Aspirin
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applies to online activations, requires port in and auto pay. Customers activating in stores may be charged non-refundable activation fees. Welcome everybody to another episode of Dr. Matt and Dr. Mike's A to Z of the human body. I'm your host, Dr. Mark Todorovic, and I'm joined by my co-host, Dr. Matthew Lorraine Franklin James

But that's right, ladies and gentlemen, it's Matthew. Why is there no aspirin in the jungle? Why? Because the paracetamol. Because the paracetamol. Paracetamol. There we go. Because the paracetamol. Oh, gosh. Well, that's all for today, folks.

Matt, we are talking obviously about aspirin. We're talking about a drug. We are talking about a pharmacological agent that individuals probably one of the, what most, most widely used drug on the planet. You reckon? Be up there for sure. I mean, I read a paper saying it is the most widely used drug on the planet. Uh,

And we're going to go through what it does, how it works, why we use it, and some interesting facts, maybe a little bit about the history. What do you think? Sure. We can do that. Do you want to start? With the history? Go for it. Do you want to talk about what it is first? Aspirin? What is aspirin?

Okay, so, well, it's medication. It's got... I think everyone knew that part. Four, I guess you'd say four main clinical indications, meaning the reasons for why it's used. Right. So, I would say it's used...

Will I put this in order or just say them? Well, it's up to you, my friend. You do it. It's an anti-platelet, which means it prevents platelets coming together and holding hands to cause a formation of a clot. Reduces clotting, yeah. It's antipyretic, which means it's an anti-fever medication. It's an anti-inflammatory medication.

And it's an analgesic. Pain relief. Pain relief. Right. So they're the four main broad categories. So if you were to open up a textbook, a pharmacology textbook. I would never. You just look on the computer. Exactly. Just like everybody else does. So if you were to do that and try to find where it sits...

It probably would fit within the sections of hematology around its anti-platelet activity. Okay. As its main function. That would be a primary use of it. All right. Now, we'll get into today that the way that it works in this regard is actually different to how it works as an anti-inflammatory. Though it's unique in that regard that it kind of has two modes of action. Yes. Actually, probably...

but two main ones. Yeah. I think the way that it's now regarded is it's potentially doing more than we think or we understand. Yeah.

Clearly. Yeah, I agree. All right. So aspirin, commonly used drug, used to treat fevers, reduce inflammation, help mitigate pain, but also help reduce clotting. Yeah. Yeah. But with that, it's really based on the dosage of it. So when you want it to be used as an antiplatelet, you will be taking less than 300 milligrams of it per day.

When you want to use it as an anti-fever or an analgesic, you're probably using somewhere in the region of 300 milligrams to 2,000 milligrams per day. Oh, that high? That high. I thought it's... And then when you want to go into anti-inflammatory, above 2,000, probably above even 2,400 milligrams a day. Right. Yeah. That's now gone into an anti-inflammatory use. And that would be...

when it gets to its mechanism of action, how it blocks certain enzymes. Therefore, the inflammatory media is behind it. Okay. All right. So you want to talk about the history? History, yeah. Excuse me. All right. So it's probably not only the drug of, what did you say, the most commonly used drug on the planet? Probably true or be close to it.

But it's probably one of the oldest drugs as well. That's probably true as well. So it goes back to, well, what are you, 6,000 years ago? Wow. So it wasn't documented. So it was pretty much when your mum was born. Yeah, was it?

She listens to the podcast, so this is going to go down poorly. I'm sorry, Betty. So the Sumerians seem to be one of the first civilizations to use it, but probably the Egyptians as well and some other ancient cultures. Now, it derives from certain trees. Now, it's well known to have come from willow bark.

But it also comes from meadow sweet trees, which I think the Latin term is spirea. Oh, is it? Yeah, something like that anyway. So that's...

Kind of the family lineage of where the plant derives itself from. Now, they would have used it in... They would have chewed it. So possibly the bark of this tree, chewed it, put it into tea or poultice. Is that correctly termed? Poultice. Poultice, which is like a paste. Oh, okay.

So it's basically like Voltaren of today, where you just have this paste and you just put it on your aching joints. I don't know if it gets absorbed. Does aspirin get absorbed? Yeah. Now, you haven't said what the actual technical name of aspirin is. Yeah, I'll get to it. Oh, okay. Because the Sumerians didn't know the actual chemical name at this point. Well, that's very far, isn't it?

Hippocrates used it. So that was 400 BC. So he commonly used it for fevers and pain.

related ailments. Then it started to be understood better, probably in the 1700s, strongly used for its antipyretic use. And then probably in the 1800s, it started to be discovered that the chemical was salicylic acid. That was kind of the understanding that this is the chemical behind the wonder drug. You remember the discount store Silly Solly's?

Oh, okay. There's one down the Gold Coast. Silly Sollies. It's like a dollar store. Every time I think salicylic acid, I think Silly Sollies. And I'm sure nobody else does. I'm glad I brought that up. So I think it was getting to the late 1800s and it was starting to get closer to understanding...

the chemical structure of it, but also how you could make it or isolate it. And I think one of the big players was Felix Hoffman. Yeah. And he worked in the Bayer company, which is still around today as a pharmaceutical company. I believe his father...

Is it you who was telling me that? His father was using it for rheumatism? Yeah, salicylic acid was commonly used throughout the 1800s as a way to treat rheumatism or joint pain. Probably like arthritis. Arthritis. And it was being produced by pharmaceutical companies of the day prior to Bayer.

But Felix Hoffman was tasked with the job of trying to sort of isolate the compound and create a better version that they could mass produce, right? And he thought, well, this is pretty good because my dad uses it every day and he can't take it without vomiting every day because it was so disruptive to his gut. And so he figured out a way to acetylate it. To dilate it. So that went from salicylic acid to acetyl.

salicylic acid. And that's kind of what aspirin is today. Yeah. So he...

His father, as you said, was getting the GIT upsets, which we'll get to a bit later. But also it was well known that if you had it in high dose, you would get tinnitus and go deaf. Really? Yeah, so it's also autotoxic. And it is still today. But because the drug is slightly different to salicylic acid, it is maybe less. And so then Bayer, I think, patented it, right? Yeah. And they named it.

A stands for, of the aspirin, A stands for acetyl. Aspirin.

stands for the tree that it comes from. Yeah. Virea. And then IN at the end is the common suffix for drugs or chemicals. So that's where aspirin... But I don't know if that is confirmed because I read that it might have meant a couple of different things. But I think that what they said was at the end of the day that that's probably the most likely reason why it's called aspirin. But it's...

I'm just trying to grab it right now. So they said here that at least two accounts are given for the choice of name. Some say that it was named after Saint Asperinius, right? An early Neapolitan bishop who was the patron saint against headaches.

Right. I like that. So that makes sense. But they, they say that obviously probably the more prosaic explanation is that it's derived from the spirit, spirit or spirit. I don't know. You probably said it better than I, for once. Um,

Which, like you said, is that plant for the meadow sweet. That meadow sweet belongs to where they originally isolated from. Yeah, so I think you're probably right, but I do like the St. Asperius. I do as well. Yeah. So maybe we just say that that's what it's named after. So that's a bit of its history. So now... And then, sorry, just jump forward to the 1970s. But before that, up until this point though, aspirin's been used to treat...

pain, fever. Joints. Joints. So rheumatoid. So it's been used for three of those four functions you mentioned earlier. So anti-inflammatory, antipyretic and analgesic. But it's not really being used right now for its anti-thrombotic effect, right? Platelet, anti-platelet. Anti-platelet effect. I don't think it was known at this point. It might have just been...

Like I'm sure they probably saw that people bled more or things like that. But in terms of preventing heart attack and stroke that it is today, probably not to that degree. So what happened in the 70s? The 70s, then John Vane, who was a pharmacist, he discovered the actual mechanism of action behind it. That being, which we can get into now. Yeah. That being affecting the cyclooxygenase enzymes. Ah, yes. Everyone's favorite enzyme. Yes. Cox. Cox.

So did you want to explain this quickly? Sure. Oh, I've, I've got to do my part quickly. Do I take your time? That's right. You can spend 20 minutes talking about the history. Uh, and I'll do three minutes on the most important part of the drug. Uh, see now this is ladies and gentlemen, this is what we call banter. Uh, a lot of people think that this is me. Uh,

Queensland banter. Bullying Matt. But it's not bullying because if you saw how I spoke to him after the podcast, that's bullying. So, yes. Basically, the way that aspirin works is it hijacks the way that a set of enzymes called COX enzymes, cyclooxygenase enzymes...

something called arachidonic acid. Which comes from where? I'll tell you in a second. Okay, sorry. Turns it into something called prostanoids and eicosanoids.

But broadly speaking, we're just going to call them prostaglandins and thromboxanes. So effectively, what happens is you've got cell membranes and all of our cells have cell membranes. It's made up of phospholipid bilayers, two layers of a lipid soluble substance called a phospholipid. And embedded in the phospholipids, we have something called arachidonic acid.

And arachidonic acid can get released from these cell membranes when the cell membranes are damaged or when they're triggered by chemicals. They can be triggered, not triggered in the sense that they're being teased like the way I trigger you most days, but it could be triggered immunologically. It could be triggered hormonally. Usually just injury, right? Mechanical injury. Well, that's one type, that's one set of prostaglandins produced through injury.

which we'll get to, but a lot of them are triggered just due to cellular interactions. Right. The arachidonic acid is converted by these COX enzymes into prostaglandins and thromboxane. And we haven't said what they do yet, but prostaglandins...

...effectively everywhere in the body. They're what we call ubiquitous, all over the place. And they do so many different roles. A lot of housekeeping roles, but they also play important roles... ...in regulation, in response to certain things, which we'll again get to. It also produces something called thromboxane. And thromboxane is very important to the discussion of aspirin... ...as we'll talk about in a second. So what aspirin does is it acetylates...

acerine, which is an amino acid, residue. It acetylates an acerine residue on the COX enzymes. So it does this irreversibly. And it's the only one, right? Out of all the class of medications that I guess you'd say are non-steroid anti-inflammatory drugs. Which we haven't even said that aspirin fits on. But aspirin is one. It's the only one that does this?

Yes. Irreversibly. Irreversibly. Yeah. So it basically means that your body needs to make more Cox enzymes in order for it to function properly again. Right? And there's two major types of Cox enzymes. So there's Cox 1 and Cox 2. There is a Cox 3. Central Cox. Yeah. Which I don't even know what that means. But yeah, there's a Cox 3, but we'll probably talk about that maybe when we do a paracetamol episode. So...

The two major COX enzymes, COX-1 and COX-2, there's about a 60% homology or similarity between those two. And aspirin binds to that serine residue on the active side of both of COX-1 and COX-2 enzymes. But the active side of COX-2 is larger than COX-1. And what that means is the arachidonic acid can squeeze past the aspirin

for COX-2 and make those prostaglandins. But we haven't spoken about what the prostaglandins are that are made by COX-1 and COX-2 respectively, which I think we need to talk about. So this is the way I think about it. The COX-1 enzyme will make prostaglandins that are there to help maintain the body. What do you call that? What's the term they use?

Constituent? Yeah, it's constitutively active. So it's required, it's turned on when it's required. And so the prostaglandins made by COX-1 are there to maintain our gastric mucosa. So it helps keep the stomach lining nice and healthy so that the acid doesn't destroy our gut. It helps vasodilate and the...

Well... Blood vessels. Yeah, but specifically the renal blood vessels. Okay. So the blood vessels at the kidneys, it helps maintain renal perfusion. So it helps feed the kidneys. That's what these prostaglandins do. They also promote platelet aggregation. Yeah. And that's the thromboxane. Yeah. That's made by COX-1. Yeah. And also promotes some degree of vasoconstriction as well, just broadly. So a generalized vasoconstriction. So...

maintains gut mucosa, helps maintain kidneys getting fed, promotes platelet aggregation, but also promotes... This is all COX-1. All COX-1, a generalized vasoconstriction. A couple of additional ones. Also decreases stomach acid production and also nutrient contraction. Yep. So that's COX-1. Now COX-2...

This is not constitutively active. It's not there to maintain homeostasis. It gets turned on when cells are damaged, right? And so this is when we're talking about you were saying, oh, the arachidonic acid gets released due to cell damage. Right. So the arachidonic acid that's required for COX-2 creates pro-inflammatory. So it promotes vasodilation. Yes. Right? And other inflammatory events. It...

It promotes pain, it promotes fever, and these prostaglands can stop platelet aggregation and they can cause vasodilation. So quite different to the COX-1. I think the only thing I'll add here is I believe COX-2 more recently has been found to have a homeostatic role at the kidney as well.

in blood flow, and that's part of the reason. And I think we spoke about this some time ago, that the COX-2 inhibitors, which have been created to counter some of the ill effects of blocking COX-1, like the GIT, but some of the COX-2 specific, which is not aspirin but other medication, have been shown to also cause issues to the kidney, and that's because COX-2 can also...

regulate blood flow to the kidney. And if you block that, that can also cause kidney injury as we will see later with aspirin. Yeah. So if you've got COX-1, therefore maintaining your gut, feeding your kidneys and platelets aggregating, and then you've got COX-2 for pain, inflammation, fever, but stopping platelet aggregation, you create a set of drugs aimed at blocking these COX enzymes and

which we call NSAIDs, non-steroidal anti-inflammatory drugs, right? There's a range of them and aspirin is one of them. If you were to choose, if you were to design an anti-inflammatory drug like aspirin, which one would you want it to block more specifically? Two. Yeah, you'd want it to block COX-2 because that's the inflammatory pain and fever one, right?

Now, aspirin, if we have a look at it, blocks both. So it blocks, like I said, the active side of both. However, the COX-2 has a larger active side. So the arachidonic acid can get past it and it can be pro-inflammatory pain and fever, which makes you go, wait a minute. So that means aspirin probably more so is a COX-1 inhibitor than a COX-2, which means

It's not good for the gut lining. It's not great for kidney perfusion, but it's great for stopping platelets from aggregating. Now, how could you leverage this to your therapeutic advantage, Matt? Yeah, so the thing with platelets is, well, in our blood, we've got a trillion platelets at any time. Sorry, say that again. We've got one trillion platelets. How many zeros? To the 12, power of 12. Power of 12. That's right, yeah. I don't know. But...

100 billion die per day. 100 billion die per day. Wow. Now, what I'm telling you is that just basically means that platelets only live for 10 days. Oh, okay. That's their lifespan. That's their lifespan. Well, I suppose they have no nucleus. They've got no intracellular organelles. If they're damaged in any way, they can't replenish. That's right. This gets to the point of how aspirin is useful today.

As a COX-1 inhibitor. Right. In low dose. Okay. Because when you take it, it's absorbed reasonably well across the GIT into the blood. Okay. And then at that dosage, so when we're talking about low dose, which is less than 80 milligrams per day. I was going to say less than 100, but it's probably no. Well, usually when we refer to the baby aspirin or the low dose aspirin, it's under 80. I think America, it's 75 milligrams. Right. Other parts is 80. Yep. Yep.

So when you're at this dose, it's really only going to be impacting the COX-1 enzymes. Right. So gastric mucosa, renal perfusion and stopping platelets. Right. And so with platelets, because remember we said aspirin is a irreversible inhibitor. Yes, we did. You've now inhibited...

the COX-1 enzymes on platelets. Irreversibly. Irreversibly. So they can't remake any more COX-1 enzymes. Other cells can, but platelets can't because as you said, they have no nucleus. They have no machinery. So they are now irreversibly blocked to COX-1 for their life, which is only 10 days. But that then means for probably about 48 hours, all your platelets in your body are now inhibited.

or produce in thromboxin. I think within five days, 50% have been regenerated. That's why... After you take aspirin, within one hour, you have these platelet inhibiting effects. Right. So that speaks to one of its most useful...

clinic indications and that's preventing or use during a heart attack, myocardial infarction. So to prevent clots. Right. And so I'm led to believe one of the most important drugs that are given at the point of a heart attack is aspirin at reducing mortality. Okay.

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the rest of your life? I don't know. Until your ultimate demise. What if we just say forever? Okay. $25 a month forever. Get unlimited talk, text, and data for just $25 a month with Boost Mobile forever. After 30 gigabytes, customers may experience slower speeds. Customers will pay $25 a month as long as they remain active on the Boost Unlimited plan. Reduce immortality. Yeah. Okay. And because of this, it's stopping further aggregation

clot formation in the coronary arteries, which is going to block further blood flow to the heart to kill the heart and then lead into the person probably dying. Would you say then that historically aspirin was used as an antipyretic, anti-inflammatory and analgesic, but contemporary its use is as an antithrombotic? That's right. As an antiplatelet? Antiplatelet, not thrombotic. Platelet, yeah. That's right. Okay.

So yes, correct. And I think that would be where it's profoundly used as, you know, you said the number one drug in the world would be used for that clinical indication. So that speaks to how it's going to be beneficial to platelets, blocking platelets. Remember, platelets are just fragments of a cell. So they're just bits of cell. That's why they're called platelets. From megakaryocytes. Megakaryocytes. So you are producing, you know,

50,000 megacarrier sites a day and from a megacarrier site that can break up into 5,000 parts which are platelets. So they can regenerate. It's like a Greek wedding when you smash a platelet. That's right. That was your analogy. Yes. So that is in low doses but when I spoke to you earlier about when you take it at

above 300 milligrams, what then happens is it gets taken to the liver, which then is modified back into salicylic acid, and then that becomes more COX-2 selective, right? Not selective-selective like some of the more selective, but much more closer to COX-2, which I guess in that form might be more beneficial in its...

blocking of COX-2, therefore it's anti-inflammatory, it's anti-pyretic, it's analgesic effects. Yeah, yeah. But, but, and this is an important but, um,

Because it's COX-1 specific mostly in its general use, it also can affect the gastric mucosa, right? And so while people are told to take aspirin long-term in the small doses, that can still have its effect on the gut long-term potentially. They do try and do things like enterically coat it. But the thing is that most aspirin is absorbed in the stomach, right?

Yeah, so that's interesting. So I'd imagine the enteric coated... It reduces... It reduces the local irritation because I would imagine aspirin is both a systemic irritant to the stomach but also a local irritant because it is an acid. So what you mean by that is the systemic irritant meaning its ability to stop prostaglandins that maintain the gut mucus is the systemic...

Why? Because if you don't make the prostaglandins that maintain the gut mucus, then the acid that your gut produces is going to be more likely to burn ulcers within your stomach. And that can be, it's irritative, irritative, irritative? Irritative.

But you can also have local effects where you can just directly be an irritant to the stomach lining itself. But yeah, it's interesting because once you take aspirin, the stomach and upper GI is where it's primarily absorbed. It's absorbed within 5 to 30 minutes of taking it. And like I said, it starts inhibiting platelets after one hour.

And its maximum blood serum, well, that's a bit redundant, but its maximum serum concentration is at about 30 to 40 minutes after ingestion. But yeah, it seems to be low doses. I know you don't like me saying antithrombotic, but that's sort of the umbrella term used for things that stop clots. Oh, okay. Because I always thought antithrombotic was more to do with the cascade opposed to maybe the primary...

kind of... Well, it will reduce the cascade because part of the cascade is going to be the platelet aggregation. Obviously, yeah. Without that, you're not going to have the other downstream effects, yeah. But yeah, its ability to reduce platelets at the low doses and then the high doses having its anti-inflammatory, analgesic and antipyretic effects. But just quickly, so there was a thought when...

started to better understand its anti-platelet, anti-thrombotic effect to help mitigate the effects of heart attack and stroke. That, well, maybe as we get to a certain age, we should all be taking it because of the cardiovascular protectiveness of it. But there was a study in at least 2009, I'm sure there has been others, which is a meta-analysis that actually found that

the GIT symptoms outweighed the cardiovascular protective for those that didn't have a risk, cardiovascular risk. If you had a cardiovascular risk, then there is that benefit for being cardiovascular protective. But if you were just, let's say, quite and quite normal, Yeah.

Then take an aspirin. You started to, the GIT outweigh, started to outweigh the protective benefits from the cardiovascular. Even at low doses? Even at low doses. And it was estimated that people who take aspirin somewhere in the region of 30 to 40% of users will have some degree of GI damage. And I think there was another study, 2021 study that reviewed that,

Somewhere in the region of 400 to 1,000 deaths in the UK were the result of GIT complications of aspirin. I'd be also interested to see, however, how many deaths are associated with aspirin

Myocardial infarction, heart attack, that could have been mitigated by aspirin. This again speaks to those that don't have the risk profile. So just not everyone should be taking it willy-nilly. You have a risk profile, a cardiovascular risk profile, where you are high risk, like acute coronary syndrome, or you've already had, let's say, a TIA, which is a transient stroke, then...

you could be well advised to consider this with your physician. Yeah. And let me just iterate that when, so we are not,

telling you what to do or what not to do. We are simply having a look at the evidence. You know, we're not clinicians. We are not here to tell you to take or not take aspirin. You must consult your primary care physician, your GP, or whether it be your specialist, cardiologist, whether you should or should not take it.

You don't just suddenly jump on a drug because you've heard two dopes talk about it on a podcast. You should be talking to people that are qualified as healthcare professionals. So we need to keep that in mind. So a couple of other side effects I'll just mention, which is interesting because going back to what you said, a side effect, because you hear two terms commonly in pharmacology, adverse effect and side effect. Yeah.

Side effect is the effect on the side of its mode of action. Right. Okay. Which I guess you would say wasn't its initial desired effect. Yeah. Now going back to how aspirin was first clinically indicated, which was pain, fever, probably more inflammation. Actually, I forgot to say this. Let me just say, these are the common things that aspirin are used for. Pain associated with headache, migraine. Actually, I think migraine, it's fairly common.

a fairly good drug for that regard. That's good for migraine. Yeah, yeah. And again, I'm not sure they exactly know why it's so good for migraine. Maybe to do with a blood vessel changes. Could be. Any rheumatic, so it's any joint kind of, so that could be osteoarthritis, rheumatoid arthritis. Don't think it's so good for gout.

Period pain, toothache, cold and flu. I think that's one of the first uses of it when Bayer marketed it in the start of the 20th century. You're not saying why people should use it. You're saying how people have used it, right? Well, this is currently the clinical indications. If you looked in the pharmacology textbooks, these would be why people are using them for these reasons. They would gargle with it. So it would be a...

A dissolvable liquid. Right. Like AsproClear, where it would just dissolve effervescently. Effervescent. There we go. And they'll just go. Great band effervescent. They'll just gargle it. And that could probably work at a local level just to help with the pain of the pharynx. Yeah, maybe. Sore throat, well, that same thing. And then back muscle strain, sprain kind of. So that's musculoskeletal. So they're the common uses for it.

Now, what was I saying before I went back to that? No idea. Totally forgot. That's okay. You said, oh, something interesting. Oh, side effect. Oh, that's right. So then it would have been used for those reasons. But then as you've mentioned, then we figured out it had a platelet effect. That would probably have been a side effect at some point that, oh my God, if you take this drug,

you're more likely to bleed. But now we've actually seen that's actually a benefit. So now it's a clinical indication. Not the more likely to bleed as a benefit, but less likely to clot as a benefit. Correct. That's right. And so when you look at adverse effects, I guess you would say adverse effects are the...

predictable effects that go at the dosage that is recommended. So an adverse effect of aspirin would be the GIT bleeding. Another one would be the renal effects. So we know that by taking aspirin, let's say at high doses, it will block COX-2 as well.

That then changes the prostaglandins within the renal vasculature. Now, this seems to be more problematic for people who have vulnerable kidney. Existing kidney disease. Yeah, the elderly or people who are taking medications that are nephrotoxic, like certain antibiotics, as an example.

Or they've already had kidney injury because usually when you try to regulate, when your kidneys are trying to regulate blood flow to itself, it does this like its own intrinsic system, but also through the RAS system, would you say? But when you get older or your kidneys are less resilient, they rely more on prostaglandins to regulate blood flow to itself. Now, if you take an NSAID, it's not just aspirin, but aspirin is one,

it blocks this prostaglandin, which then inhibits its ability to regulate blood flow, which then causes more kidney injury and can actually also increase hypertension because of the RAS pathway. Well, not just that, because it has direct vasoconstriction, vasodilation effects. Yeah. So if you're using a COX-2 inhibitor because the enzymes...

the prostaglandins or COX-2 produce, they can vasodilate. If you block them, it can result in vasoconstriction. Right. So you can get a vasoconstrictive effect, which can happen. So people's blood pressure can go up with some NSAIDs. Right. Okay. Yeah. So there is that...

thing to be concerned, well, at least mindful of. Then there's another big side effect or consideration is the asthma or hypersensitivity associated with it. Now, from my understanding of a part of what causes that is

is going back to your, what did you call it? Connoisseurs, which come from arachidonic acid. One other pathway they didn't mention, but it wasn't related is leukotrienes, which seem to have more of an effect in the bronchioles. Now, when you take aspirin, that pathway seems to stay active. So people who have...

what would you say, a sensitive, hypersensitive airway, a reactive airway, an airway that's more likely to respond to allergens and irritants. When you take aspirin, it pushes the person more into a leukotriene pathway, which then produces more bradykinin, which then produces more lung irritation, which can then put you into an asthmatic-like pathway.

Yes. I guess you'd say. That's because aspirin only blocks the COX enzymes, which make the prostaglandins and thromboxanes. But it's the LOX enzymes. LOX, so lipoxygenase 5, yeah. Lipoxygenase, that's right. So they're the ones that make the leukotrienes.

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School made from arachidonic acid. Yeah, yeah. But just a different pathway. Just different cousins. Yeah. Another one to be mindful, this is more for children. There's a syndrome called Reye syndrome, which- R-E-Y-E-S? Yeah, yeah. Now that only seems to come about concurrent with an infection. So if a child four to 12 ballpark age is currently got a viral infection like chickenpox or even the flu, and then they were to take aspirin,

Seems that these things together cause injury to the liver. Right. And then the liver damage affects its way of detoxifying ammonia. And then ammonia can then build up and lead to an encephalopathy, which I guess you'd say a toxicity to the brain. Brain swelling. Brain swelling, yeah. So it's generally suggested not to take aspirin in those ages, full stop.

But it's especially damaging if it was a parent with an infection. Yeah. Yeah, generally speaking, when kids are sick, the recommendation is the other NSAIDs such as the paracetamol. Paracetamol's great, yeah. Which probably isn't an NSAID, but paracetamol and ibuprofen tend to be the ones that physicians will be happy to support you, given your kids within the therapeutic dose. But yes, the...

The last one I'll mention is just aspirin in overdose. So it's in its toxicity end. So if you were taking too much of it, this would in its early stage, well, it can cause ototoxicity. So that's where you'd get. What's its therapeutic range? Do we know? I don't know exactly. But as I said, you can go up towards, what did I say? 2000 milligrams a day. So I'm guessing beyond that. Yeah.

So in its overdose toxicity end, it is autotoxic. It will induce vomiting, but it does have an effect on the respiratory center. And so in its early stages- In the brainstem. In the brainstem. So in its early stages of effect in overdose or in toxicity-

it will actually activate the breathing center and lead to hyperventilation, which then can lead to a respiratory alkalosis. Yes. But as this continues on, one of the effects that aspirin does have, I think it always has it, and this probably also works into the Ray syndrome, it seems to uncouple...

Mitochondria and its oxidative phosphorylation, which then its ability to make ATP, which shifts the mitochondria into an anaerobic state, which then causes it to produce lactic acid as a byproduct, lactate, which is going to decrease pH. So then you're more likely to go metabolic acidosis in a later toxicity form.

But there's kind of pH shifts. Yes. Yeah, it's something that I teach my students is that one of the ways that we can have metabolic disturbances or pH disturbances, I should say, is aspirin can be one of them depending on the dosage and the individual and so forth. But yeah, it can be an alkalosis or an acidosis depending on the stage and what's happening.

But that's really it. I mean, I guess we would say as summary, it's been a great wonder drug. It's saved millions of people. As a drug, like all drugs, there's the benefit and then there's some limitations. Always work with your primary healthcare physician around this.

And yeah, have you got anything else? I do, yeah. Well, because you alluded to it at the beginning is that there's some evidence coming out that it might have anti-cancer effects, right? These are very early stage studies. This is like looking at cells in dishes and animal models and things like that. But there is some evidence

positive results coming out. Now, again, this doesn't mean that you should be taking aspirin to avoid cancer, but the thing is you should watch the research, keep your eyes on it and see what comes out of it. Because again, like Matt said, there's pros and cons of all drugs and they have their therapeutic doses and they also have their recommended uses and

And if you do want to take aspirin, you should do it in consideration with your healthcare physician. Don't just take drugs, like Matt said, willy-nilly. Matt likes to use the term willy-nilly. Is that a universal term, willy-nilly? Just meaning just take it whenever you like. But-

You should be always consulting. And just to... I'm very mindful of this, Matt. We need to really highlight this to people that just because we're talking about drugs and we say, oh, it's really good at X, Y, and Z, that is not us saying, you should now go take it for X, Y, and Z. That is not our recommendation because we are...

professors here to profess about how these drugs work. That's the job. We're just educating on the mechanisms of the drug, the history of the drug, how it's being used, not how you should use it. Yes, that's right. And just to underscore that, I remember I had a...

a headache one day. Oh. And I... One day you had a headache. Other migraine every two weeks. But that's cool. You have a headache once. And I, um, I only had aspirin in the house. Okay. And I took aspirin. And? Mind you, I took it on an empty stomach, which was probably bad news. Okay. And I developed gastritis. I do remember this. That lasted you a good week, that gastritis. And that was... And you had to take next... And it was an interesting experience. It's an...

I've had gastritis multiple times. It's a gnawing pain. Hollow pain. Hollow pain. Almost like you want to eat. Yes. Yes. And eating can help the pain and then it feels worse again. But yes, gastritis is not fun and that is an irritation of your gastric lining, which you got from taking... Potentially, you got it from taking aspirin on an empty stomach. It's probably silly on my behalf, but it just, again, demonstrates that...

When you take a medication that may be not the best indication for or the best correct, not means, but it could be better options than things like this could happen. So don't follow Matt's example. Bye.

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Hi. Who here loves when their nails are perfectly done? Me.

Me, I'm Sarah Gibson Tuttle, and I started Olive in June because let's be real, we all deserve to have gorgeous nails, but who wants to spend a fortune or half their day at the salon? And that's why I created the Manny System, so you can have that salon perfect manicure right at home.

And guess what? The best part? Each mani only costs $2. Yep, you heard me, $2. No more $30, $40, $50 salon trips that eat up your day. Now you can paint your nails whenever you want, wherever you want. And trust me, you're going to be obsessed with your nails and everyone is going to ask you, where did you get your nails done? And here's a little something extra.

Head over to OliveandJune.com and get 20% off your first Manny system with code PERFECTMANNY20 at OliveandJune.com slash PERFECTMANNY20. That's code PERFECTMANNY20 for 20% off at OliveandJune.com slash PERFECTMANNY20. You're all set for a nail glow up. Let's get those nails looking fabulous, shall we?