Chapter 2: Pharmacokinetics or What the Body Does to the Drug

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Welcome back to The Deep Dive.

Today we are opening up the hood on something that happens inside of us every single time we swallow a pill or get a shot or, you know, use a patch.

Right.

But we rarely start to think about the actual mechanics of it.

We are looking at chapter two of Brenner and Stevens' pharmacology.

Specifically the sixth edition.

And this chapter covers pharmacokinetics.

Which is, I have to say, a pretty dry word for what is actually a very dramatic process.

Oh, absolutely.

I've always thought of medicine as like a helper.

You take an ibuprofen and it somehow knows where your headache is.

It's a magic bullet.

But this chapter just destroys that idea right out of the gate, doesn't it?

It really does.

I mean, if you take away one single thing from this deep dive today, it should be this.

The human body does not want to be medicated.

It treats the drug like it's a poison,

an invader.

It treats it like a xenobiotic stranger.

From the very moment that chemical touches your tongue, your body initiates this massive coordinated defense system designed to block it, neutralize it, shred it, and then So pharmacokinetics isn't just how drugs move around.

No, it's a war story.

It's the story of the drug's odyssey through a really hostile environment.

And that distinction is actually how we define the field itself.

We usually think about what the drug does to us, you know, curing the infection, lowering the blood pressure.

Right.

And that's a different field.

That's pharmacodynamics.

That's the drug acting on the receptor.

But today we're talking about the complete reverse.

Pharmacokinetics is what the body does to the drug.

Exactly.

And it's not just biology.

It's physics.

It's all about barriers and pressure gradients and, you know, these little enzymatic shredders and fluid dynamics.

It's a whole system.

And the text organizes this war into four specific battlegrounds.

I think everyone in med school or pharmacy school learns the acronym, but let's recontextualize it for everyone listening.

It's ADME.

ADME.

Absorption, distribution, metabolism, and excretion.

You know, it sounds like a nice, neat, linear list.

First this, then that.

Right.

But it's really a simultaneous equation.

These things are all happening at the same time.

But to understand it, we kind of have to slow it down and follow a single molecule on its journey.

Okay, let's do that.

But before we even get to the A for absorption, we should probably talk about the setup.

Figure 2 .1 in the text gives us this great roadmap.

It's good visual.

It shows the drug entering, hitting the blood, going to the liver, then the tissues, and finally out through the urine.

And it looks so orderly.

It looks orderly, but every single arrow on that chart represents a hurdle,

a barrier.

And the ultimate goal for you, the learner today, is to understand not just the biology, but the math that governs it all.

The math.

The math.

By the end of this hour, we're going to be talking about things like half -lives, clearance rates, and volume of The math that keeps the patient alive.

That's the one.

You cannot safely dose a human being without understanding the math of ADME.

Period.

Fair enough.

Okay, let's start at the beginning, then.

The A in ADME.

Absorption.

Right.

So absorption is defined very specifically as the passage of drug molecules from the site of administration into the circulation.

Into the blood.

Now, looking at the text, there seems to be a major, major exception right out of the gate.

The intravenous route.

Four.

Right.

If I stick a needle directly into a vein and I push the plunger, have I bypassed absorption?

You have.

Technically, yes.

You have placed 100 % of that drug directly into the systemic circulation.

There is no barrier to cross.

There is no absorption phase.

It's just there.

Which sounds incredibly efficient, but if we go back to our war metaphor, if absorption is the body's first line of defense, the castle wall,

then skipping it seems pretty risky.

It is incredibly risky, and that is exactly why 5E is the most dangerous route of administration.

Because there's no turning back.

Once you push that plunger, you can't take it back.

The body has zero chance to filter it or vomit it up or break it down before it hits the heart and the brain and everything else.

You basically bypass the bouncer and walk straight onto the dance floor.

But for almost everything else, pills, intramuscular shots, subcutaneous injections, the drug has to cross some kind of barrier to get to the blood.

Exactly.

And the text makes a really good distinction here between the difficulty of those barriers.

It's not a one size fits all situation.

Okay.

So let's compare those.

Let's say injecting into a muscle IM versus just swallowing a pill, the oral route.

Okay.

If you inject a drug into a muscle or into the subcutaneous tissue, the drug is now sitting in the interstitial fluid, right?

The fluid between the cells to get into the blood from there, it just has to slip into the capillaries.

Now, capillaries are by design pretty leaky.

They have these little gaps between the endothelial cells.

So it's like walking through a picket fence.

The gaps are already there.

Exactly.

It's a perfect analogy.

Unless the drug molecule is absolutely huge, it just slips right through the slats.

Absorption is relatively easy, relatively fast.

But if I swallow a pill.

Totally different story.

Now that drug is in your gut.

To get to the blood, it has to cross the entire intestinal lining.

And that lining is a layer of epithelial cells that are bound together by something called tight junctions.

No gaps.

No gaps at all.

It's a brick wall.

The drug has to go through the brick.

It has to enter the cell membrane on one side, travel across the entire cell, and then exit the other side to reach the blood.

Much, much harder.

Which brings us to the physics of how something actually moves through a cell.

And the text introduces a really core concept here called Fick's Law.

Fick's Law of Diffusion, yeah.

This is basically the constitution of passive diffusion.

It governs the speed limit of absorption for most drugs.

It says that the rate of absorption is proportional to two main things we need to worry about.

Right.

The concentration gradient and the surface area.

Okay, let's break those down.

The concentration gradient seems pretty intuitive.

It is.

It's just pressure, really.

If you have a massive amount of drug in the gut, say, from a high dose, and you have zero drug in the blood, the drug wants to rush across that membrane to equalize the pressure.

So the bigger the difference, the faster it flows.

The bigger the difference, the faster the flow.

This helps explain why a loading dose works, right?

You give a big initial dose to create a massive gradient.

You're using physics to just force the drug across the wall faster.

You got it.

You're manipulating Fick's Law.

Okay, now, the second variable in the law,

surface area.

This is where anatomy comes into play.

Fick's Law states that absorption is directly proportional to the surface area available, and this, as the text points out, is the trump card of the GI tract.

Explain that.

What do you mean, trump card?

Okay, think about the stomach.

It's a pouch, right?

It has some folds, sure, but it's a relatively smooth walled organ.

Okay.

Now think about the small intestine.

It's not smooth.

It's lined with these things called villi, which are like millions of tiny little fingers, and then on those fingers are microvilli microscopic fingers.

So it's fractal.

It's fingers on fingers on fingers.

Exactly, and the result is that if you could somehow unfold the human small intestine and lay it out flat, it would cover a tennis court.

A tennis court.

The surface area is absolutely massive.

So let me see if I get this.

Even if the chemistry in the stomach is, let's say, perfect for a drug, and we'll get to the chemistry in a second, the intestine will usually absorb more of it just because it has so many more doors.

Precisely.

The text calls this out specifically.

Even weak acids, which theoretically should prefer the ascetic stomach, are often absorbed better in the intestine.

The sheer size, the surface area trump card, just overrides the chemical preference.

That is a fascinating nuance.

You can do all the chemistry math you want, but at the end of the day, anatomy gets the final vote.

Anatomy and physiology usually do.

Okay, so let's talk about the actual mechanism of crossing that wall.

Fick's law tells us the speed, but how does a molecule get through?

Right.

So for passive diffusion, you have two main routes,

lipid diffusion and aqueous diffusion.

Lipid versus water, fat versus water.

The cell membrane is a lipid bilayer.

It's basically a sandwich made of fat.

So if your drug is lipid soluble, if it likes fat, it can just dissolve right into that membrane and pop out the other side.

Like a ghost walking through a wall.

It's a great way to think about it.

And that is by far the most common and most effective way drugs get in.

But if your drug is water soluble, it just bounces off that fat.

It can't get through.

Unless, there must be an unless.

Unless it's really, really tiny.

If it has a very low molecular weight, it might be able to squeeze through something called aqueous pores.

These are tiny water filled tunnels in the membrane,

but these are small.

Most drugs are way too big for this route.

So if a drug is big and water soluble, it's just stuck outside the cell.

It would be unless nature provides a helper.

And this brings us to carrier mediated transport.

The ferry boats.

I like that.

We have two kinds.

Active transport and facilitated diffusion.

Active transport is the real heavy lifter.

It requires energy ATP.

It uses a specific carrier protein to grab the drug and literally pump it across the membrane.

And because it uses energy, it can pump against the gradient, right?

Yes, that's the key.

It can pump uphill from a low concentration to a high concentration.

The text gives the example of five fluorosil, a cancer drug, basically hijacks a natural transport system to force its way into cells.

And facilitated diffusion.

How's that different?

It also uses a carrier.

So it's specific for a certain type of molecule, but it uses no energy.

It can only go downhill with the concentration gradient.

It just speeds up a process that would have happened anyway, just much slower.

It's like a revolving door instead of a pump.

Perfect.

The antibiotic sufflexin is the example here.

It hitches a ride on an oligopeptide transporter.

So we have ghosts walking through walls.

That's lipid diffusion.

We have tiny tunnels for tiny molecules, aqueous diffusion.

And we have ferry boats or carriers.

But here is where we hit, I think, the most difficult concept in the chapter.

The chemistry of ionization.

The pH partition hypothesis.

Yeah, this is a big one.

The text has a whole box on this box, 2 .1, with the Henderson -Hasselbalch equation.

I feel like this is where students' eyes usually glaze over.

It is.

It's daunting.

But we can simplify it without losing the science.

It all comes down to one single golden rule of absorption.

Okay.

What is it?

Only the non -ionized form of a drug crosses membranes easily.

Okay.

Let's unpack that.

Non -ionized means neutral, right?

No electrical charge.

Exactly.

No charge.

Think of the cell membrane like a night club with a very, very strict bouncer.

The bouncer hates electricity.

Okay.

If you walk up to that velvet rope and you have a plus sign or a minus sign floating over your head, if you ionized, the bouncer says no entry.

You just bounce off the lipid wall.

So to get into the club, to get into the blood, you have to be neutral.

No charge.

Correct.

Now, most drugs are either weak acids or weak bases, and they are shapeshifters.

They can switch back and forth between being neutral and getting into the club and being ionized and being locked out.

And what decides which ship they take?

The pH of the environment, the soup that they're swimming in.

Okay.

Let's play this out.

Let's take a weak acid.

The text uses aspirin acetylsalicylic acid as the prototype.

A weak acid, which we can write as HA,

is happy, meaning it's neutral and non -ionized when it is holding onto its proton.

Okay.

Acid holding a proton equals neutral.

Neutral gets into the club.

You got it.

Now, where do you find a lot of free protons?

In acid.

Right.

Specifically the stomach.

The stomach is a pool of hydrochloric acid, pH one.

It is absolutely teeming with protons.

So if I drop an aspirin into the stomach.

The aspirin molecule looks around and sees protons everywhere.

There's no chemical reason for it to give its proton away.

In fact, it's more likely to grab one if it doesn't have one.

So in the stomach, the vast majority of the weak acid stays protonated.

It stays neutral.

And because it's neutral, it walks right past the bouncer through the stomach wall.

Exactly.

Weak acids absorb well in the stomach.

Okay.

Now let's take that same aspirin molecule and move it into the intestines.

The pH jumps way up to around seven.

It's neutral to slightly basic.

Now the environment has very few free protons.

The aspirin looks around, sees a shortage,

and chemically, it wants to donate its proton to the solution to help out.

It lets go of its H.

But if a weak acid, HA, loses its proton.

It becomes A-, a charged anion.

It becomes ionized.

And the bouncer kicks it out.

It's charged.

Correct.

So chemically, a weak acid struggles to cross the membrane in the intestine because the pH causes it to become ionized.

This is that ion trapping concept, right?

The drug gets trapped in the compartment where the pH makes it ionized.

That's the one.

But remember our Trump card?

A tennis court.

The surface area.

Right.

Even though the chemistry is bad for aspirin in the intestine, because it's mostly ionized, the surface area is so enormous that a lot of absorption still happens there.

But the rate is much slower than it would be if the chemistry were perfect.

Okay.

So what about weak bases?

The text mentions these two.

It's just the opposite.

It's the perfect mirror image.

A weak base, which we can call B, is neutral ionized when it is unprotonated.

When it grabs a proton, it becomes positively charged, Hb+.

So in the stomach, the proton soup, a weak base like amphetamine grabs a proton.

It gets a positive charge, becomes ionized,

and the bouncer says, nope, it can't cross the wall.

Weak bases absorb terribly in the stomach.

But in the intestine where the pH is seven?

There are fewer protons around.

The base lets go of its proton.

It becomes neutral B, and it crosses the membrane easily.

It feels like a logic puzzle.

But if you just remember the bouncer rule charge implies locked out.

It makes a lot of sense.

That is the absolute key.

And this isn't just trivia.

We're going to see later in the excretion section how doctors actually use this exact math to treat drug overdoses.

We can hack the system.

Okay, fantastic.

So we have successfully navigated the stomach and the intestine.

The drug is absorbed.

It is in the blood.

Now we can move to the D in ADME distribution.

Now the drugs in the circulatory system.

So the question is, where does it go?

I would assume it just goes everywhere?

Eventually, maybe.

But initially, it goes where the blood goes fastest.

This is the distribution phase.

And the text categorizes our organs by perfusion, basically.

How many blood flow they get.

So who gets the drug first?

Who are the VIPs?

The high perfusion organs.

The text lists them.

The brain, heart, liver, and kidney.

They are absolutely drenched in blood.

They get the drug within minutes of it hitting the circulation.

And the others, the low perfusion areas.

They'll be your muscle, your skin, your fat, and your bone.

The blood just trickles into these areas more slowly.

So the drug concentration in these tissues rises much more slowly over time.

So if I inject a sedative, my brain goes to sleep almost immediately because it has high blood flow.

Exactly.

But my body fat might not even see that drug for another hour.

That's a perfect example.

And this can create a redistribution effect later on, which we'll touch on.

But once the drug is in the blood, it faces a new enemy.

Or maybe a frenemy is a better word.

Plasma proteins.

Right.

The text spends a lot of time on this.

Albumin, specifically.

Albumin is the most abundant protein in our blood.

It acts like a big sticky sponge,

or I like to think of it as a bus.

It has all these binding sites that certain drugs love to attach to.

Acidic drugs, specifically, right.

The text says basic drugs prefer a different one.

Alpha -1 acid glycoprotein.

Correct.

But the concept is exactly the same.

Imagine the albumin is a bus driving through the bloodstream.

If the drug molecule is sitting in a seat, if it's bound back, it is stuck in the vascular system.

It's too big to leave the capillary now.

Way too big.

It can't get to the brain.

It can't get to the liver to be metabolized.

And most importantly, it can't get to the receptor to do its job.

It is functionally inactive.

So only the drug that is off the bus, the free drug, can actually do anything.

Yes.

Free drug is the active drug.

Now, this creates a kind of equilibrium.

As the free drug leaves the blood to go into the tissues to fix your headache, some of the bound drug will hop off the bus to replace it.

So it acts as a reservoir.

But the text mentions a huge danger here.

Displacement.

This is a classic board exam question and a very real clinical danger.

The bus has a limited number of seats.

It is saturable.

Okay.

So suppose you're taking drug A, let's say warfarin, which is a blood thinner.

It is famously about 99 % down to albumin.

It really loves that bus.

So only 1 % of the drug is free and actually working.

And your dose is calibrated specifically for that 1 % to be effective.

Exactly.

Now you get an infection and you start taking drug B, maybe a sulfonamide antibiotic.

Drug B also loves albumin.

And maybe it binds a little more tightly.

It gets on the bus and kicks warfarin out of its seat.

So the warfarin gets shoved off the bus into the plasma.

Suddenly that warfarin is free.

You might go from 1 % free to 2 % free.

Which doesn't sound like a lot.

It's just a 1 % change.

But you just doubled the active dose of the blood thinner.

That is a 100 % increase in potency.

The patient could have a major bleed internally all because of a game of musical chairs on a protein molecule.

That is terrifying.

It really shows how interconnected all of these systems are.

It's why pharmacists are so obsessive about checking for drug interactions.

This is one of the big ones.

Now, speaking of barriers, we have to talk about the most famous one, the fortress, the blood brain barrier or BBB.

The brain is the VIP of VIPs.

It does not trust anything in the blood.

So the capillaries in the brain are different.

They're wrapped in glial cells called astrocytes and they have extremely tight junctions.

So that picket fence with the gaps we talked about in the muscles.

Gone.

Completely sealed shut.

To get into the brain, a drug must pass directly through the lipid membrane of the cells themselves.

No, it must be lipid soluble.

That's the only way in.

Highly lipid soluble.

Or it needs to be carried by a very specific transporter.

If a drug is polar or ionized or water soluble, it just pounces off.

This is why you can't treat meningitis with just any old antibiotic.

Most of them can't get into the brain to kill the bacteria.

But the brain doesn't just rely on a passive wall.

It also has an active defense system.

The text introduces these ABC transporters, specifically P -glycoprotein or PGP.

This is the bouncer I mentioned earlier, but on steroids.

P -glycoprotein is what we call an efflux pump.

Efflux means outflow.

Its only job is to find xenobiotics that manage to sneak into the cell and physically throw them back out.

It literally grabs the molecule and pumps it back into the blood.

And where do we find these pumps?

All over.

In the blood -brain barrier, protecting the brain.

In the intestines, pumping drugs back into the gut so you poop them out instead of absorbing them.

In the placenta, protecting the fetus.

It sounds like a great evolutionary adaptation.

It is.

Probably saved our ancestors from eating poisonous berries.

But there is a dark side.

Context highlights this expletively.

Some tumor cells evolve to express extremely high levels of P -glycoprotein.

We call this multi -drug resistance.

So let me see.

You send a chemotherapy agent to kill the tumor.

The drug gets in.

And the tumor's PGP pump immediately grabs it and throws it right back out before it has a chance to kill the cell.

The tumor has effectively armored itself against our medicine.

Can we stop it?

Can we block the pump?

We can try.

The text mentions that drugs like erythromycin or verapamil can inhibit PGP.

They can hold the bouncer's arm, so to speak.

But remember that PGP is also protecting your brain.

If you inhibit the pump systemically to kill the tumor,

you might accidentally let other toxic drugs or substances into your brain.

It's a classic double -edged sword.

It always is in pharmacology.

Okay, so the drug has been absorbed.

It's been distributed.

Let's say it has done its job.

Now, the body decides it's time to get rid of it, but there's a problem.

Most drugs are lipid -soluble.

That's how they got in.

But the kidney, the main exit, runs on water.

This is the fundamental problem of excretion.

The kidney filters blood to make urine.

Urine is water.

If a drug is lipid -soluble, the kidney can't hold on to it.

As soon as it's filtered into the urine, it just diffuses right back through the kidney walls into the blood.

It gets reabsorbed.

Every time.

So to pee something out, we have to fundamentally change its chemistry.

We have to make it water -soluble.

We have to make it polar.

And this brings us to the M in ADME.

Metabolism, also called biotransformation.

Or, as I like to call it, the liver's laboratory.

The text mentions that the main goal of metabolism is to inactivate and detoxify.

But based on what you just said, the real chemical goal is simply to make the molecule polar.

That's it.

Now, usually, making a polar also inactivates it.

But the text is very careful to warn us.

Do not assume that metabolism always equals inactivation.

Why not?

Because of prodrugs.

Ah, right.

The text gives dipifrin and enalaprol as the examples.

A prodrug is a drug that is designed to be completely inactive when you swallow it.

Maybe the active form absorbs poorly, or it tastes terrible, or it's unstable in stomach acid.

So we give an inactive precursor.

And wait for the liver to turn it on.

Once it hits the liver, the enzymes chop it up or modify it and turn it into the active drug.

So for a prodrug, metabolism is the on switch, not the off switch.

And there's another exception, active metabolites.

Right.

The drug diazepam, Valium, is metabolized into nordizepam, which is also a sedative.

So the effect of the drug lasts long after the original drug is gone because its children are still active.

Before we look at the specific enzymes, we have to talk about the first pass effect.

We mentioned the liver is a checkpoint.

This is a really clever quirk of our anatomy.

The veins that drain the stomach and the intestines, we call the portal system, they don't go back to the heart with the rest of the blood.

Where do they go?

They go straight to the liver.

A security checkpoint.

It is.

The body essentially says, before I let anything you just ate into the main blood supply, I'm running it through the filter first.

This is the first pass effect.

And the liver might take a pretty heavy tax on that first pass.

It might.

The text uses philodipine, a blood pressure med, as an example.

If you swallow 100 milligrams, the liver might destroy 80 milligrams of it on the very first pass.

Only 20 milligrams ever reaches the systemic circulation.

So your bioavailability is only 20 percent.

Exactly.

And this explains why we have roots like sublingual under the tongue or rectal.

The veins under the tongue drain directly into the superior vena cava.

They go right to the heart.

They bypass the liver.

They bypass the first pass effect.

That's why nitroglycerin for chest pain is given under the tongue.

You need it to skip the liver and get to the heart instantly.

Let's get into the chemistry happening in that liver laboratory.

The text divides metabolism into two phases, phase one and phase two.

A simple way to think about it is that phase one is modification and phase two is conjugation.

Let's do phase I first.

The goal of phasine is to create a handle on the drug molecule.

We're using reactions like oxidation, hydrolysis, or reduction to add or expose a small polar chemical group, usually a hydroxyl group.

And the workers doing this are the CYP enzymes.

The cytochrone P450 system.

This is a huge family of enzymes that live the endoplasmic reticulum of the liver cells.

They're the absolute workhorses of drug metabolism.

The text lists a few families of them.

CYP1, CYP2, CYP3.

Yes.

And if you're going to remember one, you need to know the heavyweight champion, CYP3A4.

The text says the CYP3A subfamily handles more than half of all microsomal oxidation reactions.

More than half.

If you are taking a drug, there is basically a coin flips chance that CYP3A4 is the enzyme metabolizing it.

This whole system is prone to sabotage the concepts of induction and inhibition.

This is huge clinically.

These enzymes are not static.

Their numbers can go up or down.

Okay.

Explain induction first.

Some drugs, the text gives phenobarbital or rifampin as examples.

They send a signal to the liver's DNA to build more CYP enzymes.

It's like hiring more workers for the factory.

So if I'm taking rifampin for, say, tuberculosis.

Your liver becomes a hyper -efficient drug shredding machine.

Now, if you were also taking other drugs, say, birth control pills, the induced enzymes will shred that brisk control so fast that its level in the blood drops and it stops working.

So you could get pregnant while taking the pill because an antibiotic wrapped up your liver?

It happens.

Now, inhibition is the opposite.

Drugs like simididine or even something as simple as grapefruit juice can block the enzymes.

They shut down the factory.

And so the other drugs just build up.

Yes.

Yeah.

They aren't being cleared from the body.

Their levels rise and rise and you can get severe toxicity.

This is the classic reason doctors say don't drink grapefruit juice with your statins.

The juice kills the CYP3A4 enzyme, the statin level skyrockets, and your muscles can start to break down.

OK.

That's phase one, creating the handle.

What's phase two?

Phase two is conjugation.

Think of this as attaching a giant water -soluble luggage tag to the handle you just made in phase one.

OK.

We take a large endogenous substance from the body like glucuronide, acetate, or sulfate.

And an enzyme welds it onto the drug.

Making it huge and very, very water -soluble.

Exactly.

Glucuronidation is the most common one.

Once you slap a big glucuronide molecule onto a drug, it is extremely polar.

It cannot cross membranes anymore.

It is destined for the urine.

Game over for the drug.

Usually, yes.

Now, this section of the text has a really fascinating diversion into pharmacogenomics.

This is the idea that my liver might be very different from your liver.

This is so critical.

For 100 years, we treated everyone as an average patient.

But genetics proves that the average patient doesn't exist.

So what's an example?

The text talks about N -acetyltransferase, or NET.

This is a phase two enzyme.

It's a welder that attaches an acetate group.

And people have different versions of this enzyme.

Yes.

It's purely genetic.

You have slow acetylators and rapid acetylators.

The text notes that about half of the white and African -American populations are slow acetylators.

Their welder just works at half speed.

What does that mean for them if they take a drug that needs that welder?

It means if they take a drug like isoniazid for tuberculosis,

which relies on acetylation for clearance,

the drug piles up in their system.

They are at a very high risk for toxicity,

specifically peripheral neuropathy, nerve damage.

Just because of their genes.

Just because of their genes.

And look at CYP2D6.

This is a phase I enzyme that handles codeine.

And codeine is a prodrug, right?

The liver has to turn it into morphine for it to work.

Correct.

And it needs CYP2D6 to do that, to unlock the pain relief.

But some people are what we call poor metabolizers.

They are born lacking a functional copy of the CYP2D6 gene.

So they take codeine.

And absolute nothing happens.

It just stays codeine.

They get zero pain relief.

And for decades, these patients were dismissed by doctors as drug seekers or fakers because they kept saying it's not working and asking for more meds.

When biologically, they were taking a placebo.

Exactly.

And on the flip side, you have ultra -rapid metabolizers who have extra copies of the gene.

They convert codeine to morphine so fast they can overdose and stop breathing on a standard dose.

It really hammers home that the standard dose is a myth.

It's a statistical approximation, not a biological truth.

So we've metabolized the drug.

It's now big and water -soluble.

It's time for the final letter, the E in ADME excretion, the exit strategy.

Primarily the kidney.

The text breaks renal excretion down into three specific mechanisms.

And box 2 .2 walks through the logic really well using penicillin G as an example.

Okay.

Step one is glomerular filtration.

This is just a passive sieve.

Blood flows at high pressure into the glomerulus.

The pressure forces fluid and small molecules out.

Anything small and free in the blood flows into the urine.

Free being the key word there.

We're back to the protein both.

We are.

If the drug is stuck to albumin, the whole complex is too big to fit through the sieve.

It stays in the blood.

Only free drug gets filtered.

Okay.

That's step one.

Step two is active tubular secretion.

This happens a little further down in the proximal tubule.

This is an active pump system like the ones we saw in the gut.

And here is the kicker.

It doesn't care about protein binding.

It doesn't.

Why not?

Because it's so efficient, it strips the drug off the protein.

The pump grabs the free drug from the blood and throws it into the urine.

That shifts the equilibrium.

So more drug immediately falls off the protein to replace it.

And the pump grabs that too.

It just vacuums the drug out of the blood.

The text mentions penicillin G here.

Penicillin G is a classic example.

It's actively secreted so fast that back in World War II, they actually had to collect the urine of treated soldiers to recrystallize the penicillin because it was so scarce.

They were just peeing it all out.

Almost all of it.

Unchanged.

And the text notes that we can block this with a drug called probenacid.

How does that work?

Probenacid competes for the same pump.

If you give probenacid, it occupies the pump so the penicillin can't get on.

It stays in the blood much longer.

It's a way to boost the duration of the antibiotic.

Clever.

Okay, step three.

Passive tubule reabsorption.

This sounds like a mistake.

The body is taking the drug back.

It's just physics again.

As the urine flows down the long tubule of the nephron, a lot of water is reabsorbed back into the body.

So the urine gets more and more concentrated.

Exactly.

And the concentration of the drug in the urine rises higher than the concentration in the blood.

This creates a gradient pointing back toward the blood.

And if the drug is lipid soluble?

It just follows the gradient.

It drips right back into the blood.

It escapes.

This is why we have to metabolize it.

To make it polar.

This is the whole point.

If the liver did its job in phase one and phase two and made the drug polar and water soluble, it cannot reabsorb.

It hits the lipid wall of the tubule and bounces back into the urine.

It gets flushed out.

And this leads to that really practical clinical trick the text describes in Box 2 .3, manipulating urine pH to treat an overdose.

This is ion trapping, but we're applying it to the kidney.

Suppose a patient comes into the ER with an aspirin overdose.

Aspirin is a weak acid.

If we want to trap that aspirin in the urine, we need to make sure it's in its ionized form.

Remember the rule.

A weak acid in a basic environment will be ionized.

It gives away its proton.

You got it.

So we give the patient a continuous IV drip of sodium bicarbonate.

This makes it blood, and therefore they're urine, alkaline, basic.

The aspirin gets filtered into this now basic urine.

It sees the environment and it gives away its proton, becomes charged.

And it is trapped.

It's ionized, so it cannot be reabsorbed.

The kidney is forced to clear it much, much faster.

We have hacked the system to speed up excretion and save the patient's life.

That is just brilliant.

There was one final exit route mentioned, and that's the bile, biliary excretion.

Right, for bigger molecules.

For large molecules, over 300 molecular weight, or for conjugated drugs.

The liver just dumps them directly into the bile, which then gets squirted into the intestine.

But then something really weird can happen.

The cycle.

Enterocytic cycling.

So imagine a drug is conjugated in the liver, it's got its luggage tag on, and it's dumped into the gut to be pooped out.

But the bacteria in our gut, our microbiome, have enzymes that can actually eat that conjugate tag off.

They reverse the metabolism.

They act like the welder, but in reverse, they cut the tag off.

They cut the luggage tag off.

The drug is now lipid soluble again.

And it gets reabsorbed.

And it gets reabsorbed.

It goes right back into the portal vein, back to the liver, back into the bile, and around it goes.

It circles.

This can significantly extend the half -life of some drugs, like oral contraceptive steroids.

It's like a recycling program you didn't ask for.

All right.

We have covered the biological journey.

We've fought the war.

ADME is done.

Now we have to face the music, the quantitative pharmacokinetics,

the math.

Don't be intimidated by it.

The math is just a way to describe and predict everything we just talked about.

It's the navigation system for the journey.

The text starts with compartment models.

One compartment versus two compartment.

Figure 2 .5 in the book explains this pretty well.

The one compartment model is the simple one.

It treats the entire body like a single bucket.

You pour the drug in.

It mixes instantly, and it leaks out at a certain rate.

But the body isn't a single bucket.

We talked about high perfusion and low perfusion organs.

Exactly.

That's why we have the more realistic two -compartment model.

In this one, you have a central compartment, which is the blood and the well -perfused organs like the heart and brain.

And then you have a peripheral compartment, which is the tissues, the fat, the muscle, the places the drug gets to more slowly.

And this creates two distinct phases on the concentration graph.

It does.

When you first inject a drug, you see a really steep drop on the graph.

That is the alpha phase.

That's distribution.

That's the drug rushing from the central compartment, the blood into the peripheral compartment, the tissues.

It's filling the peripheral bucket.

And then the curve flattens out into a slower straight line on a semi -log plot.

That is the beta phase.

That's elimination.

That's the kidney and liver finally clearing the drug from the whole system.

Okay.

Let's talk about the big variables that describe all this.

First up, bioavailability, which we use the letter F for.

We touched on this already.

It's the fraction of the administered dose that reaches the systemic circulation unchanged.

And how do we actually calculate it?

We use something called the area under the curve, or AUC.

If you look at figure 2 .6, they show it.

If you give an IV dose, by definition, the bioavailability is 100%.

All of the drug is there.

So you measure the AUC for that IV dose.

Okay, that's your gold standard.

That's your 100%.

Then you give the patient the same dose orally, and you measure the new smaller AUC.

It'll be smaller because of stomach acid, incomplete absorption, and that first pass effect in the liver.

And you just divide one by the other.

You divide the oral area by the IV area.

That fraction is your F value.

So if the oral areas have the size of the IV area, F equals 0 .5, or 50 % bioavailability.

Simple as that.

Okay, now for the term that always confuses me, volume of distribution, or VD.

It confuses everyone because the name is a complete lie.

It is an apparent volume.

It is not a real anatomical space in your body.

The formula in figure 2 .7 is the dose you gave divided by the concentration at time zero.

Right.

Let's use an analogy.

Imagine you have a big black tank of water, but you don't know how big it is.

Okay.

You pour 100 milligrams of a red dye into it, and you mix it up really well.

Then you take a one -cup sample of water out, and you measure how red it is, its concentration.

Right.

If that cup of water is bright red, a very high concentration, what does that tell you about the tank?

They must be pretty small, but dye didn't have much room to spread out, so it stayed concentrated.

Exactly.

High concentration means a small volume.

This is like a drug such as warfarin.

You inject it, it binds to protein, it stays trapped in the blood.

So when you measure the blood concentration, it's high.

The math tells you the VD is small, about four to eight liters, which is basically just the blood volume.

Okay.

Now let's flip it.

I pour the same 100 milligrams of dye in, I mix it, I take a cup out,

and the water is almost clear.

There's barely any dye in my sample, a very low concentration.

So when you plug that tiny concentration number into the formula, dose divided by concentration, the math tells you the tank must be huge -y -y, thousands of liters.

But where did all the dye go?

It's not in the water.

It must have stuck to the walls of the tank or soaked into some sponges at the bottom.

In the body, this means the drug has left the blood and is sequestered in the tissues like fat or muscle.

So chloroquine, the anti -malaria drug, has a V of something like 13 ,000 liters.

Which is impossible.

We don't have that much fluid in our bodies.

Of course not.

It just means the drug is not in the blood.

It is hiding out somewhere else.

And why does this VD matter clinically?

It's critical for something like dialysis.

Dialysis works by filtering the blood.

If a patient overdoses on a drug with a huge VD, like chloroquine, can you save them with dialysis?

No, because the drug isn't in the blood to be filtered.

It's in the tissues.

The machine can't reach it.

Exactly.

You can only effectively dialyze a drug with low Vs.

That makes perfect sense.

Okay, next up, clearance or VL.

This is the volume of blood that is completely cleared of a drug per unit of time.

It's not the amount of drug removed.

It's the volume of blood that gets cleaned.

It's like the flow rate of a filter.

And we compare this to creatinine clearance, right?

Yes.

The GFR, the filtration rate of the kidney, is about 100 mellow in.

Creatinine clearance is a good measure of that.

So if drug's clearance is also 100, it's probably just being filtered.

And if it's much higher than 100?

Then the kidney must be actively pumping it out.

That's active secretion.

And if it's much lower?

Then it's either being reabsorbed back into the blood, or it's so highly protein -bound that it can't even get filtered in the first place.

This leads us to the different patterns of elimination.

The kinetics.

First order versus zero order, shown in figure 2 .8.

Right.

The good news is that 95%, maybe more, of all drugs are first order.

Which means?

It means the rate of elimination is proportional to the concentration.

You eliminate a constant percentage of the drug per hour.

So if you have a lot of drug, you eliminate a lot.

If you have little, you eliminate a little.

So the half -life is constant.

It always takes the same amount of time to get rid of 50 % of the drug.

But then there is zero order.

This is the dangerous one.

The classic examples are ethanol, so alcohol, and high doses of aspirin or finny toine.

What happens here?

The enzymes are saturated.

The metabolic factory is running at 100 % capacity, and it simply cannot go any faster.

So you eliminate a constant amount per hour.

Not a percentage, an amount.

Let's say 10 milligrams per hour.

So it doesn't matter if I have 100 milligrams in me or 1 ,000.

I still only clear 10 milligrams an hour.

That's it.

It's a traffic jam.

And the danger is, if you increase the dose just a little bit, the drug level can pile up drastically because the exit door is jammed.

A small dose increase in pheny toine can cause a massive spike in concentration and lead to toxicity.

Okay, finally, let's talk about how we use all this math.

Dosing strategies.

Section 7 of the chapter, the steady state.

The steady state is the goal of chronic dosing.

You want to get to a point where the rate in equals the rate out.

The level in the blood is stable.

And there's a famous rule here, the rule of five.

It takes approximately four to five half -lives to reach the steady state.

Now here is the part that I think is really counterintuitive.

Does the size of my dose change how fast I get to that steady state?

No, this blows people's minds.

If I give you 100 milligrams every day or the thousand milligrams every day, it still takes five half -lives to plateau.

But the plateau will be much higher with the bigger dose.

The plateau will be 10 times higher, but the time to get there is exactly the same.

It is determined solely by the drug's half -life, nothing else.

And stopping the drug is the same thing in reverse.

Same rule.

It takes four to five half -lives for the drug to be essentially washed out of your system completely.

So if a drug has a very long half -life, say four days, it would take 20 days to reach a steady therapeutic level.

That's too slow for a sick patient.

Exactly.

And that's why we use a loading dose.

Vox 2 .4 explains this.

You calculate the VEDE, you figure out how much drug you need to fill the tank, and you give a giant bolus dose right at the start.

You force the concentration up to the target range on day one.

And then what?

Then you switch to a smaller, regular maintenance dose.

The maintenance dose is just designed to replace what the body's clearance removes each day.

It's just to keep the tank full.

We have gone from the pill in the mouth, through the acid of the stomach, past the bouncer of the cell membrane, through the shredder of the liver, the sieve of the kidney, and finally into the equations of the steady state.

It is a long, long journey for a little molecule.

If you had to summarize this whole ADME concept for our listener in one sentence, what would it be?

I would say, respect the barriers.

The body is an incredible obstacle course, and pharmacokinetics is the science of how we navigate that course to get the drug where it needs to go.

And the math, the VEED, the clearance, the half -light, these aren't just abstract concepts.

They're the tools we use to drive the car.

Precisely.

Without the math, we're just guessing.

In a medicine, guessing kills people.

I want to end on that thought we touched on earlier about pharmacogenomics.

We spent this whole hour talking about the body, what the body does to the drug.

But the reality is, there is no such thing as the body.

There is your body, and there is my body.

It's so true.

We are rapidly moving toward a world where the standard dose printed on the bottle might become completely obsolete.

Your specific CYP enzymes, your N -acetyltransferase status, your PGP pumps, that profile will dictate your personal prescription.

The average patient is a myth.

It's a myth.

And treating patients as an average is becoming less and less acceptable as we understand this science better.

A huge thank you to everyone listening to this deep dive.

We hope you feel a little more informed, a little smarter, and maybe a little more amazed at the complex war happening inside you right now.

This has been the Last Minute Lecture Team.

Keep learning.

See you next time.