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Amiodarone and Digoxin: Drug Interaction Explained · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: Hey guys, digoxin is one of the most well-known drugs out there.
• 0:04
  SPEAKER_00: I mean, it's been around for decades, and most people recognize that digoxin is not only used for heart failure, but also for rate control and atrial fibrillation.
• 0:13
  SPEAKER_00: But it is also known to have a narrow therapeutic index where small increases in drug concentration can have profound impact on the patient's physiology that can easily lead to clinically relevant toxicity and unfortunately bad patient outcomes.
• 0:32
  SPEAKER_00: And one of the reasons for this comes from the use of other medications known to do that.
• 0:38
  SPEAKER_00: And one of the best examples of that is the addition of ambiodarone in a patient already on stable doses of digoxin.
• 0:48
  SPEAKER_00: Even more relevant is knowing that the drug interaction is not only or related to the cytochrome P450, but it's related to transporters, specifically P.
• 1:01
  SPEAKER_00: glycoprotein.
• 1:02
  SPEAKER_00: And on that note, welcome to This Is Why, a show where I help healthcare professionals transform their medical knowledge from what to why, because that improves the how.
• 1:14
  SPEAKER_00: I'm Dr.
• 1:15
  SPEAKER_00: Bustaye, and on this episode, I'm gonna walk you through the drug interaction between the use of amuterone and adoxin.
• 1:23
  SPEAKER_00: And I'm not only gonna cover why it happens, but also how it impacts the patient.
• 1:30
  SPEAKER_00: Now, many clinicians know the interaction exists.
• 1:34
  SPEAKER_00: That's good, but few understand exactly why it happens.
• 1:40
  SPEAKER_00: Once you understand the mechanism, then managing the interaction becomes easier.
• 1:46
  SPEAKER_00: Now, before we talk about the interaction, let's briefly review digoxin.
• 1:52
  SPEAKER_00: Well, we know digoxin has a relatively narrow therapeutic index or window with a reference range of about 0.5 to 0.9 nanograms per ml in those patients being treated for heart failure and up to two nanograms per ml in atrial fibrillation.
• 2:12
  SPEAKER_00: But remember the concerns for side effects toxicity really start to grow when we go above 1.2.
• 2:20
  SPEAKER_00: That all means, guys, that small changes in exposure can potentially lead to relevant toxicity.
• 2:29
  SPEAKER_00: Now think about what happens after a patient takes digoxin.
• 2:34
  SPEAKER_00: The body, you take it by mouth, it needs mechanisms to move the digoxin to the heart and places where we want it to work.
• 2:42
  SPEAKER_00: But it also needs to eventually eliminate it.
• 2:46
  SPEAKER_00: So there are normal processes of drug elimination, and those include things like phase one metabolic pathways.
• 2:54
  SPEAKER_00: That's our cytochrome P450 system.
• 2:56
  SPEAKER_00: There's also phase two pathways, which are conjugative pathways like glucuronidation.
• 3:04
  SPEAKER_00: And then there are transporters, okay, both influx and efflux.
• 3:10
  SPEAKER_00: But one of the most important systems involved is a transport protein called P glycoprotein.
• 3:16
  SPEAKER_00: It's an efflux cell membrane transporter with the abbreviation of PGP.
• 3:22
  SPEAKER_00: Okay, now think about P glycoprotein as a cellular efflux pump.
• 3:27
  SPEAKER_00: It's an open door.
• 3:29
  SPEAKER_00: Its job is to move certain drugs that got inside the cell and get them out.
• 3:34
  SPEAKER_00: So for digoxin, P glycoprotein plays a major role, okay, guys, major role in limiting the absorption and promoting elimination.
• 3:45
  SPEAKER_00: Now you can see that there are four main steps to remove digoxin from the cell once it's made its way inside.
• 3:54
  SPEAKER_00: Step one is the drug binding to the transporter.
• 4:00
  SPEAKER_00: Once it has bound itself to the P glycoprotein, efflux cell membrane transporter, that is when intracellular ATP binds and undergoes something called ATP hydrolysis.
• 4:16
  SPEAKER_00: That process causes a change in the shape of the transporter, also referred to as a conformational change.
• 4:23
  SPEAKER_00: And what that does is it allows it to eliminate the bound digoxin into the extracellular space outside the cell.
• 4:34
  SPEAKER_00: And so the question becomes what happens if we interfere with that specific transport system?
• 4:42
  SPEAKER_00: Well, obviously, the concentration of the drugs are going to rise, and that would be true for digoxin.
• 4:47
  SPEAKER_00: And that's where amiodorone really enters this clinical picture.
• 4:53
  SPEAKER_00: Now, many people immediately think about cytochrome P450 enzymes when you discuss drug interactions.
• 5:02
  SPEAKER_00: Nothing wrong with that.
• 5:03
  SPEAKER_00: And that is especially true with amiodarone, okay, as it's known to interfere with not just one, but multiple phase one metabolic enzymes of the cytochrome P450 system.
• 5:16
  SPEAKER_00: And they're known to cause clinically relevant drug-drug interactions.
• 5:21
  SPEAKER_00: But this drug interaction is a primarily a transporter-mediated story.
• 5:28
  SPEAKER_00: Amyoton is also, guys, listen, well known to inhibit P glycoprotein.
• 5:35
  SPEAKER_00: So think about it this way: if P glycoprotein functions like a series of exit doors for digoxin from getting it from inside to outside the cell, and amyoturin interferes with it and partially closes those doors, well then less digoxin is going to be transported from inside the cell to outside the cell.
• 5:58
  SPEAKER_00: It's going to stay inside.
• 5:59
  SPEAKER_00: And that also means that less digoxin is going to be eliminated in the GI tract where absorption occurs when you take it by mouth, and also in the elimination in the kidneys.
• 6:09
  SPEAKER_00: So the result is higher systemic exposures due to the positive or overall net positive bioavailability of digoxin in the body.
• 6:20
  SPEAKER_00: And this is why those concentrations increase after the amioderone is initiated.
• 6:27
  SPEAKER_00: And this increase can be clinically significant given its narrow therapeutic window and efficacy.
• 6:35
  SPEAKER_00: Now, the important lesson here is not memorizing that the drug interaction exists.
• 6:40
  SPEAKER_00: The important lesson is understanding that amyodurone alters the body's handling of digroxin by interfering with a key transport mechanism.
• 6:51
  SPEAKER_00: Now let's consider the patient that we see, whether it's in a patient in front of us in clinic or in the bed or whatever, and the stretcher at the hospital, right?
• 7:00
  SPEAKER_00: How does this manifest clinically?
• 7:03
  SPEAKER_00: Well, maybe the patient has atrial fibrillation or maybe they have heart failure.
• 7:07
  SPEAKER_00: It really doesn't matter, right?
• 7:09
  SPEAKER_00: But if they're on stable doses of digoxin, especially for stable doses for months, and then amiodarone is all of a sudden introduced, and nothing else changes, well, you can expect in a few days or weeks later, that patient's going to start developing symptoms that may initially seem nonspecific to someone who's not paying attention or asking the right questions.
• 7:33
  SPEAKER_00: Things like nausea, loss of appetite, fatigue, weakness, confusion, uh visual changes or disturbances, a slowing of the heart rate, bradycardia, it's a rate controlled drug, digoxin, both of them will do that.
• 7:51
  SPEAKER_00: Cardiac conduction abnormalities, or potentially dangerous cardiac dysrhythmias.
• 7:59
  SPEAKER_00: And that's why this matters, okay?
• 8:01
  SPEAKER_00: The clinician may focus on new symptoms without recognizing that the underlying issue is really increased adjoxin exposure caused by the addition of amiodarone.
• 8:13
  SPEAKER_00: Now, understanding the mechanism helps you to anticipate the problem before it occurs rather than reacting after the toxicity has already started to set in.
• 8:25
  SPEAKER_00: So, how do we use this in real-world clinical practice?
• 8:29
  SPEAKER_00: One of the most common clinical approaches is to proactively reduce the digoxin dose when amyoderone is being initiated.
• 8:38
  SPEAKER_00: You will often hear recommendations to consider a 50%, 5-0, okay?
• 8:43
  SPEAKER_00: 50% reduction in the dose of digoxin, followed by close clinical monitoring and assessment of the serum digoxin concentrations when appropriate.
• 8:54
  SPEAKER_00: Now, why?
• 8:55
  SPEAKER_00: Because we already know that the pharmacokinetic interaction is likely to increase the digoxin exposure.
• 9:01
  SPEAKER_00: Now, the exact adjustment in digoxin may vary depending on the patient, their kidney function, the indication for which it's being used that I highlighted earlier, baseline digoxin concentrations already, and then the patient's overall clinical status.
• 9:19
  SPEAKER_00: Now, so the real issue is not the specific percentage, although we should keep that in the back of our minds, a good starting point.
• 9:27
  SPEAKER_00: The real issue is recognizing that the interaction is predictable and should be anticipated.
• 9:33
  SPEAKER_00: Now, in addition to dose adjustments, clinicians should also monitor not just the heart rate, guys, but the changes potentially that are occurring on the ECG.
• 9:45
  SPEAKER_00: So symptoms suggestive of digoxin toxicity, renal function, all those things and concentrations are appropriate, but we need to remember that laboratory values support decision making, but they never replace the assessment of the overall patient.
• 10:01
  SPEAKER_00: So let's take this one step further.
• 10:03
  SPEAKER_00: Both amniodorone and digoxin can influence cardiac conduction and the heart rate.
• 10:08
  SPEAKER_00: So even beyond the pharmacokinetic interaction, there can be an additive pharmacodynamic effect.
• 10:17
  SPEAKER_00: This means that patients may be more susceptible to excessive bradycardia or slowing of the heart rate, conduction disturbances that can also then manifest on the ECG.
• 10:30
  SPEAKER_00: And one of the classic teachings that developed are the formation of these scooped-looking ST segments that are known as the Salvador Dolly sign.
• 10:42
  SPEAKER_00: But there are many other dysrhythmias due to conduction delays by when you use both amuroterone and adoxin concomitantly.
• 10:50
  SPEAKER_00: So when evaluating a patient receiving both agents, always think about both sides of the interaction.
• 10:56
  SPEAKER_00: There's increased adjoxin exposure, but there's also a combined electrophysiologic effect on the heart.
• 11:04
  SPEAKER_00: That framework, guys, helps to explain why many of the clinical findings that we end up seeing sometimes in clinical practice, especially if we unfortunately are reactive.
• 11:15
  SPEAKER_00: So if you remember only three things from this episode, remember these.
• 11:20
  SPEAKER_00: First, the amyroterone digoxin interaction is driven by amyroterone, inhibition of P glycoprotein, okay, which digoxin is a major substrate of.
• 11:32
  SPEAKER_00: Second, inhibition of that transporter, P.
• 11:36
  SPEAKER_00: glycoprotein, increases digoxin exposure and raises the risk of toxicity given its narrow therapeutic index.
• 11:44
  SPEAKER_00: Third, understanding this mechanism allows clinicians to anticipate the interaction, adjust therapy appropriately, and monitor patients proactively.
• 11:57
  SPEAKER_00: That is the difference, guys, between memorizing a drug interaction and understanding the why behind it.
• 12:04
  SPEAKER_00: Okay?
• 12:05
  SPEAKER_00: So thank you guys for joining me on this episode of This Is Why.
• 12:08
  SPEAKER_00: If you found this discussion helpful, please share it with your colleagues, people like students, residents, fellows, pharmacists, nurses.
• 12:14
  SPEAKER_00: We all take care of patients and they're all on these medicines, and we need to be vigilant at monitoring for them.
• 12:20
  SPEAKER_00: But remember, when we understand the why, it helps us to improve the how.
• 12:25
  SPEAKER_00: How do we manage patients?
• 12:26
  SPEAKER_00: How do we deal with this interaction?
• 12:28
  SPEAKER_00: And ultimately, that helps us take better care of our patients.
• 12:32
  SPEAKER_00: And I'll see you next time.
• 12:33
  SPEAKER_00: Take care, bye bye.