WEBVTT - Ep 120 Acetaminophen/Paracetamol: Pain. Killer. 0:00:00.320 --> 0:00:03.480 On that September day, the postal worker picked his daughter up, 0:00:03.600 --> 0:00:06.480 as he often did, from preschool, at our lady of 0:00:06.519 --> 0:00:10.039 the wayside in the Chicago suburb of Arlington Heights, Illinois. 0:00:10.680 --> 0:00:13.200 They stopped at a nearby grocery store on the way home. 0:00:13.600 --> 0:00:17.200 Cassia always loved running errands with her dad. She wanted 0:00:17.239 --> 0:00:20.640 to go everywhere he did. She remembers walking with him 0:00:20.680 --> 0:00:23.520 down the aisles of jewel Osco that day. He picked 0:00:23.560 --> 0:00:26.880 out a bouquet of gladiolas for her mother. Cassia paused 0:00:26.880 --> 0:00:29.960 to point out a travel sized bottle of mouthwash. She 0:00:30.080 --> 0:00:33.440 loved how it fit in her hand so easily. That's 0:00:33.520 --> 0:00:36.639 when her dad picked up the bottle of extra strength Tylanol. 0:00:37.120 --> 0:00:40.440 They headed home together. She didn't know then it would 0:00:40.479 --> 0:00:41.360 be the last time. 0:01:25.520 --> 0:01:27.959 Oh, that's awful. 0:01:29.800 --> 0:01:31.720 It is it is so. 0:01:32.319 --> 0:01:37.040 That is from a CNN article titled Transformed by Tragedy 0:01:37.240 --> 0:01:42.000 by Catherine E. Schochet, published September twenty fourth, twenty twenty two. 0:01:42.200 --> 0:01:45.120 And that is about the tailand all murders, which we 0:01:45.200 --> 0:01:52.360 will chat about later in the episode. It is horrible. Yeah, yeah, Hi. 0:01:52.640 --> 0:01:54.600 I'm Aaron Welsh. 0:01:53.960 --> 0:01:55.080 And I'm Erin Allman. 0:01:55.200 --> 0:01:58.200 Updank and this is this podcast will kill You. 0:01:58.920 --> 0:02:02.880 And today we're talking about tilan all we are well 0:02:02.920 --> 0:02:07.760 because benefici paracetamol, the whatever, not to use the trade 0:02:07.840 --> 0:02:11.680 name or well it's It's also really difficult because I 0:02:11.720 --> 0:02:15.480 feel like there are like why are there two generic 0:02:15.600 --> 0:02:20.200 names for it? There are two official like chemical like 0:02:20.440 --> 0:02:25.359 short names for it, but why why Because two different 0:02:25.360 --> 0:02:28.880 people decided they wanted to name it, no joke, but like. 0:02:28.919 --> 0:02:31.440 Couldn't we come to a consensus, like for the coin, 0:02:31.919 --> 0:02:35.120 let's just know with I think mostly I use paracetamol 0:02:35.240 --> 0:02:35.560 in this. 0:02:35.960 --> 0:02:38.600 And I usually use the CEDAMNIFFM because that's what we 0:02:38.680 --> 0:02:40.160 call it in the US. 0:02:40.440 --> 0:02:42.520 Yeah, I don't know why I use paracetamol. I think 0:02:42.520 --> 0:02:44.839 it was the papers I read must have been UK 0:02:44.960 --> 0:02:45.760 based or something. 0:02:45.760 --> 0:02:47.120 You're at the post. 0:02:47.520 --> 0:02:49.679 It's good to know that paracetamol is the same thing, 0:02:49.800 --> 0:02:54.560 because it's definitely worldwide the more common term. 0:02:54.960 --> 0:02:57.079 Okay, that must be why it was in the papers too. 0:02:57.280 --> 0:03:01.840 Yeah, yeah, yeah, So a cedamniff in paracetamol today. 0:03:02.000 --> 0:03:04.760 Yeah, it's going to be a really interesting one and 0:03:04.840 --> 0:03:08.200 I can't wait to get to it. But first, it's 0:03:08.280 --> 0:03:12.240 quarantine any time, certainly is what are we drinking this week? 0:03:12.560 --> 0:03:14.560 We're drinking the chills Pills. 0:03:15.120 --> 0:03:16.840 Nice? Get it nice? 0:03:17.080 --> 0:03:21.320 Yeah? Pretty good is when you have chills, often a cedamtafin. 0:03:21.400 --> 0:03:24.919 Paracetamol is one of the drugs that you reach for. 0:03:25.320 --> 0:03:27.280 Yeah, and as we'll talk about, there might be other 0:03:27.360 --> 0:03:30.320 mechanisms by which it chills you out, but. 0:03:30.400 --> 0:03:32.720 I'm interesting, we'll get there. 0:03:33.240 --> 0:03:37.200 And the Chills Pills is based on a very classic 0:03:37.240 --> 0:03:40.720 cocktail called the Painkiller, which we also could have gone with, 0:03:40.800 --> 0:03:42.800 but like, I don't know, we wanted to put our 0:03:42.840 --> 0:03:43.880 own little spin on it. 0:03:44.000 --> 0:03:45.360 I suppose as we do. 0:03:45.720 --> 0:03:46.480 But it is a. 0:03:46.480 --> 0:03:51.000 Delicious set of ingredients. It has rum, pineapple juice, orange juice, 0:03:51.040 --> 0:03:54.200 cream of coconut. Pretty sure we haven't done this, but 0:03:54.200 --> 0:03:56.280 we've probably done something very similar. 0:03:57.160 --> 0:04:01.480 It's inevitable after six seasons. Yes, we'll post the full 0:04:01.560 --> 0:04:04.600 recipe for that quarantine, as well as our non alcoholic 0:04:04.680 --> 0:04:07.800 plusy Brita on our website, this podcast, wikill you dot Com, 0:04:07.840 --> 0:04:09.640 and all of our social media channels. 0:04:09.960 --> 0:04:13.840 We certainly will. On our website you can find all 0:04:13.880 --> 0:04:17.320 sorts of cool things, like the sources for each and 0:04:17.360 --> 0:04:21.040 every one of our episodes, transcripts, our bookshop dot Org 0:04:21.040 --> 0:04:25.520 affiliate account, our Goodreads list, merch music by Bloodmobile Patreon. 0:04:26.279 --> 0:04:28.560 So you check it out? Are you post it on 0:04:28.600 --> 0:04:32.480 our website? Actually? So, I'm just scrolling over the top. Men. 0:04:31.880 --> 0:04:35.080 You see your eyes like flicking back and forth. Those 0:04:35.160 --> 0:04:36.560 nice well done. 0:04:37.040 --> 0:04:39.200 I was like, Wow, finally I don't have to just 0:04:39.279 --> 0:04:41.800 like somehow bring this to the surface of. 0:04:41.760 --> 0:04:44.480 My brain to rank here. Anyway, check it out. 0:04:44.480 --> 0:04:47.280 It's great stuff, It's really great stuff. Well with that, 0:04:48.360 --> 0:04:51.680 shall we get into paracetamol aceta benefit. 0:04:52.120 --> 0:05:10.920 Let's do it right after this break. 0:05:14.760 --> 0:05:17.080 N acetyle para amino phenol. 0:05:18.040 --> 0:05:21.040 Huh oh, I'm already that's already too much. 0:05:21.160 --> 0:05:25.920 Well, then that's why they shortened it. It's aka acedamnifin, 0:05:26.320 --> 0:05:31.640 aka paracetamol. Both of those names are just literal shorthand 0:05:31.800 --> 0:05:36.400 for that chemical name and a style para amino phenol. 0:05:36.680 --> 0:05:41.240 Acetamnafin or paracetamol also in the literature, often called a 0:05:41.440 --> 0:05:47.880 pap aka brand name tailanol. In the US, I'll probably 0:05:47.920 --> 0:05:51.719 call it acetaminofin for most of this section, and it 0:05:51.760 --> 0:05:54.240 sounds like erin. You'll call it paracenamol, And both are 0:05:54.560 --> 0:06:01.280 entirely correct in pretty much every single paper I read, 0:06:01.960 --> 0:06:06.080 acetaminifin is cited as the most popular and widely used 0:06:06.200 --> 0:06:10.120 over the counter medication, possibly of any class, but certainly 0:06:10.200 --> 0:06:14.560 of analgesic anti pyretic medications, that is, pain relievers and 0:06:14.600 --> 0:06:19.320 fever reducers. And this is like worldwide, worldwide. Is true, 0:06:19.920 --> 0:06:24.159 it's a very common medication on its own, but it's 0:06:24.240 --> 0:06:28.040 also very common in combination medications. Like all of those 0:06:28.120 --> 0:06:31.280 coffin cold mixes that you buy, almost all of those 0:06:31.360 --> 0:06:36.279 have acetaminifin in them. Some studies suggest that nearly eighty 0:06:36.400 --> 0:06:41.359 percent of for example, the US general population use acetaminifin 0:06:41.440 --> 0:06:44.200 at some point in their lives, if not on the regular. 0:06:45.680 --> 0:06:50.039 And because of this, acetaminifin is also in many countries 0:06:50.640 --> 0:06:55.559 the most commonly used drug in intentional overdoses, as well 0:06:55.600 --> 0:07:01.000 as responsible for the most unintentional medication over in a 0:07:01.040 --> 0:07:04.120 lot of countries. And we'll talk about why that's so 0:07:04.240 --> 0:07:09.000 important in terms of the dangers of acetamenifin. But first, 0:07:09.200 --> 0:07:12.320 like what does it actually do? Like what what does 0:07:12.320 --> 0:07:14.440 the ceeda menafin do? What is it? What does it 0:07:14.520 --> 0:07:18.640 do to you? No one knows, That's what's the answer, 0:07:20.080 --> 0:07:24.120 as always on this podcast. So like I mentioned, it's 0:07:24.160 --> 0:07:27.480 bought and sold as an antipyretic meaning a fever lowering 0:07:27.600 --> 0:07:32.160 and an analgesic meaning pain reducing medication. So it reduces 0:07:32.200 --> 0:07:35.280 pain and it reduces our fever. And like you said, 0:07:35.400 --> 0:07:39.840 as it turns out, we don't fully know how it 0:07:40.000 --> 0:07:46.400 actually does this, and that fact alone still blows my mind. 0:07:46.800 --> 0:07:52.400 Like I knew that we didn't fully know the mechanisms 0:07:52.560 --> 0:07:57.040 of acetamenifin, but it was astounding to read so many 0:07:57.080 --> 0:08:02.200 papers about the potential theoretical mechanisms of this drug and 0:08:02.240 --> 0:08:05.480 have them all be like, so, just what we hypothesize 0:08:05.560 --> 0:08:09.239 on other people hypothesize this so well, who knows? 0:08:10.600 --> 0:08:13.320 It's like I feel like it's really interesting, and I 0:08:13.400 --> 0:08:17.200 think that when I tell you the origin story of 0:08:17.760 --> 0:08:20.960 acetum it might make a bit more sense. Why we 0:08:21.080 --> 0:08:21.680 don't know? 0:08:22.000 --> 0:08:24.600 Oh okay, I can't wait, it's gonna be fun. I 0:08:24.640 --> 0:08:28.280 know nothing except like, well, yeah, I know essentially nothing. 0:08:30.720 --> 0:08:33.320 So let's get into what we do know and what 0:08:33.880 --> 0:08:35.880 is hypothesized in the literature, shall we? 0:08:36.360 --> 0:08:36.720 Mm hm. 0:08:37.480 --> 0:08:42.040 The thing about pain that I will grant everyone trying 0:08:42.040 --> 0:08:45.439 to figure out the mechanisms of acetamenofin, and the thing 0:08:45.480 --> 0:08:49.760 about fever is that they're both a bit complicated to 0:08:49.800 --> 0:08:53.040 say the least, meaning it's not all just one mechanism 0:08:53.080 --> 0:08:56.880 to begin with. The other drug that we've talked about 0:08:56.880 --> 0:09:01.480 in detail on this podcast that has similar effects is aspirin. 0:09:02.320 --> 0:09:05.520 Aspirin is also a medicine that reduces pain and can 0:09:05.559 --> 0:09:09.920 be used as an antipyritic reduces temperature. In that episode, 0:09:09.960 --> 0:09:13.360 which was all the way back in season two, yeah right, 0:09:13.440 --> 0:09:18.479 yeah wow, I talked in detail about inflammation, the process 0:09:18.559 --> 0:09:24.600 of inflammation, the indicators of inflammation like redness, swelling, pain, 0:09:25.000 --> 0:09:29.520 and heat. And I talked in more detail than I 0:09:29.559 --> 0:09:33.720 realized about one of the main pathways that mediates inflammation, 0:09:34.320 --> 0:09:38.520 and this is something called the arachotonic acid pathway. I 0:09:38.679 --> 0:09:41.520 promise it's not going to be too heavy biochemistry in 0:09:41.559 --> 0:09:45.760 this episode, so please don't tune out. But I talked 0:09:45.800 --> 0:09:52.319 specifically about these enzymes called cyclooxygenase or cox enzymes, so 0:09:52.600 --> 0:09:56.479 to review that, because none of us remember, a racktonic 0:09:56.559 --> 0:10:00.520 acid is this substance that's present in all our cells. 0:10:00.520 --> 0:10:04.680 It's in our cell membranes and it is released when 0:10:04.800 --> 0:10:08.640 we have damage to our cells and then metabolized by 0:10:08.840 --> 0:10:13.320 cox enzymes into a whole bunch of different molecules like 0:10:13.480 --> 0:10:20.120 prostaglandins and leukotrienes and thromboxanes. These are different kinds of 0:10:20.280 --> 0:10:27.160 signaling molecules that induce inflammation, which again you'll have swelling 0:10:27.240 --> 0:10:29.760 and pain and heat things like that. Right when we 0:10:29.800 --> 0:10:35.960 have inflammation. En sids like aspirin and ibiprofen are what 0:10:36.000 --> 0:10:43.360 are called cocks blockers. But and in blocking these cox enzymes, 0:10:43.559 --> 0:10:47.720 they act as anti inflammatory medicines, and that is how 0:10:47.760 --> 0:10:53.000 they reduce pain and swelling and temperature. But pain is 0:10:53.120 --> 0:10:57.760 not just from inflammation, and neither is fever or rather 0:10:57.880 --> 0:11:04.560 our temperature regulation. Pain is incredibly complex and probably worthy 0:11:04.559 --> 0:11:07.680 of its entire own episode someday if we can figure out. 0:11:07.559 --> 0:11:08.040 How to do that. 0:11:08.120 --> 0:11:10.360 But I don't know how to do that. Yeah, But 0:11:10.520 --> 0:11:14.120 inflammation is just one potential cause of pain. There are 0:11:14.480 --> 0:11:17.640 a lot of other kinds of no susceptive pain, which 0:11:17.679 --> 0:11:20.600 is when we have pain from like an actual or 0:11:20.679 --> 0:11:24.640 a threatened like an almost damage to our tissue. That's 0:11:24.640 --> 0:11:28.520 called no susceptive pain. But you can also have neuropathic 0:11:28.600 --> 0:11:32.320 pain if you have damage to the nerves or what's 0:11:32.360 --> 0:11:37.000 called no subplastic pain, and this is from alterations in 0:11:37.080 --> 0:11:39.760 the way that we perceive pain, the way that pain 0:11:39.840 --> 0:11:44.040 signals are scent without any actual damage. And then we 0:11:44.080 --> 0:11:46.400 can also have mixed pain, like pain that comes from 0:11:46.440 --> 0:11:50.480 a lot of different sources. And our temperature regulation process 0:11:50.679 --> 0:11:54.040 is mostly mediated in our brain, but there are a 0:11:54.080 --> 0:11:57.800 lot of messengers and receptors that are involved in this process. 0:11:59.080 --> 0:12:04.280 So back to what we're actually talking about. Acetaminifin is 0:12:04.480 --> 0:12:09.359 not an end set. It's not like aspirin, like a coxblocker. 0:12:10.600 --> 0:12:16.600 It doesn't work directly by this Cox pathway, but it 0:12:17.040 --> 0:12:20.600 kind of works by that pathway. And the reason that 0:12:20.640 --> 0:12:22.880 I brought it all up is because we thought for 0:12:22.920 --> 0:12:25.679 a really long time that that is the way that 0:12:25.760 --> 0:12:29.520 it worked. So there is still confusion out there as 0:12:29.559 --> 0:12:33.440 to what the effects of thailanol are on inflammation. But 0:12:33.520 --> 0:12:38.040 as it turns out, thilanol doesn't affect our inflammatory pathways 0:12:38.120 --> 0:12:44.600 at all, and yet it still mediates both pain and fever, 0:12:45.480 --> 0:12:49.280 but by a different mechanism than things like iboprofen and aspirin, 0:12:49.320 --> 0:12:50.720 which is really cool. 0:12:51.360 --> 0:12:54.880 Are there other drugs that are similar to acedaminifin in 0:12:55.000 --> 0:12:59.560 that they also either reduce pain or fever, but also 0:12:59.640 --> 0:13:01.920 don't act as and SAIDs act. 0:13:02.520 --> 0:13:05.880 Yes, there are a lot of other medicines, especially for pain, 0:13:06.040 --> 0:13:08.920 that are going to act on entirely different parts of 0:13:08.920 --> 0:13:13.360 the system than things like iberprofen or aspirin when it 0:13:13.360 --> 0:13:16.200 comes to fever. I think there are at least a couple, 0:13:16.240 --> 0:13:21.280 but I'm not super familiar with them. Okay, yeah, so 0:13:21.400 --> 0:13:26.000 let's get into how thailanol actually does work, and then 0:13:26.040 --> 0:13:28.440 we'll learn a lot about some of these other ways 0:13:28.480 --> 0:13:32.880 that pain is kind of mediated. Besides inflammation, there are 0:13:33.120 --> 0:13:39.560 three main pathways by which acetaminifin probably we think exerts 0:13:39.600 --> 0:13:43.440 its effects, and one of them does in fact involve 0:13:43.720 --> 0:13:47.240 COX cyclooxygenase. So it was worth me telling you that 0:13:47.280 --> 0:13:53.080 whole story. So it turns out that we thought for 0:13:53.120 --> 0:13:56.560 a long time a cetaminifin worked very similarly to iberprofen 0:13:56.840 --> 0:14:01.080 just blocked this enzyme. It turns out, does do some 0:14:01.280 --> 0:14:06.959 COX blocking, but it's neither direct nor is it universal 0:14:07.200 --> 0:14:11.560 in our body. So rather than binding to this enzyme 0:14:11.679 --> 0:14:16.360 and blocking its activity, it seems more likely that aceenamtiphin 0:14:16.520 --> 0:14:21.240 what it does is reduce the active form of this enzyme, 0:14:21.560 --> 0:14:25.400 not like reduce the amount of it, but like oxidation reduction. 0:14:25.560 --> 0:14:30.320 Reaction donates some electrons and renders it inactive in that way. 0:14:31.120 --> 0:14:33.800 But and here's where it gets really fun and interesting. 0:14:34.880 --> 0:14:38.880 Acetamnafin seems to only do this in our central nervous system, 0:14:39.400 --> 0:14:42.400 not in all the cells in our body like most 0:14:42.480 --> 0:14:43.520 COX inhibitors. 0:14:44.040 --> 0:14:46.680 What the how I knew? 0:14:46.680 --> 0:14:51.760 You'd ask? Again. We hypothesize that it has to do 0:14:51.840 --> 0:14:55.120 with the levels of peroxide, because this is like an 0:14:55.160 --> 0:14:59.320 oxidation reduction reaction. It only works under certain conditions that 0:14:59.400 --> 0:15:02.440 are present the brain, but not in our peripheral tissues. 0:15:04.320 --> 0:15:08.840 Okay, So because it's not straight up blocking, it's just 0:15:08.880 --> 0:15:12.840 sort of interfering with this enzyme that the conditions have 0:15:12.880 --> 0:15:15.800 to be right. Okay, that's interesting and weird. And why 0:15:15.880 --> 0:15:19.720 aren't the conditions the same? Why are they different? What 0:15:19.840 --> 0:15:22.320 makes them different? What purpose does that difference serve? 0:15:22.680 --> 0:15:28.640 Those are two deep of biochemistry questions for me. But 0:15:28.840 --> 0:15:31.280 what I can tell you is that in doing this 0:15:31.520 --> 0:15:36.160 in our brain, the end result is that acetaminophin inhibits 0:15:36.200 --> 0:15:40.720 the production of prostaglandins, which are some of these molecules 0:15:40.720 --> 0:15:45.400 whose normal action is to increase our temperature and increase 0:15:45.440 --> 0:15:49.600 our sensitivity of pain receptors to various stimuli in our brain. 0:15:50.520 --> 0:15:55.800 So by blocking the production of prostaglandins, acetaminophin in our 0:15:55.960 --> 0:16:02.600 brain is reducing our temperature and reducing our sensation of pain. 0:16:03.160 --> 0:16:06.920 Fascinating Number one, I love it. Number two is it 0:16:07.040 --> 0:16:11.520 too early to ask about compare and contrast with end sets? 0:16:11.760 --> 0:16:13.160 And how like. 0:16:14.160 --> 0:16:19.640 Does aceta menafin work better than at these targeting proseglandins 0:16:19.680 --> 0:16:20.320 in your brain? 0:16:20.560 --> 0:16:21.160 Stuff like that? 0:16:22.520 --> 0:16:24.120 I love it, You know, I don't think that it's 0:16:24.160 --> 0:16:30.000 too early. We've got several more mechanisms to get through. 0:16:30.360 --> 0:16:31.960 We can just put a pin in it and come 0:16:32.000 --> 0:16:33.040 back if okay. 0:16:33.200 --> 0:16:34.960 Let's do that. We'll go through these and then ask 0:16:35.040 --> 0:16:37.520 me that again, because it's it is a really interesting question. 0:16:37.840 --> 0:16:39.160 Okay, okay, okay. 0:16:39.320 --> 0:16:44.360 But but there's more so another big mechanism by which 0:16:44.440 --> 0:16:48.440 acetamnifin seems to have an effect, and this one's really fun, 0:16:49.480 --> 0:16:54.640 also involves a rackadonic acid. That molecule that's released from 0:16:54.640 --> 0:16:59.840 our cell membranes. Turns out that a metabolite of acetaminifinn 0:17:00.480 --> 0:17:03.720 so binds up with a rackadonic acid and is then 0:17:03.880 --> 0:17:09.200 converted into something called AM four four N, a rackadinoil 0:17:09.440 --> 0:17:14.240 fenolamine huh, AM four O four it's easier. This molecule 0:17:14.920 --> 0:17:20.320 happens to be a weak but present agonist of our 0:17:20.880 --> 0:17:26.040 cannabinoid receptors in our brain, So this ends up leading 0:17:26.080 --> 0:17:29.960 to an increase in cannabinoids and has an effect on 0:17:30.000 --> 0:17:33.520 this other receptor that's related. Okay, what does that actually mean, 0:17:34.119 --> 0:17:38.360 I'm lost? Yeah, cannabinoids. Does that word sound familiar? 0:17:38.720 --> 0:17:39.000 Yeah? 0:17:39.160 --> 0:17:44.679 Sounds like cannabis. Yeah. Yeah. So cannabinoids are a group 0:17:44.720 --> 0:17:48.159 of substances, some of which are found in marijuana, cannabis, 0:17:48.200 --> 0:17:52.400 among other things. We have in our bodies and brains 0:17:52.840 --> 0:17:57.720 an entire system called the endocannabinoid system. We don't fully 0:17:57.800 --> 0:18:01.359 understand it or how it works. It's involved in a 0:18:01.359 --> 0:18:04.199 lot of different things. But some of the things that 0:18:04.280 --> 0:18:08.000 has been shown to be involved in, especially via a 0:18:08.080 --> 0:18:12.880 couple of specific receptors, is the perception of pain and 0:18:13.160 --> 0:18:18.880 our temperature regulation. Turns out that this molecule that acetamenifin 0:18:19.160 --> 0:18:24.120 can turn into in our brain AM four four acts 0:18:24.160 --> 0:18:30.439 on these receptors indirectly and increases the production of cannabinoids 0:18:30.840 --> 0:18:34.200 that interact with these systems and then mediates both pain 0:18:34.280 --> 0:18:38.320 and temperature in our brain. Through these receptors. 0:18:38.800 --> 0:18:41.080 Are these different hypotheses. 0:18:41.920 --> 0:18:45.800 Mutually exclusive, absolutely not, which is the most fascinating thing 0:18:45.880 --> 0:18:46.320 about them. 0:18:46.520 --> 0:18:50.040 Okay, So it could be through interfering with the production 0:18:50.119 --> 0:18:56.080 of prosseaglandins, or it could be by upregulating these cannabinoid 0:18:56.160 --> 0:18:57.040 receptor things. 0:18:57.240 --> 0:18:59.959 Yeah, but they're not mutually exclusive, so it's likely like 0:19:00.119 --> 0:19:01.840 all of this is happening at the same time the 0:19:01.880 --> 0:19:04.840 same time. Yeah, it's interacting with like a number of 0:19:04.920 --> 0:19:09.200 different receptors and enzymes in a number of different ways, 0:19:09.240 --> 0:19:11.320 which is probably why it's been so hard for us 0:19:11.359 --> 0:19:17.560 to pinpoint the exact mechanism if it's multifactorial, because there's 0:19:17.640 --> 0:19:20.639 one more okay, there has to be three, you know. 0:19:20.960 --> 0:19:27.119 Always acetaminefin seems to additionally activate again in our brain 0:19:27.920 --> 0:19:34.040 our descending inhibitory SARAH to nergic pathway. So many words, 0:19:34.720 --> 0:19:39.159 so much complication, but okay, let me simplify. When we 0:19:39.240 --> 0:19:43.760 have an injury or tissue damage or whatever, and pain 0:19:44.119 --> 0:19:48.440 is a result, that information of pain is transmitted from 0:19:48.560 --> 0:19:51.600 our skin or wherever that injury is through our spinal 0:19:51.640 --> 0:19:54.879 cord and through what's called the dorsal horn of our 0:19:54.880 --> 0:19:57.520 spinal cord and then up to our brain via these 0:19:57.680 --> 0:20:01.200 ascending pathways. Right, like skin, spinal cord brain, the pathway 0:20:01.240 --> 0:20:04.760 goes up. Then our brain has these other pathways that 0:20:04.840 --> 0:20:07.520 go back down through our spinal cord and then out 0:20:07.560 --> 0:20:11.879 to the periphery. These are called descending pathways. One of 0:20:11.920 --> 0:20:16.800 these descending pathways involves serotonin, which most people have probably 0:20:16.880 --> 0:20:22.000 heard of because of things like serotonin reuptake inhibitors or 0:20:22.040 --> 0:20:29.320 antidepressant medications. Serotonin is like a happy hormone, right. Serotonin 0:20:29.640 --> 0:20:34.800 via this pathway helps to mediate decrease the perception of pain. Right. 0:20:35.040 --> 0:20:37.679 So it's like our brain gets a signal, ah, we 0:20:37.720 --> 0:20:41.800 have pain, and it has these pathways to go. It's cool, man, 0:20:41.920 --> 0:20:43.800 we can deal with it. We don't have to feel 0:20:43.920 --> 0:20:47.080 the hurt. That's this very simplified way of looking at it. 0:20:47.880 --> 0:20:54.440 But by activating these inhibitory pathways, these serotonin pathways, acetamenafin 0:20:54.520 --> 0:20:57.600 likely has at least some small effect on the sensation 0:20:57.720 --> 0:21:01.280 of pain via these serotin pathways as well. 0:21:01.760 --> 0:21:06.080 So it like says, reassure this person even more that 0:21:06.080 --> 0:21:09.359 they're okay and they can handle this pain exactly okay. 0:21:09.400 --> 0:21:12.439 Interesting yeah, yeah right, interesting. 0:21:12.720 --> 0:21:15.520 I know That's why I said the chills pills thing 0:21:15.600 --> 0:21:17.880 works on so many different levels. 0:21:18.160 --> 0:21:19.200 Yeah right. 0:21:20.280 --> 0:21:22.199 It doesn't mean that tyl and ill's making everyone just 0:21:22.240 --> 0:21:24.880 feel really happy or anything. That's not how It's more 0:21:24.880 --> 0:21:29.359 complicated than that. But it's so many different little mechanisms 0:21:30.000 --> 0:21:33.159 that all of which are in our central nervous system, 0:21:33.160 --> 0:21:36.480 which I think is fascinating. So again, acidamenefin seems to 0:21:36.840 --> 0:21:42.119 pretty specifically affect pain via our central nervous system rather 0:21:42.200 --> 0:21:45.760 than peripherally or like directly at the sight of wherever 0:21:45.800 --> 0:21:49.919 that pain is coming from. And it's likely these multiple 0:21:50.240 --> 0:21:55.320 little mechanisms that all together produce the overall effect. 0:21:56.040 --> 0:21:58.960 Now, can I ask my question ages, please compare and 0:21:59.040 --> 0:22:04.560 contrast please with the following drugs, eprofen, aspirin. Those are 0:22:04.560 --> 0:22:05.679 the only two I can think of. 0:22:07.080 --> 0:22:09.360 You could even say opioids, opioids. 0:22:09.480 --> 0:22:09.919 There we go. 0:22:10.200 --> 0:22:14.920 Yeah. So, in general, acetaminefin is considered a very mild 0:22:15.000 --> 0:22:19.120 analgesic and a mild antipyritic, and mild really does seem 0:22:19.119 --> 0:22:22.800 to be the keyword. Most studies have shown it results 0:22:22.800 --> 0:22:26.200 in about like a point two two point four degree 0:22:26.640 --> 0:22:30.160 I believe that's fahrenheit decrease in human body temperature, which 0:22:30.200 --> 0:22:33.880 is even less than I would have thought based on 0:22:33.960 --> 0:22:35.360 my personal usage of it. 0:22:36.119 --> 0:22:38.480 Yeah, that's that seems really low. 0:22:38.680 --> 0:22:42.800 It's really minor. Yeah, it's a minor decrease in overall temperature, 0:22:43.040 --> 0:22:45.200 but it might be enough to make you feel a 0:22:45.240 --> 0:22:46.199 lot better Nutuh. 0:22:46.280 --> 0:22:46.520 Yeah. 0:22:46.840 --> 0:22:52.720 Yeah. Pain is something that's obviously very difficult to quantify 0:22:53.000 --> 0:22:59.439 and measure. But one thing that's interesting at least about 0:22:59.520 --> 0:23:04.320 the pain relieving effects of acetaminophin in comparison to end sense, 0:23:05.359 --> 0:23:10.320 is that it's not having any anti inflammatory activity. So 0:23:10.480 --> 0:23:15.119 if the pain is primarily and directly from the process 0:23:15.160 --> 0:23:19.760 of inflammation, it's generally not well treated with tailanol, and 0:23:19.800 --> 0:23:23.959 that's been shown in some studies. Things like rheumatoid conditions 0:23:23.960 --> 0:23:27.600 and things are not very well treated with something like acetaminifin. 0:23:28.440 --> 0:23:32.280 In some things like osteoarthritis, which is more of a 0:23:32.560 --> 0:23:37.560 direct pain rather than an inflammatory pain. Some studies have 0:23:37.560 --> 0:23:41.320 shown it's about equivalent or maybe a little less effective 0:23:41.400 --> 0:23:43.880 than something like n sets for that kind of purpose. 0:23:44.359 --> 0:23:46.960 So in general, it's considered pretty similar in terms of 0:23:47.000 --> 0:23:51.640 pain reduction to something like an ibiprofen. Okay, some studies 0:23:51.680 --> 0:23:55.000 show that it does fairly well at things like cancer pain, 0:23:55.160 --> 0:23:59.760 at least mild cancer pain, not severe cancer pain. And 0:24:00.080 --> 0:24:02.160 migraine headaches, though I feel like a lot of people 0:24:02.160 --> 0:24:06.359 with migraines would disagree with that, and is less good 0:24:06.359 --> 0:24:09.320 for things like tension headaches. So it's like very specific 0:24:09.440 --> 0:24:11.600 types of pain that it seems to be more effective 0:24:11.680 --> 0:24:12.720 versus less effective. 0:24:13.080 --> 0:24:16.760 Well, I would imagine that just person to person variation 0:24:16.920 --> 0:24:18.520 is probably pretty big. 0:24:18.600 --> 0:24:19.880 One thousand percent. 0:24:20.080 --> 0:24:20.640 Yes, yeah. 0:24:20.880 --> 0:24:21.400 Interesting. 0:24:22.880 --> 0:24:26.280 The other interesting thing is that because of the dominifin 0:24:26.359 --> 0:24:30.760 as a mild analgesic and a mild antipyretic is considered 0:24:30.840 --> 0:24:34.359 very similar to something like ibiprofen, which is another over 0:24:34.400 --> 0:24:39.439 the counter medication. Again is working via a different anti 0:24:39.520 --> 0:24:44.159 inflammatory pathway. Ibiprofen is an end said, a non steroidal 0:24:44.320 --> 0:24:48.679 anti inflammatory. They're very similar in terms of used to 0:24:48.760 --> 0:24:55.880 treat mild pain mild fevers. The difference often is cited 0:24:56.320 --> 0:25:01.320 as the risk of these two medicines, and depending on 0:25:01.359 --> 0:25:04.399 what paper you read and who you talk to, you 0:25:04.520 --> 0:25:08.120 might think that one is very risky and the other 0:25:08.400 --> 0:25:11.920 is not. But which one might be up in the 0:25:11.960 --> 0:25:17.240 air for a long time By a lot of people. 0:25:17.880 --> 0:25:24.920 Acetaminifin was considered very, very, very safe and safer compared 0:25:25.040 --> 0:25:29.159 to n sets. The reason for this is because n 0:25:29.280 --> 0:25:33.520 sets do have a significantly increased risk of GI side effects, 0:25:33.560 --> 0:25:38.480 specifically bleeding from the gastrointestinal tract, and that is because 0:25:38.600 --> 0:25:42.800 of their effects on cocks peripherally and in our stomach. 0:25:44.119 --> 0:25:47.240 That's a whole episode on its own, but it greatly 0:25:47.280 --> 0:25:53.479 does increase the risk of gastrointestinal bleeding more so than 0:25:53.520 --> 0:25:59.200 a seedaminifin. However, that's not to say that a cetaminifin 0:25:59.720 --> 0:26:05.720 is without risk. And so I think in recent years, 0:26:05.840 --> 0:26:09.639 as we've learned more and more about acetaminophin, the risk 0:26:09.840 --> 0:26:12.480 benefit calculus for some people and in some of the 0:26:12.520 --> 0:26:18.000 studies that I read, has perhaps shifted. And so especially 0:26:18.000 --> 0:26:21.000 if you're talking about short term versus long term use 0:26:21.560 --> 0:26:27.680 and degree of severity of the possible side effects, one 0:26:27.720 --> 0:26:31.560 could argue that a setaminifin might be more dangerous than 0:26:31.800 --> 0:26:34.960 hyberprofen and some people do argue that in the literature. 0:26:36.080 --> 0:26:39.879 So let's talk about the adverse effects of acetaminifin. 0:26:40.440 --> 0:26:46.280 Yeah, it's also it's interesting that I feel like sometimes 0:26:46.880 --> 0:26:50.720 the mechanism of a drug is figured out, at least 0:26:50.760 --> 0:26:54.040 in part by looking at adverse effects. 0:26:54.440 --> 0:26:56.200 Yeah, that's a good point. 0:26:56.359 --> 0:26:59.280 And so it's it's interesting that that doesn't seem to 0:26:59.280 --> 0:27:00.960 be the case with a seedaminifin. 0:27:01.359 --> 0:27:05.560 Yeah, not at all. Okay, Yeah, I don't know. It's 0:27:05.560 --> 0:27:10.320