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. This podcast

Narrator - ?  00:11
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.

Speaker 1  00:31
Welcome to HelixTalk episode 53 I'm your co host, Dr. Kane. I'm Dr. Schuman and I'm Dr. Patel. Today we're continuing on with our previous topic on drug interactions with the topic of drug mixology and dangerous consequences part two.

Speaker 2  00:46
And with that being said, let's dive right into one of the popular question we get from not only student pharmacists, but patients. You know what to do with the beloved grapefruit or grapefruit juice? Can I drink it or not. And so that being said most commonly, the issue that we see is grapefruit juice is known to cause inhibition of the CYP3A4 enzyme in the small intestine. And this can lead to reduction in the first‑pass metabolism, which means it basically increases the concentration of some of the drugs that are metabolized by CYP3A4. So examples of these drugs are certain statins, as we discussed in the previous episode, amiodarone, and certain calcium‑channel blockers such as amlodipine, nifedipine, and the anti‑rejection/transplant agent cyclosporine.

Speaker 1  01:41
So Dr. Patel, what you're saying is, if I drink grapefruit juice with my statin, my statin will work a lot better.

Speaker 2  01:48
Potentially, it would work a lot better. But then we have to worry about not only the good effects, but also the side effects. So then you're also putting yourself at an increased exposure of side effects, such as the myopathies, myalgia, and it could, in extreme cases, lead to rhabdomyolysis as well.

Speaker 3  02:05
And that's the important thing here, is there are a lot of you know, if you were going to a site such as Lexicomp or a number of databases with interactions, there are going to be a lot of purported interactions involving drug, drug interactions with this SIP enzyme system. But however, this is one that we have a lot of documentation, not just about Rhabdo, but for example, calcium channel blockers that you can see further decreases in blood pressure. We know that cyclosporine, which is again used to prevent transplant rejection, can have its concentrations increased by as much as 70% — anytime you are doing that, you are getting increased side effects. So it's not just one that's theoretical, but we have documentation

Speaker 1  02:43
that it occurs. And you know, to touch on the idea of getting more bang for your buck, it's also not a reliable amount that you're increasing the drug level. So if we really wanted to give you more statin, we can just pick a bigger dose, right? So in terms of reliability, of making sure we get a certain drug level every single day, it's much better to actually give the drug amount that you want, as opposed to relying on, let's say, grapefruit juice to kind of boost you up a

Speaker 2  03:06
little bit. Yeah. And keep in mind, people who are on statin for prevention of cardiovascular condition or because they've had an event, they more likely, are on other medications altogether. And if any of those meds are going through the CYP3A4 pathway, we're not only changing statins, but the other meds are being affected too. So all together, the recommendation is, if possible, do not combine grapefruit or grapefruit juice consumption with any of these agents.

Speaker 1  03:32
So then the next drug interaction that we should always be concerned about is Qt prolonging drugs. So you'll see Qt and QTC. The difference is, QTC is where you normalize that QT interval based on the patient's heart rate. So if you have a very slow heart rate, your QT interval will actually be a little bit longer. But if you correct for it, then QTC, seeming corrected gives you kind of a fair assessment of how long that QT interval is, regardless of what your heart rate is.

Speaker 2  04:00
And we have a good variety of drugs that impact QT interval available, and they are further categorized in the high risk, which definitely will increase QT interval by a greater degree than we have moderate risk. And then we have some low risk medication as well. So examples at high risk include dronedarone, amiodarone, escitalopram, quetiapine and other atypical antipsychotics — and ziprasidone; those are ones that fall under the high‑risk category.

Speaker 1  04:40
And just so we're clear. You know some of these, using sotalol or dofetilide as an example, the risk is so significant that you have to be in the hospital to initiate therapy with these drugs because of the risk of QT prolongation, which can cause Torsades de pointes, a potentially fatal arrhythmia. So some of these are holy cow. Risks. We have to watch you overnight. Some of these are just if it's one agent, that's okay, but as you kind of stack more and more agents on we have to be at least aware of it and potentially monitor for that.

Speaker 2  05:11
I like the point you mentioned, like there are the agents individually, they might be indicated to be used, but when you're combining or piling up one or more the agents that impact the QT interval, then you're running the risk of some of the fatal arrhythmia that you mentioned,

Speaker 3  05:27
Dr. Kane, and this is one that comes up a lot, again, for example, in the world psychiatric medicine, if a patient that's been stabilized on one of those medications you mentioned, for example, citalopram or escitalopram, which may be on for an extended period of time, and then the individual presents in the hospital. And again, perhaps there's either an arrhythmia or, let's say, maybe there's a bacterial infection, and we're looking to use a fluoroquinolone in these kinds of cases. There's been a lot of questions about, you know, what's safe to use and what's appropriate? And a lot of it comes down to looking at individual in the context, for example, of what is going to be the duration of therapy there? How long is it going to be? How long they've been on this? What are the alternatives that are available for example? Yeah.

Speaker 1  06:07
So for me, you know, if you go to a list of Qt prolonging drugs on any you know, drug reference, you're going to see a list of, like, almost 100 if not more, drugs. And that, to me, that's not something that I can use in clinical practice to screen patients quickly. So for me, my criteria for screening is class I anti‑arrhythmics or class III anti‑arrhythmics. Some examples include dofetilide; class I agents such as propafenone; and sotalol, which would be a class III. So these anti rhythmics, even though they're anti rhythmic, can be pro rhythmic by prolonging that Qt, I think especially the typical antipsychotics like Haldol, I think are fluoroquinolones or macrolides. You know, I have kind of a list in my brain of what are like, the really key ones that you're going to see fairly commonly, that are big players that Dr. schman, like you said, where you're really thinking how long, what is their risk? And probably more important than just thinking about the drugs is, are there patient specific factors that we have to worry about that either increase the risk of that Qt prolonging or, more importantly, increase the risk of a fatal arrhythmia in the form of Torsades? So you're talking

Speaker 2  07:13
about people of older age, people who have underlying bradycardia have irregular electrolyte levels such as hypokalemia or hypomagnesemia, have underlying heart conditions, or we're giving these agents in a very, very high dose concentration. So these are all the factors to be considered, along with just looking at the drugs themselves.

Speaker 1  07:33
A great example of that would be, let's say we're dosing a fluoroquinolone for a patient with renal impairment, like, let's say ciprofloxacin. And maybe they that particular patient is an older female on the cusp of getting a dose reduction because of their renal impairment at this point, this is where a clinical pharmacist is going to say, well, do I care more about treating the infection, or am I more worried about an arrhythmia caused by under or overdosing? And you have to make a clinical decision of what pathway would be more appropriate if they're on truly the cusp of keeping them at the same dose or dose reducing them this risk factor assessment is really important.

Speaker 3  08:11
And we've had, you know, in issues where, for example, it's like, well, this patient is getting infection, they need to be on a certain antibiotic, so we're just going to stop their antipsychotic and we again counsel up the availability of alternatives for one versus the other. That if you look through the list, there are a whole host of different antipsychotics. They may not all be at high risk. They're at varying levels of it. Choosing a more favorable antipsychotic may be difficult, depending upon the individual. That's where a dialog with providers about what can else be managed? What are the alternatives for this infection?

Speaker 1  08:38
For example, one thing that to me is still baffling, is that we've known about Qt prolongation for decades, and we still don't have firm criteria of more of a black and white, of what is a patient that should, let's say, have an EKG done to assess their QT. How prolonged of a Qt do we allow before we say they have prolonged QT? What is our criteria for some of these things. And unfortunately, because we have these lists of like 100 drugs or more that prolong Qt, it kind of becomes this witch hunt, where if you prolong Qt by five milliseconds in your drug, you make this list that is so minor compared to a Haldol, where if you give a big dose, you can prolong it by 50 milliseconds. So quantification of how big of a risk is an important consideration. So for me, in the ICU, I see a lot of patients with borderline, prolonged QTS, and typically I don't get worked up until they get above, let's say, about 500 milliseconds. But you'll see other resources that say somewhere around 450 you'll also see resources that say maybe it's not the actual Qt itself, but how long, how much you've prolonged it from their baseline, and you'll see plenty of different resources, something like prolonging it more than, let's say, 60 milliseconds. And unfortunately, there's not one guideline, if you will, that says these are the drugs that we most worry about, that you have to get an EKG for. These are the ones that, if you combine multiple ones, you should and then if you see a prolongation of X amount. That constitutes discontinuation of therapy. It's a super great area, which is frustrating given that these drugs and knowledge about Qt has been out for so long,

Speaker 2  10:09
yeah, just so kind of rounded up, you know, try to avoid these drugs. Try to use it for the less duration, less dose as possible. And if you must use it together, make sure you're monitoring the patient. Again, we don't have any guidelines. There might be institutional specific guidelines, or, you know, cardiology specific guidelines available within that institution that recommends how to monitor and what cut out points to use.

Speaker 3  10:32
All right, so the next one of these interacts we're looking at is of another medication that we've come to a fairly commonly, especially in a pharmacy setting, the outpatient world, and that's looking at levothyroxine or Synthroid. And then the mechanism here, we believe, is that that medication can interact specifically with bivalent or trivalent cations that are that, example, minerals, calcium, iron, magnesium, and also PPIs, that it decreases the absorption of the thyroid supplement by chelating it, and thus changing the amount of the absorption out of the GI tract into the system.

Speaker 2  11:06
And I think it becomes more important, because most providers will tell patients to take their levothyroxine first thing in the morning. And if the patients are on one so they PPIs guess when they're told to be taken, right, first thing in the morning. And usually then they pile up their multivitamin dose, you know, right along with the breakfast or right around that time too. So that's where we are seeing more and more drug interactions here, and

Speaker 1  11:29
even in the ICU, this is actually a fairly common problem, because typically, you know, hypothyroidism is seen, not always, but typically in a more elderly patient population, as you get older, you'll see more hypothyroidism, and in the ICU, that's typically the patient population that we see. Unfortunately, in the ICU, as patients get intubated, they have to have NG and OG tubes for feeding, which is a continuous feed. So in the ICU, if we want to give a patient their Synthroid appropriately, we kind of have to hold their tube feeds, because you have to take it basically on an empty stomach is that tube feed has these divalent and trivalent cations. The problem is that it's hard to remember to hold it, and you have to recalculate what is their internal nutrition amount, given that you're going to hold it, you know, once a day, if they have other meds that you're holding forward, it becomes a really big headache, because basically you have to take this on an empty stomach, just like a bisphosphonate, for example.

Speaker 3  12:20
And speaking of bisphosphonates in the elderly, again, because when you think elderly, we think about osteoporosis prevention. So we start thinking about those higher those calcium supplements. And again, another reason why this is something to observe in the elderly. And then there's also a part about it is if it's inconsistency as well. So you're attempting to manage someone's thyroid hormone levels, and you got to make consistency in terms of what someone eats or whether they take or don't take these vitamins. And that can change, as you can imagine, as providers attempting to adjust one regimen, you see that, you know, the the person's compliance with with these diet or recommendations or medication avoidance, right?

Speaker 2  12:57
So then the drug interaction with the the cat ions we talked about is more related to the absorption of levothyroxine. It impedes the absorption. The interaction with the proton pump inhibitor is that the proton pump inhibitors decrease the acidic environment that's needed for the levothyroxine absorption, again. So both of these interactions are not really metabolism related, but more so levothyroxine is absorption related,

Speaker 1  13:20
and one good thing about Synthroid, specifically with this drug interaction, is that we titrate that dose based on a TSH, typically. So just like with warfarin, it's not that you can't eat a salad with warfarin, it's just that you have to be consistent. And we'll give you a three salad a week Warfarin dose, right? And if you deviate from three solids a week, then that dose has to change. The same is true of Synthroid, if a patient has always taken their Synthroid with their ppi, that is a PPI plus Synthroid dose that they're going to be on. And if they change their ppi, if they take it with or without their multivitamin, and they've always done it a certain way in the past, they have to be consistent, because this is a titrated thing that we do. Clearly, we should do it right at the beginning, in terms of advising a patient when they initiate some thread of how to take it appropriately to avoid that drug interaction. But if they've done this forever again, we've titrated that dose to be appropriate for that patient with the drug interactions in place. Yeah.

Speaker 2  14:13
So we're kind of dealing with what's easier for patients to remember and adhere to, the regimen, versus Okay, well, let's by definition, let's change that regimen. Have the multivitamins be taken four hours after a Synthroid or levothyroxine dose, and then having them forget to take one or the other medication. So if they're always doing it that way, we can always adjust the dose, like you said. Dr. Kane, but if not, the idea is to avoid giving bivalent ions within four hours of the levothyroxine dose and then, if a PPI is started, check TSH and adjust levothyroxine as needed. I think the issue is not when patients are at home. I see this happening a lot when I'm looking at patients' med recs or discharged from nursing homes, or they come to the family physician's visit, and I see the list of medications being administered next to each other. And I always wonder if the their profiles are being reviewed in the in the nursing home facility, and they're being separated or not.

Speaker 1  15:17
So the doctor tell what was the last drug interaction that you identified as something that all pharmacists and pharmacy students should be aware of.

Speaker 2  15:24
I think this is a very important one. We're going to talk about the PDE‑5 inhibitors and nitrates. And often in times, we run simulation sometimes, and we kind of sneak this drug interaction in. And, you know, the students don't ask the right questions. These PD five inhibitors are sort of a recreational type of drugs, meaning patients are not on these agents. You know, on a regular basis, they take it as needed. And so some of the nitrates are also available in fashion where they are only used in extreme chest pain, versus there are some that are used chronically. So if the patients doesn't come right up and tell you that they're using these agents, so oftentimes this drug interaction is missed, but it's very vital for us to identify,

Speaker 3  16:11
Dr. Patel, you're exactly right about this one being missed. It's something I but we've observed in individuals who may be on certain kinds of supplements. We have a number of individuals, again within our VA system, who sometimes are on antidepressants and there may be sexual dysfunction. So you put somebody that is also now on a PD five inhibitor, that individual try is exercising. For example, there's a lot of advertised gain or formulas, or these exercise or endurance types of formulas that are to use with somebody lifting weights, and those products usually take some derivative of a vasodilator, some nice nitrate, like product. And you have to be very careful about it, because, again, it's going to be very hidden where the name of it may not be something that instantly flags through a provider, but then you have to look at it and analyze it. And the same thing for certain, again, natural or herbal forms of, they say, by an alternative to Viagra. So it's not just about these other phosphodiesterates, like products. And so you have to be vigilant about that too. We've had individuals. We've had a council on the you're already on a long acting nitrate for your heart, and so we really, safety wise, cannot use this product. And then you have to again, discuss with the individual, rather than saying you can't use this, but just describe the evidence for it and the concern. I think that's what allows the individual to gain the report and say, Hmm, I'm not going to use I'm not going to use it because otherwise it's a very touchy subject to discuss it with somebody and just say, No, you know, you can't be on Viagra.

Speaker 1  17:28
So, just so the listeners are clear, there's three main PDE‑5 inhibitors on the market. There's a couple others, but the ones that will come up most commonly are Viagra (sildenafil), Cialis (tadalafil), and Levitra (vardenafil). And you know, they have different half‑lives, with tadalafil (Cialis) being the longest. So that means that in the case of tadalafil, you actually have to wait a longer period of time between taking the drug and being exposed to a nitrate. in the acute care setting, the most common times that we'll see this would be sublingual nitroglycerin or even topical ointment nitroglycerin, or IV nitroglycerin, or nitroglycerin oriented products. Typically these are used for angina, but they could also just be used for someone, let's say, with pulmonary edema caused by very severe hypertension. So it's not always for an MI patient, but it typically would be, and using the idea of a Swiss cheese model, ideally the nurse who's about to give the nitrate should be asking, have you taken Viagra or something like Viagra recently? Hopefully the pharmacist is thinking about that as well. Hopefully the physician is asking that. And the reason is that, especially in the acute care setting, even with all the monitoring that we do, one of the worst things that can happen to let's say that acute in my patient is to drop their blood pressure from 150 to 70. So that acute drop in blood pressure causes a ton of problems, and we want to avoid that. And that's really the risk of this drug interaction. Is a precipitous, bad drop in your blood pressure caused by this drug interaction.

Speaker 2  18:59
So we know PD five inhibitors, they increase the nitrate levels and cause vasodilatory effect. And then same thing goes with the nitrates. They make more nitric oxide available in the endothelium. By dilating those blood vessels, it can cause blood pressure drop. So combining these two mechanisms together can even cause a greater blood pressure drop, so important acutely in the inpatient too. But if you're having older patients outside and you're using those drug combination, hypotensive effect fall, you know, this equally is just becomes more critical to manage.

Speaker 1  19:37
And I think for me, when I was a pharmacy student, you know, you'll hear in the direct commercials talk to your doctor if you take a nitrate for chest pain, nitrate is not a drug, right? Like there's drugs that are nitrates, but there's no drug name called nitrate. A patient isn't going to know that isosorbide mononitrate is a nitrate, or that nitroglycerin is a nitrate, so the term 'nitrate' may not be meaningful to them. Even in patient‑friendly language, patients may not recognize these drug names, so as healthcare providers we have to be aware of which drugs are nitrates.

Speaker 3  20:12
drug interaction, I agree. Again, a lot of individuals are brand‑conscious, and so they may say, "I'm on Imdur," and not even think about the full generic name or salt form.

Speaker 1  20:23
So just to review some of the key drug interactions for part two here. So we started with grapefruit juice, and the problem there was with statins and certain calcium channel blockers, that you'll end up getting more statin absorbed because we're blocking the metabolism of that statin or that calcium channel blocker, which means that you're going to be at a higher risk for adverse events like myopathies with your statins or hypotension with your calcium channel blockers.

Speaker 3  20:48
Another point that there's a number of categories of medications that are known to cause Qt prolongation or change the rate of contraction in the heart, and that's medications that are in antidepressants, antipsychotics, antiarrhythmics and certain antibiotics do that on some medications. Do it on their own. Combining them can also increase the risk of arrhythmias as well. So you really need to again, fully discuss the providers the and for providers to consider the cost of having those additive regimens. And if so, then you really need to do consistent EKG monitoring.

Speaker 2  21:19
The next one we discussed was levothyroxine and how addition of cations or PPIs can actually interfere with the absorption of levothyroxine. So the rule of thumb is to educate patients and educate them about this drug interaction, but also educate them about keeping consistency in levothyroxine dose so we can titrate the levels as needed that are inhibited by these drug interactions.

Speaker 1  21:44
Then finally, our last drug interaction was PDE‑5 inhibitors like Viagra, Cialis, Levitra, and their interaction with nitrates like nitroglycerin (IV, topical, sublingual) or even some of the longer‑acting angina products like Imdur — and basically we worry about a sharp, rapid drop in blood pressure caused by this interaction. This should be a never happen, where, if you're on a nitrate for chest pain, you should never get a PD five inhibitor or vice versa. If you've been on a PD five inhibitor and taken it recently, you should not be given a nitrate product with that. I think that wraps up our section on drug mixology and dangerous consequences. Please visit us on our website, at HelixTalk.com we're also on Twitter at HelixTalk. We love five star reviews and iTunes to help promote the podcast. And with that, I'm Dr. Kane, I'm Dr. Schuman, and

Speaker 2  22:34
I'm Dr. Patel, and as always, study hard.

Narrator - Dr. Abel  22:37
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Narrator - ?  22:49
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.