about NSAID that you know some people aspirin is an NSAID, but the risk with the small dose aspirin for those who are using it for cardiac protection is not included in this risk. So it's still okay to use aspirin as prescribed for your cardiac protection, along with the antihypertensives we were talking about; the NSAIDs used for pain management are the ones of concern.

Dr. Sean Kane  24:50
That's a great point, because really this is a dose dependent adverse effect, and if you think about it, if you're taking aspirin for pain, your doses for pain are much higher than your cardiac protection. Of aspirin dosing. So given it that it's a dose dependent effect, that any one of aspirin is going to do almost nothing for your blood pressure in terms of risk of some of these problems from happening. And I think the other thing to consider too is, why are we trying to treat a patient's hypertension? It's because we don't want them to have a cardiovascular event, right? So again, the risk of these cardiovascular events is over a very long period of time, so short term use not a big deal, but in the packaging for all NSAIDs except for aspirin, it says, use the lowest possible dose for the shortest period of time because of hypertension, cardiovascular risk and GI bleed. So again, something like a Tylenol is a very reasonable alternative if you're thinking of these high risk patients for a very long period of time, if their osteoarthritis is never going to get better, in my mind, it makes sense to consider an alternative for them, but for the short term acute patient, NSAIDs seem like a very reasonable option.

Speaker 2  25:52
And I think a further point on that too is the certain types of pain which don't respond well to anti-inflammatories or to over-the-counter meds. In and of itself, I think of things like cervical radiculopathy, for example, where we have a lot of individuals who have that radiating type of pain, and it just generally does not respond. So what you're doing is you're continuing that, throwing medications at it with lack of evidence, and then you're further harmed. You're getting lack of benefit, as well as potential side effects, and a piece of education about what a medicine can and can't do, I think is also important.

Dr. Sean Kane  26:20
So I think that wraps up part one of our drug interaction talk. You know, the first one we talked about with serotonin syndrome, where we have a lot of different drug classes that can be serotonergic, and probably educating the patient or the provider about what does serotonin syndrome start to look like, to be able to contact their healthcare provider, to back off seems like a very reasonable option.

Speaker 2  26:40
And I think with St John's Wort, again, an education piece, that you treat this medication if it were an antidepressant, it still has a similar mechanism. It still has drug drug interactions and concerns about safety. And so you have to treat it like that, so that if it is going to be used for depression, again, ideally not with a lot of other medications on board. And it really needs to be with full disclosure to primary care psychiatry and any other specialist treating that individual.

Speaker 1  27:04
And the third interaction we talked about was statins and CYP3A4 inhibitors, how they increase statin concentration, and then you see side effects such as myalgia and rhabdomyolysis. And the point over here is, you know, try to use alternative agents when possible, or in the interacting side, but also alternative statins when possible, when you're kind of weighing out the cardiovascular benefits of statins as well. And the very last one we talked about was looking at anti hypertensives and NSAIDs again, the the end point over here is shorter duration with the lowest dose possible. It's an okay thing to do, otherwise you're running into risk such as long term hypertension and the long term use as well as cardiovascular risks. And the main mechanism over here, what we are worried for in a short term to prevent is any type of acute renal injury.

Dr. Sean Kane  27:53
So with that, I think that concludes today's episode. If you would like check us out at HelixTalk.com or on Twitter at HelixTalk, you can also find show notes on the website about today's episode as well. So with that, I'm your co host, Dr. Kane, I'm Dr. Schuman,

Unknown Speaker  28:07
and I'm Dr. Patel, and study hard.

Narrator - Dr. Abel  28:10
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Narrator - ?  28:21
to suggest an episode or contact us. We're online at HelixTalk.com. Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.