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Practice Question: Picking the Right Benzodiazepine on Metabolism · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: Hey, well, we know that not all benzodiazepines behave the same way once they enter the body.
• 0:06
  SPEAKER_00: We also know that in some patients, that difference can quietly lead to complications that we don't intend.
• 0:14
  SPEAKER_00: The practice test question I have for you is not only high yield for exams, but one that is clinically relevant.
• 0:22
  SPEAKER_00: Hey guys, I'm Dr.
• 0:23
  SPEAKER_00: Bustae and welcome to This Is Why, a show that helps healthcare professionals transform their medical knowledge from what to why, because that improves the how, even how to take, test, and maximize your ability to get the right answer.
• 0:38
  SPEAKER_00: So here's our case.
• 0:40
  SPEAKER_00: We have a 62-year-old patient who is being initiated on a benzodiazepine after failure of multiple agents for uncontrolled anxiety.
• 0:51
  SPEAKER_00: Question is which benzodiazepine would be preferred since it's not a major cytochrome P450 substrate and undergoes glucuronidation, which would avoid active metabolites.
• 1:06
  SPEAKER_00: We have choice A, chlorodiazepoxide, B diazepam, C, timazepam, and D medazolam.
• 1:16
  SPEAKER_00: Okay?
• 1:17
  SPEAKER_00: Now this question is testing about pharmacokinetics, specifically hepatic metabolic pathways and how they influence safety and selection.
• 1:31
  SPEAKER_00: So that's the knowledge that's being assessed here.
• 1:34
  SPEAKER_00: What about that bloom's taxonomy and its level?
• 1:37
  SPEAKER_00: This is one of application.
• 1:40
  SPEAKER_00: Requires you to apply those pharmacokinetic principles to a real prescribing decision.
• 1:47
  SPEAKER_00: Okay?
• 1:48
  SPEAKER_00: So when we start thinking about test-taking approaches, the question becomes how do you identify which benzodiazepine follow those metabolic pathways, right?
• 2:02
  SPEAKER_00: Well, when metabolism is in focus, guys, in the question, like this one, we need to think in terms of phase one versus phase two pathways of drug metabolisms, predominantly in the liver, but other places too.
• 2:17
  SPEAKER_00: We know that phase one involves that cytochrome P450 system, which is oxidative reductive pathways, and often produces active but also inactive metabolites.
• 2:29
  SPEAKER_00: It just varies from one drug to another, doesn't it?
• 2:32
  SPEAKER_00: And then there's phase two, which is a conjugative pathway, most commonly glucuronidation, but there's others, and typically do not generate active metabolites.
• 2:42
  SPEAKER_00: Okay, now that distinction is the key framework guiding this question that you need to get.
• 2:50
  SPEAKER_00: What about potential confounders or modifiers when we're approaching this kind of question?
• 2:58
  SPEAKER_00: Well, the patient's age is another subtle clue, right?
• 3:02
  SPEAKER_00: Early in the even early in the 60s of someone's age, right, hepatic oxidative metabolism, also renal function, of course, can both decline.
• 3:12
  SPEAKER_00: And the sensitivity to CNS depressants, we know, can increase.
• 3:18
  SPEAKER_00: And that's why we have lists and things like that, beers lists and agents that are out there, the tools that help us to identify that.
• 3:26
  SPEAKER_00: But this makes accumulation of an active metabolite more clinically relevant if we use a drug that does that.
• 3:33
  SPEAKER_00: So phrases like avoid active metabolites or not a major cytochrome P450 substrate are directing your attention specifically to phase two conjugated metabolism.
• 3:50
  SPEAKER_00: And also seeing familiar long-acting benzodiazepines in this case should prompt you to pause and reconsider their metabolic profiles.
• 4:01
  SPEAKER_00: So the correct answer here is tamazepam.
• 4:07
  SPEAKER_00: Now tamazepam undergoes only direct phase two metabolism.
• 4:12
  SPEAKER_00: It is glucuronidated and it's inactive for it to be eliminated in the kidneys.
• 4:19
  SPEAKER_00: Now this reduces the likelihood of drug accumulation and the prolonged pharmacologic effect, regardless really of that renal function.
• 4:29
  SPEAKER_00: Now the real issue is that many denzodiazepines do rely on phase one oxidation pathways that produce other metabolites that persist and can build up over time.
• 4:42
  SPEAKER_00: And I want to, I think it's important to look at that.
• 4:47
  SPEAKER_00: What this table or this diagram is showing you is a number of agents.
• 4:52
  SPEAKER_00: So we have chlorodiaz epoxide up here, right?
• 4:55
  SPEAKER_00: It gets metabolized into multiple active metabolites before it ever gets to glucuronidation for then elimination in the urine, right?
• 5:06
  SPEAKER_00: Is it inactive?
• 5:08
  SPEAKER_00: You can see that with uh diazepam as that, and timazepam goes directly through.
• 5:16
  SPEAKER_00: Okay.
• 5:17
  SPEAKER_00: Now, yes, it can go this pathway, but it it gets directly through.
• 5:21
  SPEAKER_00: It's part of the lot, okay?
• 5:24
  SPEAKER_00: L-O-T.
• 5:25
  SPEAKER_00: Right?
• 5:26
  SPEAKER_00: So the tamazepam is one of those, right?
• 5:29
  SPEAKER_00: Um you have oxazepam, okay, and then you have larazipam.
• 5:35
  SPEAKER_00: That's lot.
• 5:36
  SPEAKER_00: Okay.
• 5:37
  SPEAKER_00: But you can see that these are the various pathways of metabolism for benzodiazepines, and the ones that are up in this area up here, those are going through phase one pathways.
• 5:51
  SPEAKER_00: Okay.
• 5:51
  SPEAKER_00: And then those that you see with a direct arrow, those are the ones that are predominantly going straight into uh conjugated pathways or phase two.
• 6:03
  SPEAKER_00: Okay.
• 6:04
  SPEAKER_00: Now, coming back to our choices, okay, then you look back here, you see that chloridiaz epoxide, it's it's a long-acting agent.
• 6:14
  SPEAKER_00: Um, does stick around for quite a while.
• 6:17
  SPEAKER_00: You saw that it got metabolized into multiple metabolites.
• 6:21
  SPEAKER_00: That would increase the risk of accumulation.
• 6:24
  SPEAKER_00: Option B, diazepam, again, is a well-known long-acting one with active metabolites.
• 6:31
  SPEAKER_00: Again, prolonged duration, probably not the best.
• 6:34
  SPEAKER_00: And then midazolam at the end, while it's very short, right?
• 6:38
  SPEAKER_00: Most of the time we're administering that parentally or through some other route of administration, like intranasal sprays, that I think it still comes as an oral solution, but I don't see that used very much.
• 6:49
  SPEAKER_00: So it's not common, right?
• 6:51
  SPEAKER_00: And and this would not be the primary use for it in this situation, especially as an outpatient kind of scenario.
• 6:57
  SPEAKER_00: In an older patient, it's more procedural, seems like intermittent use.
• 7:02
  SPEAKER_00: Okay.
• 7:03
  SPEAKER_00: So that's that all that's important, right?
• 7:06
  SPEAKER_00: So the key concept here in understanding the difference between phase is phase, understand the difference between phase one and phase two metabolism.
• 7:12
  SPEAKER_00: All benzodazpines, right, at some level are processed in the liver, but some avoid that cytochrome P450 oxidation.
• 7:21
  SPEAKER_00: That group, remember, is LOT, LOT, Lirazepam, oxazipam, and timazepam.
• 7:27
  SPEAKER_00: Okay, and these agents undergo that glucaronidation and don't have active metabolites.
• 7:33
  SPEAKER_00: And they also have more predictable pharmacokinetics.
• 7:37
  SPEAKER_00: Okay, so why does this matter?
• 7:39
  SPEAKER_00: Well, because in patients with reduced hepatic function or increased CNS sensitivity, these agents do carry a lower risk of accumulation and a lower risk of prolonged sedation.
• 7:53
  SPEAKER_00: Okay, so when you're thinking about taking an exam question like this, strategies that you should consider is that you anchor yourself around the concept of phase one versus phase two.
• 8:05
  SPEAKER_00: If there's a cytochrome P450 kind of avoidance mentioned, like there was in this one, you know, shift that focus to those that are undergoing direct conjugation.
• 8:16
  SPEAKER_00: Okay.
• 8:17
  SPEAKER_00: Now you do need to be cautious anytime you see long-acting benzodazamine, especially in an older or elderly patient, because those are already a concern.
• 8:28
  SPEAKER_00: Increased risk of metabolites, also accumulation, and they represent common distractors like they were here.
• 8:35
  SPEAKER_00: Now consider the patient sitting in front of you, right?
• 8:38
  SPEAKER_00: You're not just choosing a drug based on its effect, right?
• 8:43
  SPEAKER_00: You are also on how that drug is going to be impacting and going through the body and how that body will process it over time.
• 8:51
  SPEAKER_00: So you want to select an agent with a simpler metabolism that can reduce unintended accumulation while also improving safety, especially those patients where their physiology is changing, which we see in our elderly or geriatric patient population.
• 9:08
  SPEAKER_00: If this helped you to clarify how pharmacokinetics directly impacts clinical decision making, this is exactly how we teach also over at high yield med reviews.
• 9:21
  SPEAKER_00: Okay, board preparation does require you applying concepts to questions, not just always memorizing facts.
• 9:30
  SPEAKER_00: Some things you do have to memorize.
• 9:32
  SPEAKER_00: But I created high yield med reviews to help you build that skill set because you must practice applying what you're expected to do, which is most of the time on a board exam or multiple choice question.
• 9:43
  SPEAKER_00: You could get a discount, uh, high yield med reviews by getting a uh going to thisiswhy.health and signing up for a free membership.
• 9:51
  SPEAKER_00: So I hope that that's helpful.
• 9:52
  SPEAKER_00: If you need that, otherwise, thanks for watching.
• 9:55
  SPEAKER_00: Give us a like.
• 9:57
  SPEAKER_00: Um, if there's any additional comments, like things that you've experienced, used your own practical application, always put that in there.
• 10:04
  SPEAKER_00: I like to learn from other people, hear your experiences, but also I'll respond to those individually.
• 10:09
  SPEAKER_00: So thanks so much for joining us, and we'll see you on the next episode.
• 10:13
  SPEAKER_00: Take care.
• 10:14
  SPEAKER_00: Bye.