Pop quiz! What’s small, white, really useful in helping prevent heart attacks, and absolutely murders the hell out of you if you overdose on it?

If you said aspirin, congratulations!* You earned the right to muddle your way through why. This will be long, so get yourself a glass of wine and some Oreos or something and settle in.

*If you said cocaine, okay, you’re right too, you narc. I gave you the answer in the title.

Also, if you are medically inclined and remotely interested in physiology or toxicology, it will very much pay off for you to read this in its entirety, even though it is long. The concepts here are going to be fundamental for explaining future toxy things and I’ll probably refer back to this post often.

In this second episode of Tox ‘O Clock, I thought I’d teach you, Reader Of Blog aka grandmas, a little about aspirin toxicity. I like this one because it actually has good explanations for why the things that happen happen (unlike carbon tablets, where the best I could come up with is “it just effs you up”) and because everyone knows what aspirin is. It’s aspirin! Take an aspirin and call me in the morning, right?

Well, yes. At normal doses, aspirin is totally a helpful drug. A “baby aspirin” dose is 81 milligrams, although the doses for headache or arthritis are up to ten times higher – and that’s still okay.

The nice thing is that the minimum toxic dose, where you start getting sick, is about 150 milligrams per kilogra–

I know, I know, metric system. But everyone uses the metric system except for us Americans, because we are exceptional, in the sense that we are exceptionally stupid in our measurement system.

So anyway, for an 80 KILOGRAM person – that’s about 175 pounds, for all you exceptional people out there – you would need to take down at least 12 grams of aspirin, which is… well, that’s a shitload of aspirin. This doesn’t happen by accident, unless you are still pooping in a diaper.

Okay, enough numbers. On to the fun stuff: how does aspirin cause badness?

In order to understand aspirin toxicity, you need to understand another fundamental concept: how cells make energy. We have to slog through this a little so bear with me. I will try to make this fu–

Sigh.

So. If you are like me and remember only one thing from high school biology, it is the following:

Yes, the mitochondria is the powerhouse of the cell! Congratulations, you understand the toxicology of aspirin now.

To dig deeper, we sadly need to go a little beyond 9^th grade bio.

Okay. So here is how your cell takes sugar, the basic building block of energy (everything eventually breaks down to sugar), and turns it into energy. This process has three basic steps, the first of which is here:

Hey! That’s not too bad! Four reactions! I can teach this.

HAHAHA just kidding that’s only a small, simplified part of one step. Here is all of that first step, something called “glycolysis,” which means “breaking sugar:”

Haha! Can you believe we have to memorize these during first year? What idiocy. Please don’t try to actually understand either of these things, because I can’t explain them – I almost failed biochemistry, if you remember.

Okay. So at the end of Step 1, which is breaking sugar, the breakdown product (called pyruvate) acts as fuel for an engine called the Krebs cycle. This is Step 2. Hans Adolf Krebs, as an interesting sidenote, was a German Jew and absolute GANGSTA scientist whom the Nazis unwisely kicked out when they rose to power in the early 1930’s, causing Hans here to flee to the UK. Here is Sir Hans:

What a stud!!! Proud to have the Krebsinator as a member of the tribe. Go Jews!

Anyway, the Krebs cycle takes place in the Powerhouse of the Cell and generates a large amount of stuff. This stuff is really good at holding and carrying electrons, which become very important in a second.

STAY WITH ME ITS ABOUT TO GET GOOD

Step 3 is the money step: your mitochondria uses all of this stuff, along with oxygen, to generate energy in the form of a molecule called ATP. Don’t ask why it’s called ATP, it just is, shut up and listen.

Step 1 generates a little ATP, but Step 3 generates a butt-ton of ATP. This third step is called “oxidative phosphorylation,” which again is useless medical terminology for “making energy.”

This is what happens in oxidative phosphorylation:

HAHA this is ludicrously complicated! What a ridiculous picture. The fact that I had to try to commit a substantial amount of this to memory is, uh, exceptional.

What you actually need to know from this is thankfully minimal. The key is that your Powerhouse (mitochondria) has pieces that use the stuff from Step 2, thanks Sir Krebs, to bounce electrons down a line in a series of handoffs. Each time an electron gets handed off, it generates a force that propels an atom of hydrogen from the inside to the outside of the Powerhouse. This means that at the end, a ton of hydrogen ends up outside the mitochondria and not a lot remains inside.

What happens after is exactly how a hydroelectric dam works:

All the hydrogen is allowed to flow back to where it belongs, but only through a little channel that spins as the molecules pass through. This spinning – seriously, like mechanical spinning – generates the necessary ‘oomph’ to convert a precursor molecule to ATP.

Oxygen has a really simple job: it is the trash collector. It sits at the end of this handoff process, picks up the now depleted, spent, burnt out electron, not unlike a 4th year med student, and carries it away. For this reason you may in some dim recess of your mind recall that oxygen is the “final electron acceptor.”

Here’s how I explain this whole thing: Your body turns sugar into stuff that passes electrons along a bucket brigade. The energy used to pass these electrons is also used to push a dam’s worth of hydrogen behind a wall; eventually that hydrogen breaks through and spins a turbine that makes energy. Oxygen is the cleanup crew, nothing more.

Here is a summary of everything we talked about:

WHEW okay a thousand words later we are done with the boring stuff! I am sorry. That had to happen. It’s like a flu shot, or payroll taxes.

Okay. So aspirin.

Aspirin is actually a cover name for the fact that you’re swallowing a pill of acid every time you are protecting your heart. Salicylic acid, aka salicylate, is the active ingredient in aspirin. After it dissolves it normally stays in the bloodstream and doesn’t really go too many places. There are many unimportant reasons why this is, but to avoid walking you through a completely different physiology chapter,let’s just say it likes the bloodstream because it likes highways.

When you overdose on aspirin, it changes its mind. It now likes to go pretty much everywhere because Waze tells it to take all sorts of crazy routes to avoid traffic, including into the Powerhouse of the Cell. Once it’s there, it does something you will see me mention in the future:

Aspirin uncouples oxidative phosphorylation.

CHECK OUT THE BIG BRAIN ON BRAD!!! That sounds super smart, right? Doctors are so knowledgeable. So enlightened. All hail the great $220,000 Medical Degree.

Of course, no one truly knows what that means.

Our best guess is that the normal handoff of electrons happens like it’s supposed to (the “oxidative” part) but the moving of hydrogen atoms from the inside to the outside gets stuck. The handoff still generates that necessary energy, though, and that energy has to go somewhere. So what happens?

Heat! It generates heat. This creates one of the most unintentionally ironic paradoxes of toxicology: aspirin will bring DOWN a fever (right? You take it for fever?) but will make you hot if you overdose on it.

BOOM. Mind, blown.

Okay, big deal. It generates heat. So what?

Well, so nothing. That’s just a nice side effect that makes this fun for losers like me. The problem is that now you’re not making any energy! Your mitochondria are working their powerhouse asses off but getting no payoff. They’re the exceptional middle class of America, they are getting screwed, and they are ANGRY!

So what happens? They ramp up as best they can. Your body responds to this poisoning the same way it responds to exercise. You start breaking down more and more sugar, because your cells think the reason you are low on energy is because you’re using it up too fast – for instance, running away from a bear, or powerlifting, or (if you’re me) walking up a flight of stairs. So you mobilize and break down more and more sugar.

In science-y terms, this is “increased glycolysis.”

The byproduct of this behavior is you make a TON of pyruvate in Step 1, like we talked about before. You try to dump as much of this as you can into the engine of Krebs, all hail Krebs, but the problem is you can’t have all that much carrier stuff from Step 2 around. Your cells can’t hold it. So the engine starts to stall and back up, and eventually you build up too much pyruvate.

Still with me?

This is where things start going south. Pyruvate isn’t all that stable on its own (which is why your body tries to use it immediately) and kind of spontaneously converts itself into lactate, which is better known to Lance Armstrong as lactic acid.

This is kind of why your muscles burn when you exercise: you don’t get enough oxygen to your muscles, the whole engine stalls and backs up, and your body makes more and more pyruvate to try and compensate, which diverts over to lactic acid. And acid burns.*

(*I know, that’s not what really happens, but work with me here.)

In a related move, the aspirin also tricks your body into thinking it’s out of sugar (which it isn’t). This leads to mobilization of some fat stores, which eventually will sort itself out into sugar. But before it does, the breakdown of fat creates even more acid! This is why “omega-3 fatty acids” are a thing – the breakdown product of fat is just a mix of fatty acids. Surprise, you’ve been swallowing fat pills all this time.

If you’re counting, this means your blood is now overflowing with lactic acid, these fatty acids, and the salicylic acid itself. That’s a lot of acid…

Acid is bad for you, generally speaking. Your body operates within a very narrow window of balance between basicity and acidity (called pH) and if you mess up that balance, things tend to stop working pretty fast. Compounding matters is because of a chemical property of aspirin, the more acidic your blood gets, the more aspirin leaves your bloodstream and goes into places it shouldn’t, like your brain.

Aspirin in the brain is what will actually kill you in an aspirin overdose. Basically, aspirin shuts down oxidative phosphorylation in the brain, too. And the brain is greedy – it uses a ton of energy to power your ability to mindlessly channel flip or scroll through Facebook. When you turn off its energy supply, the brain very quickly uses up all its remaining sugar.

This, predictably, leads to low blood sugar in the brain – even though the regular blood sugar might appear normal! There’s a fancy medical term for this, also: neuroglycopenia, which means “low sugar in the brain.”

Low sugar in the brain, in a word, is bad. Your neurons starve. You stop being able to think straight, you have a big-ass seizure, your brain swells from the stress, and you die.

This is a classic toxicology trap: sometimes, we don’t fix the sugar problem because we don’t know about it. A doctor might check a blood sugar, find that it’s normal, and assume that it’s normal everywhere – when in reality, the levels in the brain are already nearing Death Zone!

Okay, so last bit: what do you do if confronted with an aspirin overdose?

The answer is actually more simple than you think: get the aspirin out. This might mean giving “activated charcoal” which is medical for “the most disgusting dark paste you’ve ever seen” to basically soak up the aspirin, not dissimilar to eating a loaf of bread to soak up alcohol during a big night.

Wait, you don’t do that? I thought… never mind.

More commonly, someone with a serious aspirin overdose gets put on emergency dialysis. You’ve all heard of dialysis for people who have kidney failure; this is exactly the same. Aspirin can be filtered off via the Brita Filter of Life aka a dialysis machine. Your kidneys can’t filter the aspirin fast enough to be, as we say, “compatible with life,” so we have to give the mechanical assist.

(No, seriously, we unironically use the phrase “compatible with life,” and its sister, “incompatible with life” in medicine. I’m serious! People say that with a straight face!)

We can also give a medicine called bicarbonate, which you know more commonly as baking soda. Baking soda is alkaline – it’s the opposite of acid – and will help neutralize some of the acid in the bloodstream. The happy byproduct of this, besides preventing all your organs from shutting down simultaneously, is that aspirin gets pulled back out of these organs (including the brain) into the blood. Remember we said that aspirin leaves the blood the more acidic the blood gets!

The final treatment, as you might have guessed, is to give sugar! We will give a patient with a normal or even high blood sugar… that’s right, more sugar. The levels in the blood do not reflect levels in the brain!

So, to sum up: aspirin is bad, aspirin overdose kills you, and you treat aspirin overdose with dialysis, sugar, and baking soda. Makes sense.

All hail Krebs!